Πληροφορίες
Πέμπτη 9 Απριλίου 2020
Infection control in non‐clinical areas during COVID‐19 pandemic
Infection control in non‐clinical areas during COVID‐19 pandemic:
Glucocorticoids Enhanced Osteoclast Autophagy Through the PI3K/Akt/mTOR Signaling Pathway
Glucocorticoids Enhanced Osteoclast Autophagy Through the PI3K/Akt/mTOR Signaling Pathway:
Abstract
Autophagy is an evolutionarily conserved dynamic process and present in variety of cells at basal levels to maintain homeostasis and to promote cell survival in response to stresses. The early bone loss with excessive glucocorticoids (GCs) was reported to be related with the extension of the life span of osteoclasts. However, the connection between GCs induced bone loss and osteoclast autophagy remains to be elucidated. Autophagy was detected in a Dexamethasone (Dex) induced osteoporotic mice model and primary osteoclast cultures by autophagosome detection kit, and autophagy-related proteins were assayed by Western blotting and Immunostaining. The bone morphology was examined by micro-CT and TRAP staining. The trabecular bone micro-architecture was deteriorated, and the osteoclast number and spread area were increased in the Dex-treated mice compared with the control group (P < 0.01). Meanwhile, autophagy in pre-osteoclasts was increased in mice under Dex administration evidenced by the increased number of autophagosome and up-regulation of autophagy-related protein levels. Further, the enhanced autophagy under Dex treatment was verified in primary cultured osteoclasts, as shown by the increased levels of Beclin 1 and LC3-II/LC3-I and the autophagy complex formation members including Atg1, Atg13, and Atg7. However, the expressions of PI3K, p-Akt and p-mTOR in primary cultured osteoclasts were inhibited under Dex induced autophagy. Using the selective PTEN inhibitor SF1670 to activate the PI3K/Akt/mTOR pathway reversed this osteoclast autophagy under Dex treatment. Our study suggests that osteoclast autophagy was enhanced in glucocorticoids induced bone loss, and the PI3K/Akt/mTOR signaling pathway mediated the increased autophagy in primary cultured osteoclasts under glucocorticoids treatment.Primary fungal laryngitis: Our experiences at a tertiary care teaching hospital of Eastern India
Primary fungal laryngitis: Our experiences at a tertiary care teaching hospital of Eastern India: Santosh Kumar Swain, Priyanka Debta, Nibi Shajahan
International Journal of Health & Allied Sciences 2020 9(2):153-158
INTRODUCTION: Primary fungal laryngitis is a fungal infection of the larynx without affecting the other body parts such as the lungs, pharynx, and oral cavity. It is an extremely rare clinical entity. Hoarseness of the voice is common clinical presentations.
OBJECTIVE: This study aimed to evaluate the etiology, clinical presentations, diagnosis, and treatment of primary fungal laryngitis at a tertiary care teaching hospital in Eastern India.
MATERIALS AND METHODS: This is a retrospective study of seven cases of primary fungal laryngitis managed between 2014 and 2019. The detailed etiology, clinical presentations, investigations, and treatment of primary fungal laryngitis patients were studied.
RESULTS: Primary fungal laryngitis is common among males with a mean age ranging from 15 to 63 years. There were five male and two female patients. The most common clinical symptom was hoarseness of voice (n = 7), dry irritating cough (n = 2), odynophagia (n = 1), discomfort in throat (n = 1), and dyspnea (n = 1). Laryngoscopic pictures of primary fungal laryngitis included leukoplakic lesions (n = 3), ulcerative lesions (n = 1), polypoidal lesions (n = 1), and nonspecific lesions (n = 2). Histopathological examination is confirmatory for the diagnosis. All the patients had taken antifungal treatment for 3–4 weeks after confirmation of the diagnosis.
CONCLUSION: The diagnosis of the primary fungal laryngitis is often overlooked and delayed among patients, as it is usually evident among immunocompromised patients. It often confuses with certain laryngeal diseases such as granulomatous diseases, leukoplakia, and malignancy. Delayed diagnosis and treatment will lead to high morbidity and mortality of the patients.
International Journal of Health & Allied Sciences 2020 9(2):153-158
INTRODUCTION: Primary fungal laryngitis is a fungal infection of the larynx without affecting the other body parts such as the lungs, pharynx, and oral cavity. It is an extremely rare clinical entity. Hoarseness of the voice is common clinical presentations.
OBJECTIVE: This study aimed to evaluate the etiology, clinical presentations, diagnosis, and treatment of primary fungal laryngitis at a tertiary care teaching hospital in Eastern India.
MATERIALS AND METHODS: This is a retrospective study of seven cases of primary fungal laryngitis managed between 2014 and 2019. The detailed etiology, clinical presentations, investigations, and treatment of primary fungal laryngitis patients were studied.
RESULTS: Primary fungal laryngitis is common among males with a mean age ranging from 15 to 63 years. There were five male and two female patients. The most common clinical symptom was hoarseness of voice (n = 7), dry irritating cough (n = 2), odynophagia (n = 1), discomfort in throat (n = 1), and dyspnea (n = 1). Laryngoscopic pictures of primary fungal laryngitis included leukoplakic lesions (n = 3), ulcerative lesions (n = 1), polypoidal lesions (n = 1), and nonspecific lesions (n = 2). Histopathological examination is confirmatory for the diagnosis. All the patients had taken antifungal treatment for 3–4 weeks after confirmation of the diagnosis.
CONCLUSION: The diagnosis of the primary fungal laryngitis is often overlooked and delayed among patients, as it is usually evident among immunocompromised patients. It often confuses with certain laryngeal diseases such as granulomatous diseases, leukoplakia, and malignancy. Delayed diagnosis and treatment will lead to high morbidity and mortality of the patients.
Otomycosis due to Aspergillus versicolor
Otomycosis due to Aspergillus versicolor: Santosh Kumar Swain, Priyanka Debta, Mahesh Chandra Sahu, Jatindra Nath Mohanty
International Journal of Health & Allied Sciences 2020 9(2):192-194
Otomycosis is a common clinical entity seen in both immunocompetent and immunocompromised patients. Aspergillus and Candida are the most common causative fungi in otomycosis. Aspergillus versicolor is an extremely rare causative agent for otomycosis. The clinical symptoms presented by patients are usually itching of the ear canal, otalgia, and discharge from the ear. The diagnosis of otomycosis is done on the basis of clinical presentations, microscopy and culture. The correct identification of A. versicolor is often challenging in routine clinical practice. Successful treatment of otomycosis due to A. versicolor requires prompt diagnosis and immediate treatment as delay or nontreatment may lead into rapid spread of this infection with lethal outcome. Here, we are presenting a case of an immunocompetent male presented with itching, ear discharge, pain, and ear block due to otomycosis caused by A. versicolor.
International Journal of Health & Allied Sciences 2020 9(2):192-194
Otomycosis is a common clinical entity seen in both immunocompetent and immunocompromised patients. Aspergillus and Candida are the most common causative fungi in otomycosis. Aspergillus versicolor is an extremely rare causative agent for otomycosis. The clinical symptoms presented by patients are usually itching of the ear canal, otalgia, and discharge from the ear. The diagnosis of otomycosis is done on the basis of clinical presentations, microscopy and culture. The correct identification of A. versicolor is often challenging in routine clinical practice. Successful treatment of otomycosis due to A. versicolor requires prompt diagnosis and immediate treatment as delay or nontreatment may lead into rapid spread of this infection with lethal outcome. Here, we are presenting a case of an immunocompetent male presented with itching, ear discharge, pain, and ear block due to otomycosis caused by A. versicolor.
Comparison of omentoplasty and tube drainage as treatment option in hydatid liver disease: A retrospective hospital-based observational study
Comparison of omentoplasty and tube drainage as treatment option in hydatid liver disease: A retrospective hospital-based observational study: Jehangir Allam Bhat, Shahida Akhter, Sajad Ahmad Sheikh
International Journal of Health & Allied Sciences 2020 9(2):143-146
BACKGROUND: Hydatid disease remains an important parasitic infection requiring surgical intervention. The liver is the most common site of infection, and several methods of surgery have been described to treat this common disease. Extensive research is going on to find the best operative treatment procedure for hydatid liver diseases.
AIM: The aim of the study was to compare the results of two surgical methods used in the treatment of hydatid disease of the liver, namely omentoplasty and tube drainage.
MATERIALS AND METHODS: Fifty-seven cases of hydatid liver were treated from January 2005 to January 2011, out of which thirty patients were treated with omentoplasty (Group A) and 27 were treated with tube drainage (Group B). The results of the surgery in terms of mortality, complications, hospital stay, and recurrences were analyzed by unpaired t-test or Fisher's exact test, and P value was calculated.
RESULTS: Overall postoperative complications were seen in 9.4% in Group A and 22.5% in Group B. The average hospital stay and time to resume routine work in Group A was shorter as compared to Group B. The percentage of complications such as wound infections and abscesses formation were 3.4% each in omentoplasty group and 11.2% and 7.2% in tube drainage group, respectively. The comparison of infection frequency among two groups showed strong statistical significance withP = 0.002 in wound infection and 0.0014 in abscess formation. The comparison of jaundice development after both procedures was statistically insignificant (P = 0.037). No patient in omentoplasty group developed biliary fistula, and the percentage of this complication in tube drainage was 3.7%. The recurrence of hydatid disease in omentoplasty was nil and 7.41% in tube drainage patients. There were no recurrences in either group for a follow-up of 4 years.
CONCLUSION: Omentoplasty is better and must be preferred operative procedure than tube drainage in the treatment of hydatid cyst liver disease.
International Journal of Health & Allied Sciences 2020 9(2):143-146
BACKGROUND: Hydatid disease remains an important parasitic infection requiring surgical intervention. The liver is the most common site of infection, and several methods of surgery have been described to treat this common disease. Extensive research is going on to find the best operative treatment procedure for hydatid liver diseases.
AIM: The aim of the study was to compare the results of two surgical methods used in the treatment of hydatid disease of the liver, namely omentoplasty and tube drainage.
MATERIALS AND METHODS: Fifty-seven cases of hydatid liver were treated from January 2005 to January 2011, out of which thirty patients were treated with omentoplasty (Group A) and 27 were treated with tube drainage (Group B). The results of the surgery in terms of mortality, complications, hospital stay, and recurrences were analyzed by unpaired t-test or Fisher's exact test, and P value was calculated.
RESULTS: Overall postoperative complications were seen in 9.4% in Group A and 22.5% in Group B. The average hospital stay and time to resume routine work in Group A was shorter as compared to Group B. The percentage of complications such as wound infections and abscesses formation were 3.4% each in omentoplasty group and 11.2% and 7.2% in tube drainage group, respectively. The comparison of infection frequency among two groups showed strong statistical significance withP = 0.002 in wound infection and 0.0014 in abscess formation. The comparison of jaundice development after both procedures was statistically insignificant (P = 0.037). No patient in omentoplasty group developed biliary fistula, and the percentage of this complication in tube drainage was 3.7%. The recurrence of hydatid disease in omentoplasty was nil and 7.41% in tube drainage patients. There were no recurrences in either group for a follow-up of 4 years.
CONCLUSION: Omentoplasty is better and must be preferred operative procedure than tube drainage in the treatment of hydatid cyst liver disease.
Otological and rhinological manifestations in pregnancy: Our experiences at a tertiary care teaching hospital of East India
Otological and rhinological manifestations in pregnancy: Our experiences at a tertiary care teaching hospital of East India: Santosh Kumar Swain, Tapan Pattnaik, Jatindra Nath Mohanty
International Journal of Health & Allied Sciences 2020 9(2):159-163
BACKGROUND: Hormonal variations during pregnancy can lead to otological and rhinological manifestations. Majority of the manifestations have no harm to the expectant mother or fetus but some of them can become pathological. The objective of this study is to study the audiological and rhinological manifestations occurring during pregnancy.
MATERIALS AND METHODS: This is a prospective study where 82 pregnant women participated. Otological and rhinological manifestations were assessed by asking a questionnaire and detail clinical examinations of the ear, nose, and paranasal sinuses.
RESULTS: The mean age of the pregnant women participated in this study was 24.62 years. The most common otological manifestation was blockage feeling in the ear, whereas the most common rhinological manifestation was rhinitis. Eustachian tube dysfunction was common in the last trimester of the pregnancy.
CONCLUSION: It is important to have clinical knowledge in all clinicians regarding the manifestation of otological and rhinological manifestations and its treatment with precautions considering effects on mother and fetus during pregnancy.
International Journal of Health & Allied Sciences 2020 9(2):159-163
BACKGROUND: Hormonal variations during pregnancy can lead to otological and rhinological manifestations. Majority of the manifestations have no harm to the expectant mother or fetus but some of them can become pathological. The objective of this study is to study the audiological and rhinological manifestations occurring during pregnancy.
MATERIALS AND METHODS: This is a prospective study where 82 pregnant women participated. Otological and rhinological manifestations were assessed by asking a questionnaire and detail clinical examinations of the ear, nose, and paranasal sinuses.
RESULTS: The mean age of the pregnant women participated in this study was 24.62 years. The most common otological manifestation was blockage feeling in the ear, whereas the most common rhinological manifestation was rhinitis. Eustachian tube dysfunction was common in the last trimester of the pregnancy.
CONCLUSION: It is important to have clinical knowledge in all clinicians regarding the manifestation of otological and rhinological manifestations and its treatment with precautions considering effects on mother and fetus during pregnancy.
Walk with mobile app to fight depression: An interventional study
Walk with mobile app to fight depression: An interventional study: Pradeep Tarikere Satyanarayana, Suhas Chandran
International Journal of Health & Allied Sciences 2020 9(2):122-126
BACKGROUND: Mobile health solutions can address looming problems of health. Smartphones have been integrated into global population with minimal constraints. Walking is the most convenient exercise as it can be self-regulated in intensity, duration, and frequency.
MATERIALS AND METHODS: A single group pre–post experimental study without any comparison group was carried out for a period of 12 months. A total of 150 study participants were enrolled using nonprobability sampling from households who had to walk for 40 min/day for 5 days in a week for 3 months with Google Fit health app as an exercise adherence tool, and mental health status was assessed using Patient Health Questionnaire-9. Data were entered using Microsoft Excel and were analyzed using SPSS version 22 (IBM Corp, USA). Statistically significant P value was defined asP < 0.05.
RESULTS: Of the 150 study participants, 64 (42.7%) belonged to 21–25 years, majority belonged to nuclear family, 100 (66.7%) participants had completed high school, and 86 (57.3%) of study participants were females. Around 14 participants (9.3%) before the intervention were found to have depression postintervention of exercise therapy, only 2 (1.3%) had depression. The baseline evaluation done showed higher depression scores, and postintervention had lower scores there was a statistically significant difference in scores. The study participants in all age groups, different educational status, different type of family, and gender showed statistically significant difference preexercise intervention and postexercise intervention.
CONCLUSION: Walking as an exercise although has established beneficial effects in preventing noncommunicable diseases, but its beneficial effects in fighting depression needs more evidence. Exercise can be a substantial alternative guided with health app to cope with the emerging noncommunicable diseases.
International Journal of Health & Allied Sciences 2020 9(2):122-126
BACKGROUND: Mobile health solutions can address looming problems of health. Smartphones have been integrated into global population with minimal constraints. Walking is the most convenient exercise as it can be self-regulated in intensity, duration, and frequency.
MATERIALS AND METHODS: A single group pre–post experimental study without any comparison group was carried out for a period of 12 months. A total of 150 study participants were enrolled using nonprobability sampling from households who had to walk for 40 min/day for 5 days in a week for 3 months with Google Fit health app as an exercise adherence tool, and mental health status was assessed using Patient Health Questionnaire-9. Data were entered using Microsoft Excel and were analyzed using SPSS version 22 (IBM Corp, USA). Statistically significant P value was defined asP < 0.05.
RESULTS: Of the 150 study participants, 64 (42.7%) belonged to 21–25 years, majority belonged to nuclear family, 100 (66.7%) participants had completed high school, and 86 (57.3%) of study participants were females. Around 14 participants (9.3%) before the intervention were found to have depression postintervention of exercise therapy, only 2 (1.3%) had depression. The baseline evaluation done showed higher depression scores, and postintervention had lower scores there was a statistically significant difference in scores. The study participants in all age groups, different educational status, different type of family, and gender showed statistically significant difference preexercise intervention and postexercise intervention.
CONCLUSION: Walking as an exercise although has established beneficial effects in preventing noncommunicable diseases, but its beneficial effects in fighting depression needs more evidence. Exercise can be a substantial alternative guided with health app to cope with the emerging noncommunicable diseases.
An isolated case of maxillomandibular syngnathia in a new born
An isolated case of maxillomandibular syngnathia in a new born: Khemraj Agrawal, B Sreevidya Reddy, Swapnil Jain, Swati Agrawal
International Journal of Health & Allied Sciences 2020 9(2):188-191
Congenital maxillomandibular syngnathia is a rare disorder. It is usually seen in association with various syndromes such as Van der Woude, popliteal pterygium syndrome, or in association with other defects. Isolated case reports of bony fusion of jaws are sparse. We report an isolated case of congenital fusion of the mandible and maxilla in a newborn baby and describe the clinical and radiological features of this anomaly. A brief review of literature is also presented.
International Journal of Health & Allied Sciences 2020 9(2):188-191
Congenital maxillomandibular syngnathia is a rare disorder. It is usually seen in association with various syndromes such as Van der Woude, popliteal pterygium syndrome, or in association with other defects. Isolated case reports of bony fusion of jaws are sparse. We report an isolated case of congenital fusion of the mandible and maxilla in a newborn baby and describe the clinical and radiological features of this anomaly. A brief review of literature is also presented.
Oligometastasis liver in carcinoma breast treated with stereotactic body radiotherapy
Oligometastasis liver in carcinoma breast treated with stereotactic body radiotherapy: Anshuma Bansal, Neeru Bedi, Ripanpreet Kaur, Jaspinder Kaur, Gurpreet Singh, Harjot Bagga, Vinod Dangwal
International Journal of Health & Allied Sciences 2020 9(2):195-197
This case report highlights the management of single metastasis in the liver with stereotactic body radiotherapy in a previously treated case of carcinoma breast.
International Journal of Health & Allied Sciences 2020 9(2):195-197
This case report highlights the management of single metastasis in the liver with stereotactic body radiotherapy in a previously treated case of carcinoma breast.
Menstrual hygiene and infections: Menacing women health
Menstrual hygiene and infections: Menacing women health: Priya Sharma, NL Gupta
International Journal of Health & Allied Sciences 2020 9(2):99-104
Good menstrual hygiene is fundamental to health, education, work and wellbeing of women everywhere. Menstruation is a natural part of human existence. Yet it has been neglected for decades in all sectors as well as at individual level. Menstruation remains a taboo in many societies and various negative cultural attitudes and beliefs are still associated with it. Menstruating women and girls are often associated with terms like dirt, filth, stink, impure and so which leads to forceful seclusion, reduced mobility, social, cultural and dietary restrictions. Adolescent girls are mostly kept away from facts and thus remain ignorant of the issues they suffer due to ignorance in their daily health and hygiene practices which result into adverse health outcomes. To delineate determinants of menstruation and to assess progress on perspectives with respect to change in the process of menstruation. Relevant available literature with appropriated methodology on the topic menstruation was taken up with focus on studies over the last decade. The search was strategically done to include an extensive list of concepts, beliefs, process and management to capture the various degrees of difference in perceptions and expressions, demographic and sociocultural factors as well as related subject matter adjusted accordingly to different set of data. The United Nations millennium development goal 2 and 3 directly focused on menstrual hygiene and management for universal education and on gender equality and women empowerment. However, less attention was paid on these issues in developing countries and even the work done on this is not much to explore this neglected aspect of women health. Literature on these particular aspects of women remain extremely scarce and to make things even worse sanitary section is just not touched and more so combined with stigma around it.
International Journal of Health & Allied Sciences 2020 9(2):99-104
Good menstrual hygiene is fundamental to health, education, work and wellbeing of women everywhere. Menstruation is a natural part of human existence. Yet it has been neglected for decades in all sectors as well as at individual level. Menstruation remains a taboo in many societies and various negative cultural attitudes and beliefs are still associated with it. Menstruating women and girls are often associated with terms like dirt, filth, stink, impure and so which leads to forceful seclusion, reduced mobility, social, cultural and dietary restrictions. Adolescent girls are mostly kept away from facts and thus remain ignorant of the issues they suffer due to ignorance in their daily health and hygiene practices which result into adverse health outcomes. To delineate determinants of menstruation and to assess progress on perspectives with respect to change in the process of menstruation. Relevant available literature with appropriated methodology on the topic menstruation was taken up with focus on studies over the last decade. The search was strategically done to include an extensive list of concepts, beliefs, process and management to capture the various degrees of difference in perceptions and expressions, demographic and sociocultural factors as well as related subject matter adjusted accordingly to different set of data. The United Nations millennium development goal 2 and 3 directly focused on menstrual hygiene and management for universal education and on gender equality and women empowerment. However, less attention was paid on these issues in developing countries and even the work done on this is not much to explore this neglected aspect of women health. Literature on these particular aspects of women remain extremely scarce and to make things even worse sanitary section is just not touched and more so combined with stigma around it.
Beware of the cortical ribboning: The spectrum – Experience from a case series
Beware of the cortical ribboning: The spectrum – Experience from a case series: Sadanandavalli Retnaswami Chandra, Abhishek Gohel, Sindhu Dodmalur Mallikarjuna, Kalyani Bangalore Gangadhar, Sarada Subramanian, Maya D Bhat
International Journal of Health & Allied Sciences 2020 9(2):175-180
INTRODUCTION: Creutzfeldt–Jakob disease (CJD) is an uncommon, fatal, genetic, transmissible and degenerative, brain disorder. It affects one person in every one million in the United States. A definite diagnosis can be made by histopathological confirmation which is often not possible for various reasons. Therefore, great caution is needed before the diagnosis is offered.
MATERIALS AND METHODS: Patients with radiological diagnosis of CJD in the past 2 years were assessed clinically, reassessed at 1-month, and results are discussed.
RESULTS: Four out of the 12 patients seen had nonprion cause. Hyperacute onset with coma, nonprogressive changes in imaging and electroencephalography, were seen in those who improved. The presence or absence of 14-3-3 in cerebrospinal fluid was not useful in either confirming or excluding the diagnosis in a given case.
CONCLUSION: All patients with cortical ribboning need correlation with clinical features and follow-up to confirm or exclude prion disease.
International Journal of Health & Allied Sciences 2020 9(2):175-180
INTRODUCTION: Creutzfeldt–Jakob disease (CJD) is an uncommon, fatal, genetic, transmissible and degenerative, brain disorder. It affects one person in every one million in the United States. A definite diagnosis can be made by histopathological confirmation which is often not possible for various reasons. Therefore, great caution is needed before the diagnosis is offered.
MATERIALS AND METHODS: Patients with radiological diagnosis of CJD in the past 2 years were assessed clinically, reassessed at 1-month, and results are discussed.
RESULTS: Four out of the 12 patients seen had nonprion cause. Hyperacute onset with coma, nonprogressive changes in imaging and electroencephalography, were seen in those who improved. The presence or absence of 14-3-3 in cerebrospinal fluid was not useful in either confirming or excluding the diagnosis in a given case.
CONCLUSION: All patients with cortical ribboning need correlation with clinical features and follow-up to confirm or exclude prion disease.
Diurnal rhythmicity in breast-milk glucocorticoids, and infant behavior and sleep at age 3 months
Diurnal rhythmicity in breast-milk glucocorticoids, and infant behavior and sleep at age 3 months:
Abstract
Purpose
In previous studies, associations between breast-milk cortisol levels obtained on one occasion and infant neurodevelopment were demonstrated. However, more recent evidence indicates that breast-milk cortisol and cortisone concentrations follow the diurnal rhythm of maternal hypothalamus-pituitary-adrenal axis, peaking in the early morning and with a nadir at midnight. We studied associations between breast-milk glucocorticoid (GC) rhythmicity, and infant behavior and sleep.Methods
We included 59 mothers, and their infants, of whom 17 had consulted an expert center during pregnancy for an increased risk of psychological distress. At 1 month postpartum, breast milk was sampled (on average six times) over a 24 h period for assessment of cortisol and cortisone using LC-MS/MS, and experienced maternal distress was assessed using the Hospital Anxiety and Depression Scale questionnaire. Three months after birth, infant behavior was assessed with the Infant Behavior Questionnaire, and infant sleep pattern was quantified by questionnaire. Associations between breast-milk GC rhythm parameters (maximum, delta, and Area Under the Curve increase and ground) and infant behavior and sleep were tested with linear regression analyses.Results
No consistent associations between breast-milk GC rhythm parameters and infant behavior or sleep were found.Conclusions
Breast-milk GC rhythmicity at 1 month postpartum was not associated with infant behavior or sleep at the age of 3 months. Findings from previous studies linking breast-milk cortisol to infant neurodevelopment might be biased by the lack of GC measurements across the full diurnal cycle, and should therefore be interpreted with caution.Diagnosis of Flier’s syndrome in a patient with nondiabetic hypoglycemia: a case report and critical appraisal of the literature
Diagnosis of Flier’s syndrome in a patient with nondiabetic hypoglycemia: a case report and critical appraisal of the literature:
Abstract
Purpose
Autoimmune hypoglycemia includes rare syndromes characterized by the presence of either anti-insulin antibodies (IAA) (Hirata’s disease) or anti-insulin receptor (anti-ISR) antibodies (Flier’s syndrome). Diagnosis is usually based on identification of the specific antibodies, in presence of the Whipple triad. However, most of these cases are classified as idiopathic diseases due to the difficulty to define the pathogenic culprit.Methods
Basic research methodologies, including Western Blot and ELISA tests, have been used in this study.Results
We describe a 21-year-old young woman (PT), non-obese and non-diabetic, with a positive history of autoimmune diseases, admitted to the hospital for recurrent episodes of severe symptomatic hypoglycemia. Counterregulatory response to hypoglycemia was normal as well as the fasting test, so excluding both hormone deficiencies and insulinoma. Since an autoimmune hypoglycemic syndrome was suspected, the hyperactivation of the insulin pathway was experimentally evaluated. At this purpose, human hepatocarcinoma (HepG2) cells were incubated with serum obtained from the patient (PT) and from control individuals. Interestingly, a significant increase of phosphorylation of insulin receptor, Akt, and ERK1/2 was observed in the HepG2 cells incubated with PT serum compared with the controls. ELISA tests revealed significantly increased levels of anti-ISR antibodies in PT serum, while IAA were similar both in PT and in control sera, supporting diagnosis of Flier’s syndrome.Conclusions
This study emphasizes the importance to identify new strategies for the differential diagnosis of hypoglycemia, not always possible with the routinely used diagnostic tests.JPM, Vol. 10, Pages 22: The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) Study: Rationale, Design and Methods
JPM, Vol. 10, Pages 22: The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) Study: Rationale, Design and Methods:
JPM, Vol. 10, Pages 22: The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) Study: Rationale, Design and Methods
Journal of Personalized Medicine doi: 10.3390/jpm10020022
Authors:
Anna Picca
Daniela Ronconi
Hélio J. Coelho-Junior
Riccardo Calvani
Federico Marini
Alessandra Biancolillo
Jacopo Gervasoni
Aniello Primiano
Cristina Pais
Eleonora Meloni
Domenico Fusco
Maria Rita Lo Monaco
Roberto Bernabei
Maria Camilla Cipriani
Emanuele Marzetti
Rosa Liperoti
Mild cognitive impairment (MCI), also termed mild neurocognitive disorder, includes a heterogeneous group of conditions characterized by declines in one or more cognitive domains greater than that expected during “normal” aging but not severe enough to impair functional abilities. MCI has been associated with an increased risk of developing dementia and even considered an early stage of it. Therefore, noninvasively accessible biomarkers of MCI are highly sought after for early identification of the condition. Systemic inflammation, metabolic perturbations, and declining physical performance have been described in people with MCI. However, whether biological and functional parameters differ across MCI neuropsychological subtypes is presently debated. Likewise, the predictive value of existing biomarkers toward MCI conversion into dementia is unclear. The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) study was conceived as a multi-dimensional investigation in which multi-marker discovery will be coupled with innovative statistical approaches to characterize patterns of systemic inflammation, metabolic perturbations, and physical performance in older adults with MCI. The ultimate aim of ODINO is to identify potential biomarkers specific for MCI subtypes and predictive of MCI conversion into Alzheimer’s disease or other forms of dementia over a three-year follow-up. Here, we describe the rationale, design, and methods of ODINO.
JPM, Vol. 10, Pages 22: The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) Study: Rationale, Design and Methods
Journal of Personalized Medicine doi: 10.3390/jpm10020022
Authors:
Anna Picca
Daniela Ronconi
Hélio J. Coelho-Junior
Riccardo Calvani
Federico Marini
Alessandra Biancolillo
Jacopo Gervasoni
Aniello Primiano
Cristina Pais
Eleonora Meloni
Domenico Fusco
Maria Rita Lo Monaco
Roberto Bernabei
Maria Camilla Cipriani
Emanuele Marzetti
Rosa Liperoti
Mild cognitive impairment (MCI), also termed mild neurocognitive disorder, includes a heterogeneous group of conditions characterized by declines in one or more cognitive domains greater than that expected during “normal” aging but not severe enough to impair functional abilities. MCI has been associated with an increased risk of developing dementia and even considered an early stage of it. Therefore, noninvasively accessible biomarkers of MCI are highly sought after for early identification of the condition. Systemic inflammation, metabolic perturbations, and declining physical performance have been described in people with MCI. However, whether biological and functional parameters differ across MCI neuropsychological subtypes is presently debated. Likewise, the predictive value of existing biomarkers toward MCI conversion into dementia is unclear. The “develOpment of metabolic and functional markers of Dementia IN Older people” (ODINO) study was conceived as a multi-dimensional investigation in which multi-marker discovery will be coupled with innovative statistical approaches to characterize patterns of systemic inflammation, metabolic perturbations, and physical performance in older adults with MCI. The ultimate aim of ODINO is to identify potential biomarkers specific for MCI subtypes and predictive of MCI conversion into Alzheimer’s disease or other forms of dementia over a three-year follow-up. Here, we describe the rationale, design, and methods of ODINO.
Emergence Delirium in Perioperative Pediatric Care: A Review of Current Evidence and New Directions
Emergence Delirium in Perioperative Pediatric Care: A Review of Current Evidence and New Directions:
Key points
Emergence delirium (ED) is a transient state of marked irritation and disassociation after the discontinuation of anaesthesia in some patients which does not respond to consoling measures.
ED is much more likely to occur in paediatric patients between 2 and 5 yr of age undergoing relatively painful procedures under inhalation anaesthesia.
Various causes of ED have been proposed, including rapid emergence after the use of short-acting volatile anaesthetics and the intrinsic characteristics of such agents.
Preventative measures and treatment options include the use of premedication, analgesic adjuvants, single dose of propofol at the conclusion of the case, and comforting by a known party in the recovery room.
Children who have ED are more likely to have new-onset postoperative maladaptive behavioural changes.
Definition and measurement scales
A child with emergence delirium (ED) is in a ‘dissociated state of consciousness in which the child is irritable, uncompromising, uncooperative, incoherent, and inconsolably crying, moaning, kicking, or thrashing’.1 ED can disrupt the surgical repair, be distressing for parents and staff and may cause parental dissatisfaction with their child's care.
Many scales have been proposed to evaluate the incidence and severity of ED, and a variety of scales are used in clinical practice and for research purposes. Agitation due to pain is a significant confounding factor for the evaluation of the presence or measurement of the degree of ED.2 The Cravero scale (Table 1) has five steps from obtunded and unresponsive to wild thrashing behaviour requiring restraint.3 A score of ≥4 (from crying and difficult to console to wild thrashing) for a 5 or more min duration despite active calming efforts is regarded as indicative of ED. The Paediatric Anaesthesia Emergence Delirium (PAED) scale (Table 2) is validated but is difficult to use in routine clinical practice.2 The Watcha scale (Table 3) is a simpler tool to use in clinical practice and may have a higher overall sensitivity and specificity than the PAED and Cravero scales.4 It is more practical to use a simple scale to detect delirium and then use the PAED scale to measure its degree.5
Table 1
Cravero scale
Behaviour Score
Obtunded with no response to stimulation 1
Asleep but responsive to movement or stimulation 2
Awake and responsive 3
Crying (for >3 min) 4
Thrashing behaviour that requires restraint 5
Open in new tab
Table 2
PAED scale (from Bajwa and colleagues,4 with permission. ©2010 Blackwell Publishing Ltd). Score is sum of all values
Behaviour Not at all Just a little Quite a bit Very much Extremely
Makes eye contact with caregiver 4 3 2 1 0
Actions are purposeful 4 3 2 1 0
Aware of surroundings 4 3 2 1 0
Restless 0 1 2 3 4
Inconsolable 0 1 2 3 4
Open in new tab
Table 3
Watcha scale. Score is observed values
Behaviour Score
Asleep 0
Calm 1
Crying, but can be consoled 2
Crying, but cannot be consoled 3
Agitated and thrashing around 4
Open in new tab
Incidence and risk factors
There have been a wide range of reported figures for the incidence of ED in paediatric populations, ranging from 2% to 80%.1,6 Differences in study design and methodology account for some measure of the variation, in particular the use of disparate rating systems for ED and the wide range of surgical and anaesthetic contexts under study. Thus, there is no consensus on the incidence even within particular subgroups of paediatric patients, for example, those undergoing identical surgeries or presenting with similar psychological profiles.
But the totality of the literature does identify significant risk factors for ED pertaining to anaesthetic, surgical, and patient characteristics (Table 4). The introduction of short-acting volatile anaesthetics has been historically associated with the increased incidence of ED. In non-surgical settings, with patients undergoing magnetic resonance imaging (MRI), sevoflurane has been shown to increase the risk of ED when compared with halothane.3 More generally, anaesthetic techniques that result in rapid emergence from anaesthesia increase the risk. Indeed, a recent meta-analysis showed that propofol, ketamine, α2-adrenoreceptor agonists, fentanyl, and preoperative analgesia were effective in reducing the risk of ED presumably by delaying emergence and reducing postoperative pain.6
Table 4
Possible risk factors for ED1
Factor
Rapid emergence from anaesthesia
Use of short-acting volatile anaesthetic agents
Postoperative pain
Surgery type
Age
Preoperative anxiety
Child temperament
Open in new tab
While pain is not the sole cause for ED, surgery associated with elevated postoperative pain has been thought to increase the risk of ED. The site of surgery has been proposed as a risk factor, as well. Otorhinolaryngological and ophthalmological procedures have been shown to increase the risk of ED in comparison with urological and general surgery procedures, pointing to the possibility that surgeries affecting the head and neck may be relatively more likely to induce ED.7
Younger patients, particularly in the age range from 2 to 5 yr of age, are at increased risk of ED.8 Preoperative anxiety, as measured by the modified Yale Preoperative Anxiety Scale, has been shown to increase the risk of ED for each increment of 10 points in the child's state anxiety score.9 Temperament, as reflected in children who are more emotional, more impulsive, less social, and less adaptable to environmental changes, has been identified as a risk factor for ED.1
Aetiology
Sudden emergence from anaesthesia into a disordered state of consciousness or into an unfamiliar environment has been proposed as a cause of ED. However, the incidence of ED in patients receiving propofol is markedly lower than those receiving sevoflurane, despite the similar rapid emergence profile of both agents.10
Elevated postoperative pain has been suggested to underlie ED. But given that ED is seen in patients undergoing MRI, pain cannot be the sole cause. Studies in patients undergoing MRI are particularly useful since this removes pain as a confounding variable allowing for more controlled investigation of ED. A study performed in 2000 looked at 32 children that were undergoing sedation for MRI scanning. The patients were randomized to receive either sevoflurane or halothane for the maintenance of anaesthesia. An increase in the incidence of ED was found with sevoflurane compared with halothane, and there was no increase in time to discharge when comparing the two groups. A second study in 2003 again included patients undergoing MRI scanning with sevoflurane used for maintenance. Thirty-two children were randomized to receive either placebo (saline) or fentanyl 1 µg kg−1 10 min before the end of the scan. The incidence of ED significantly decreased in the fentanyl group, and there was no difference in time to discharge between the two groups.11 It is worth noting that while postoperative pain is not the sole cause of ED, the degree of pain produced by a surgical procedure can change the characteristics of the observed ED and may affect the efficacy of non-analgesic adjuvants such as propofol used to treat or prevent ED.5
Along with an historical increase in the incidence of ED correlating with the introduction of modern short-acting inhalation anaesthetics, studies with patients undergoing MRI support the theory that there are intrinsic properties of inhalation anaesthetic that are primarily responsible for ED. Since all inhalation anaesthetics, even halothane, increase the risk of ED, while shorter-acting agents increase the incidence further, there may be an underlying mechanism of action of inhalation anaesthetics triggering ED which has yet to be fully elucidated. Volatile anaesthetics may affect brain activity by interfering with the balance between neuronal synaptic inhibition and excitation in the central nervous system.1
Preventative strategies and treatment options
Prophylactic measures include the co-administration of propofol, midazolam, or fentanyl, but the risks associated with their use must be weighed against the self-limiting nature of ED1 (Table 5). The efficacy of propofol is dependent on the timing of administration. Due to the rapid pharmacokinetics of propofol, a bolus of 1 mg kg−1 given at the end of the procedure or continuous infusion used during maintenance of anaesthesia results in increased concentrations during emergence resulting in a decreased incidence of ED.6
Table 5
Preventative measures10
Medication
Propofol
Ketamine
α2-Adreno-receptor agonist
Fentanyl
Perioperative analgesia
Open in new tab
Perioperative analgesia has been shown to be effective in preventing ED. Several analgesics have been studied for the prevention of ED including: fentanyl (dose 1 µg kg−1 i.v. given 10 min before the end of a procedure), ketamine (0.25 mg kg−1 i.v. given at the end of procedure, or as a premedication 6 mg kg−1 orally), and α2-adrenoreceptor agonists such as clonidine (caudally 1–3 µg kg−1; i.v. 2–3 µg kg−1) and dexmedetomidine (0.15–0.3 µg kg−1).1 These preventative strategies increase sedation and therefore should be balanced against the risk of prolonging emergence or delaying discharge from the post-anaesthesia care unit.
However, prevention is important as the experience of ED may increase the incidence of new-onset postoperative maladaptive behaviour changes such as general anxiety, night-time crying, enuresis, separation anxiety, and temper tantrums for up to 14 days after surgery.9
While sevoflurane is a very effective induction agent, the use of isoflurane or propofol for the maintenance of anaesthesia may reduce the risk of ED. Studies have shown positive effects for propofol, pain prevention, ketamine, and α2-adrenoreceptor agonists with no evidence of effectiveness for midazolam or 5-HT3 antagonists.6
Once ED is established, the most common interventions are pharmacological (Table 6), whereas it may be the case that simply being reunited with a parent provides the quickest recovery.1
Table 6
Treatment options6
Medication
Fentanyl
Propofol
Midazolam
Reuniting with parent
Open in new tab
Conclusions
ED is a recognized complication most often associated with sevoflurane or desflurane anaesthesia in young children. It is distressing for children, parents, and staff but is self-limiting. Pain is a significant confounding factor. Propofol and other adjuvants may reduce the risk but may prolong recovery. Further research is required to define the best way to minimize this distressing adverse effect of anaesthesia.
References
1 Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many questions, few answers, Anesth Analg, 2007, vol. 104 (pg. 84-91)
Google ScholarCrossrefPubMed
2 Sikich N, Lerman J. Development and psychometric evaluation of the paediatric anesthesia emergence delirium scale, Anesthesiology, 2004, vol. 100 (pg. 1138-45)
Google ScholarCrossrefPubMed
3 Cravero J, Surgenor S, Whalen K. Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: a comparison with halothane, Anaesth, 2000, vol. 10 (pg. 419-24)
4 Bajwa SA, Costi D, Cyna AM. A comparison of emergence delirium scales following general anesthesia in children, Paediatr Anaesth, 2010, vol. 20 (pg. 704-11)
Google ScholarCrossrefPubMed
5 Pieters BJ, Penn E, Nicklaus P, et al. Emergence delirium and postoperative pain in children undergoing adenotonsillectomy: a comparison of propofol vs sevoflurane anesthesia, Paediatr Anaesth, 2010, vol. 20 (pg. 944-50)
Google ScholarCrossrefPubMed
6 Dahmani S, Stany I, Brasher C, et al. Pharmacological prevention of sevoflurane- and desflurane-related emergence agitation in children: a meta-analysis of published studies, Br J Anaesth, 2010, vol. 104 (pg. 216-23)
Google ScholarCrossrefPubMed
7 Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit, Anesth Analg, 2003, vol. 96 (pg. 1625-30)
Google ScholarCrossrefPubMed
8 Aono J, Ueda W, Mamiya K, et al. Greater incidence of delirium during recovery from sevoflurane in preschool boys, Anesthesiology, 1997, vol. 87 (pg. 1298-300)
Google ScholarCrossrefPubMed
9 Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors, Anesth Analg, 2004, vol. 99 (pg. 1648-54)
Google ScholarCrossrefPubMed
10 Cohen IT, Finkel JC, Hannallah RS, et al. The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children, Anesth Analg, 2002, vol. 94 (pg. 1178-81)
Google ScholarCrossrefPubMed
11 Cravero J, Beach M, Thyr B, et al. The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery, Anesth Analg, 2003, vol. 97 (pg. 364-7)
Google ScholarCrossrefPubMed
© The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Abstract
Emergence delirium (ED) is defined as psychomotor agitation and delirium that typically occurs within 45 min from emergence of anesthesia. Preoperative patient conditions such as anxiety and confusion are risk factors for the development of postoperative ED. Common signs of ED are general non-purposeful resistive movements such as kicking, pulling, flailing as well as lack of eye contact and general lack of awareness of surroundings. The use of volatile anesthetics (VA) is contributory, while the use of total intravenous anesthetic techniques (TIVA) may help to reduce the incidence of emergence delirium. Furthermore, various pharmacologic strategies and alternatively non-pharmacologic strategies have been demonstrated to further diminish its occurrence. The objective of this manuscript is to provide a comprehensive review of anesthetic considerations for pediatric ED and to provide an update on techniques that have been found to be effective in reducing the overall risk of developing postoperative ED in pediatric patients.Key points
Emergence delirium (ED) is a transient state of marked irritation and disassociation after the discontinuation of anaesthesia in some patients which does not respond to consoling measures.
ED is much more likely to occur in paediatric patients between 2 and 5 yr of age undergoing relatively painful procedures under inhalation anaesthesia.
Various causes of ED have been proposed, including rapid emergence after the use of short-acting volatile anaesthetics and the intrinsic characteristics of such agents.
Preventative measures and treatment options include the use of premedication, analgesic adjuvants, single dose of propofol at the conclusion of the case, and comforting by a known party in the recovery room.
Children who have ED are more likely to have new-onset postoperative maladaptive behavioural changes.
Definition and measurement scales
A child with emergence delirium (ED) is in a ‘dissociated state of consciousness in which the child is irritable, uncompromising, uncooperative, incoherent, and inconsolably crying, moaning, kicking, or thrashing’.1 ED can disrupt the surgical repair, be distressing for parents and staff and may cause parental dissatisfaction with their child's care.
Many scales have been proposed to evaluate the incidence and severity of ED, and a variety of scales are used in clinical practice and for research purposes. Agitation due to pain is a significant confounding factor for the evaluation of the presence or measurement of the degree of ED.2 The Cravero scale (Table 1) has five steps from obtunded and unresponsive to wild thrashing behaviour requiring restraint.3 A score of ≥4 (from crying and difficult to console to wild thrashing) for a 5 or more min duration despite active calming efforts is regarded as indicative of ED. The Paediatric Anaesthesia Emergence Delirium (PAED) scale (Table 2) is validated but is difficult to use in routine clinical practice.2 The Watcha scale (Table 3) is a simpler tool to use in clinical practice and may have a higher overall sensitivity and specificity than the PAED and Cravero scales.4 It is more practical to use a simple scale to detect delirium and then use the PAED scale to measure its degree.5
Table 1
Cravero scale
Behaviour Score
Obtunded with no response to stimulation 1
Asleep but responsive to movement or stimulation 2
Awake and responsive 3
Crying (for >3 min) 4
Thrashing behaviour that requires restraint 5
Open in new tab
Table 2
PAED scale (from Bajwa and colleagues,4 with permission. ©2010 Blackwell Publishing Ltd). Score is sum of all values
Behaviour Not at all Just a little Quite a bit Very much Extremely
Makes eye contact with caregiver 4 3 2 1 0
Actions are purposeful 4 3 2 1 0
Aware of surroundings 4 3 2 1 0
Restless 0 1 2 3 4
Inconsolable 0 1 2 3 4
Open in new tab
Table 3
Watcha scale. Score is observed values
Behaviour Score
Asleep 0
Calm 1
Crying, but can be consoled 2
Crying, but cannot be consoled 3
Agitated and thrashing around 4
Open in new tab
Incidence and risk factors
There have been a wide range of reported figures for the incidence of ED in paediatric populations, ranging from 2% to 80%.1,6 Differences in study design and methodology account for some measure of the variation, in particular the use of disparate rating systems for ED and the wide range of surgical and anaesthetic contexts under study. Thus, there is no consensus on the incidence even within particular subgroups of paediatric patients, for example, those undergoing identical surgeries or presenting with similar psychological profiles.
But the totality of the literature does identify significant risk factors for ED pertaining to anaesthetic, surgical, and patient characteristics (Table 4). The introduction of short-acting volatile anaesthetics has been historically associated with the increased incidence of ED. In non-surgical settings, with patients undergoing magnetic resonance imaging (MRI), sevoflurane has been shown to increase the risk of ED when compared with halothane.3 More generally, anaesthetic techniques that result in rapid emergence from anaesthesia increase the risk. Indeed, a recent meta-analysis showed that propofol, ketamine, α2-adrenoreceptor agonists, fentanyl, and preoperative analgesia were effective in reducing the risk of ED presumably by delaying emergence and reducing postoperative pain.6
Table 4
Possible risk factors for ED1
Factor
Rapid emergence from anaesthesia
Use of short-acting volatile anaesthetic agents
Postoperative pain
Surgery type
Age
Preoperative anxiety
Child temperament
Open in new tab
While pain is not the sole cause for ED, surgery associated with elevated postoperative pain has been thought to increase the risk of ED. The site of surgery has been proposed as a risk factor, as well. Otorhinolaryngological and ophthalmological procedures have been shown to increase the risk of ED in comparison with urological and general surgery procedures, pointing to the possibility that surgeries affecting the head and neck may be relatively more likely to induce ED.7
Younger patients, particularly in the age range from 2 to 5 yr of age, are at increased risk of ED.8 Preoperative anxiety, as measured by the modified Yale Preoperative Anxiety Scale, has been shown to increase the risk of ED for each increment of 10 points in the child's state anxiety score.9 Temperament, as reflected in children who are more emotional, more impulsive, less social, and less adaptable to environmental changes, has been identified as a risk factor for ED.1
Aetiology
Sudden emergence from anaesthesia into a disordered state of consciousness or into an unfamiliar environment has been proposed as a cause of ED. However, the incidence of ED in patients receiving propofol is markedly lower than those receiving sevoflurane, despite the similar rapid emergence profile of both agents.10
Elevated postoperative pain has been suggested to underlie ED. But given that ED is seen in patients undergoing MRI, pain cannot be the sole cause. Studies in patients undergoing MRI are particularly useful since this removes pain as a confounding variable allowing for more controlled investigation of ED. A study performed in 2000 looked at 32 children that were undergoing sedation for MRI scanning. The patients were randomized to receive either sevoflurane or halothane for the maintenance of anaesthesia. An increase in the incidence of ED was found with sevoflurane compared with halothane, and there was no increase in time to discharge when comparing the two groups. A second study in 2003 again included patients undergoing MRI scanning with sevoflurane used for maintenance. Thirty-two children were randomized to receive either placebo (saline) or fentanyl 1 µg kg−1 10 min before the end of the scan. The incidence of ED significantly decreased in the fentanyl group, and there was no difference in time to discharge between the two groups.11 It is worth noting that while postoperative pain is not the sole cause of ED, the degree of pain produced by a surgical procedure can change the characteristics of the observed ED and may affect the efficacy of non-analgesic adjuvants such as propofol used to treat or prevent ED.5
Along with an historical increase in the incidence of ED correlating with the introduction of modern short-acting inhalation anaesthetics, studies with patients undergoing MRI support the theory that there are intrinsic properties of inhalation anaesthetic that are primarily responsible for ED. Since all inhalation anaesthetics, even halothane, increase the risk of ED, while shorter-acting agents increase the incidence further, there may be an underlying mechanism of action of inhalation anaesthetics triggering ED which has yet to be fully elucidated. Volatile anaesthetics may affect brain activity by interfering with the balance between neuronal synaptic inhibition and excitation in the central nervous system.1
Preventative strategies and treatment options
Prophylactic measures include the co-administration of propofol, midazolam, or fentanyl, but the risks associated with their use must be weighed against the self-limiting nature of ED1 (Table 5). The efficacy of propofol is dependent on the timing of administration. Due to the rapid pharmacokinetics of propofol, a bolus of 1 mg kg−1 given at the end of the procedure or continuous infusion used during maintenance of anaesthesia results in increased concentrations during emergence resulting in a decreased incidence of ED.6
Table 5
Preventative measures10
Medication
Propofol
Ketamine
α2-Adreno-receptor agonist
Fentanyl
Perioperative analgesia
Open in new tab
Perioperative analgesia has been shown to be effective in preventing ED. Several analgesics have been studied for the prevention of ED including: fentanyl (dose 1 µg kg−1 i.v. given 10 min before the end of a procedure), ketamine (0.25 mg kg−1 i.v. given at the end of procedure, or as a premedication 6 mg kg−1 orally), and α2-adrenoreceptor agonists such as clonidine (caudally 1–3 µg kg−1; i.v. 2–3 µg kg−1) and dexmedetomidine (0.15–0.3 µg kg−1).1 These preventative strategies increase sedation and therefore should be balanced against the risk of prolonging emergence or delaying discharge from the post-anaesthesia care unit.
However, prevention is important as the experience of ED may increase the incidence of new-onset postoperative maladaptive behaviour changes such as general anxiety, night-time crying, enuresis, separation anxiety, and temper tantrums for up to 14 days after surgery.9
While sevoflurane is a very effective induction agent, the use of isoflurane or propofol for the maintenance of anaesthesia may reduce the risk of ED. Studies have shown positive effects for propofol, pain prevention, ketamine, and α2-adrenoreceptor agonists with no evidence of effectiveness for midazolam or 5-HT3 antagonists.6
Once ED is established, the most common interventions are pharmacological (Table 6), whereas it may be the case that simply being reunited with a parent provides the quickest recovery.1
Table 6
Treatment options6
Medication
Fentanyl
Propofol
Midazolam
Reuniting with parent
Open in new tab
Conclusions
ED is a recognized complication most often associated with sevoflurane or desflurane anaesthesia in young children. It is distressing for children, parents, and staff but is self-limiting. Pain is a significant confounding factor. Propofol and other adjuvants may reduce the risk but may prolong recovery. Further research is required to define the best way to minimize this distressing adverse effect of anaesthesia.
References
1 Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many questions, few answers, Anesth Analg, 2007, vol. 104 (pg. 84-91)
Google ScholarCrossrefPubMed
2 Sikich N, Lerman J. Development and psychometric evaluation of the paediatric anesthesia emergence delirium scale, Anesthesiology, 2004, vol. 100 (pg. 1138-45)
Google ScholarCrossrefPubMed
3 Cravero J, Surgenor S, Whalen K. Emergence agitation in paediatric patients after sevoflurane anaesthesia and no surgery: a comparison with halothane, Anaesth, 2000, vol. 10 (pg. 419-24)
4 Bajwa SA, Costi D, Cyna AM. A comparison of emergence delirium scales following general anesthesia in children, Paediatr Anaesth, 2010, vol. 20 (pg. 704-11)
Google ScholarCrossrefPubMed
5 Pieters BJ, Penn E, Nicklaus P, et al. Emergence delirium and postoperative pain in children undergoing adenotonsillectomy: a comparison of propofol vs sevoflurane anesthesia, Paediatr Anaesth, 2010, vol. 20 (pg. 944-50)
Google ScholarCrossrefPubMed
6 Dahmani S, Stany I, Brasher C, et al. Pharmacological prevention of sevoflurane- and desflurane-related emergence agitation in children: a meta-analysis of published studies, Br J Anaesth, 2010, vol. 104 (pg. 216-23)
Google ScholarCrossrefPubMed
7 Voepel-Lewis T, Malviya S, Tait AR. A prospective cohort study of emergence agitation in the pediatric postanesthesia care unit, Anesth Analg, 2003, vol. 96 (pg. 1625-30)
Google ScholarCrossrefPubMed
8 Aono J, Ueda W, Mamiya K, et al. Greater incidence of delirium during recovery from sevoflurane in preschool boys, Anesthesiology, 1997, vol. 87 (pg. 1298-300)
Google ScholarCrossrefPubMed
9 Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors, Anesth Analg, 2004, vol. 99 (pg. 1648-54)
Google ScholarCrossrefPubMed
10 Cohen IT, Finkel JC, Hannallah RS, et al. The effect of fentanyl on the emergence characteristics after desflurane or sevoflurane anesthesia in children, Anesth Analg, 2002, vol. 94 (pg. 1178-81)
Google ScholarCrossrefPubMed
11 Cravero J, Beach M, Thyr B, et al. The effect of small dose fentanyl on the emergence characteristics of pediatric patients after sevoflurane anesthesia without surgery, Anesth Analg, 2003, vol. 97 (pg. 364-7)
Google ScholarCrossrefPubMed
© The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com
Emergence Delirium in Perioperative Pediatric Care: A Review of Current Evidence and New Directions
Emergence Delirium in Perioperative Pediatric Care: A Review of Current Evidence and New Directions:
Abstract
Emergence delirium (ED) is defined as psychomotor agitation and delirium that typically occurs within 45 min from emergence of anesthesia. Preoperative patient conditions such as anxiety and confusion are risk factors for the development of postoperative ED. Common signs of ED are general non-purposeful resistive movements such as kicking, pulling, flailing as well as lack of eye contact and general lack of awareness of surroundings. The use of volatile anesthetics (VA) is contributory, while the use of total intravenous anesthetic techniques (TIVA) may help to reduce the incidence of emergence delirium. Furthermore, various pharmacologic strategies and alternatively non-pharmacologic strategies have been demonstrated to further diminish its occurrence. The objective of this manuscript is to provide a comprehensive review of anesthetic considerations for pediatric ED and to provide an update on techniques that have been found to be effective in reducing the overall risk of developing postoperative ED in pediatric patients.Distinct Serum and Vitreous Inflammation-Related Factor Profiles in Patients with Proliferative Vitreoretinopathy
Distinct Serum and Vitreous Inflammation-Related Factor Profiles in Patients with Proliferative Vitreoretinopathy:
Abstract
Introduction
Proliferative vitreoretinopathy (PVR), which is regulated by growth factors and cytokines, is the leading cause of failure in vitreoretinal surgery. In this study, we aimed to investigate the role of the human serum and vitreous inflammation-related factors in the development of proliferative vitreoretinopathy (PVR).Methods
Blood and vitreous samples were obtained from patients undergoing pars plana vitrectomy. Inflammation-related factors were detected using an immunology multiplex assay on a Luminex® xMAP® platform. Patients with PVR and rhegmatogenous retinal detachment (RRD) were compared with macular hole (MH) or epiretinal membrane (ERM) patients without any other ocular or systemic disease.Results
Thirty-six serum samples and 34 vitreous samples were obtained. Thirty-one different growth factors and cytokines were detected in serum samples. However, none of the circulating growth factors and cytokines were found to be different from the controls. Ten different growth factors and cytokines were measured in the vitreous samples. The concentration levels of PDGF-AA, TGF-α, VEGF, IL-6, IL-8, and TNFβ were found to have significantly increased in the vitreous of PVR patients.Conclusion
Our study found that none of the circulating inflammation-related factors were changed in PVR or RRD patients, indicating the absence of a system inflammatory biomarkers to predict the development of proliferative vitreoretinopathy. As a supplement to previous research, the concentrations of PDGF-AA, TGF-α, VEGF, IL-6, IL-8, and TNFβ were significantly upregulated in the vitreous of PVR patients. These factors should be considered for preventing PVR.Validation of the Farsi version of the revised Adolescent Sleep Hygiene Scale (ASHSr): a cross-sectional study
Validation of the Farsi version of the revised Adolescent Sleep Hygiene Scale (ASHSr): a cross-sectional study: Restoring sleep is associated with a broad variety of favorable cognitive, emotional, social and behavioral benefits during the day. This holds particularly true for adolescents, as maturational, social, cognitive, emotional and behavioral changes might unfavorably impact on adolescents' sleep. Among adolescents, poor sleep hygiene practices are a potentially modifiable risk factor that can be addressed via appropriate interventions. Accordingly, having reliable and valid self-report measures to assess sleep hygiene practices is essential to gauge individual responses to behavioral interventions and evaluate sleep hygiene recommendations. The aim of the present study therefore was to translate and to test the psychometric properties (internal consistency, test-retest reliability, factorial and concurrent validity) of the Farsi/Persian version of the revised version of the Adolescent Sleep Hygiene Scale (ASHSr).; A total of 1013 adolescents (mean age: M = 15.4 years; SD = 1.2; range: 12-19 years; 42.9% females) completed the ASHSr and the Pittsburgh Sleep Quality Index (PSQI) in their classroom during an official school lesson. Further, 20% completed the ASHSr 6 weeks later to evaluate the test-retest reliability. Cronbach's alpha coefficients were calculated to examine internal consistency, confirmatory factor analysis (CFA) was used to test factorial validity, whereas concurrent validity and test-retest reliability were examined via correlation analyses.; A first-order confirmatory factor analysis (CFA) corroborated the six-factor structure of the ASHSr, including a physiological, behavioral arousal, cognitive/emotional, daytime sleep, sleep environment, and sleep stability factor. A second-order CFA showed that a higher-order sleep hygiene construct explained sufficient variance in each factor. Cronbach's alpha values ranged between .71 and .75, correlations for test-retest reliability between .82 and .87. Significant correlations were found between most ASHSr scales and the PSQI indices. However, the magnitude of these correlations was weak.; The Farsi/Persian version of the Adolescent Sleep Hygiene Scale can be used as a reliable and valid tool for evaluation of sleep hygiene practices among Farsi/Persian-speaking adolescents.
Inflammatory Biomarkers and Clinical Judgment in the Emergency Diagnosis of Urgent Abdominal Pain
Inflammatory Biomarkers and Clinical Judgment in the Emergency Diagnosis of Urgent Abdominal Pain: The early diagnosis of urgent abdominal pain (UAP) is challenging. Most causes of UAP are associated with extensive inflammation. Therefore, we hypothesized that quantifying inflammation using interleukin-6 and/or procalcitonin would provide incremental value in the emergency diagnosis of UAP.; This was an investigator-initiated prospective, multicenter diagnostic study enrolling patients presenting to the emergency department (ED) with acute abdominal pain. Clinical judgment of the treating physician regarding the presence of UAP was quantified using a visual analog scale after initial clinical and physician-directed laboratory assessment, and again after imaging. Two independent specialists adjudicated the final diagnosis and the classification as UAP (life-threatening, needing urgent surgery and/or hospitalization for acute medical reasons) using all information including histology and follow-up. Interleukin-6 and procalcitonin were measured blinded in a central laboratory.; UAP was adjudicated in 376 of 1038 (36%) patients. Diagnostic accuracy for UAP was higher for interleukin-6 [area under the ROC curve (AUC), 0.80; 95% CI, 0.77-0.82] vs procalcitonin (AUC, 0.65; 95% CI, 0.62-0.68) and clinical judgment (AUC, 0.69; 95% CI, 0.65-0.72; both; P; < 0.001). Combined assessment of interleukin-6 and clinical judgment increased the AUC at presentation to 0.83 (95% CI, 0.80-0.85) and after imaging to 0.87 (95% CI, 0.84-0.89) and improved the correct identification of patients with and without UAP (net improvement in mean predicted probability: presentation, +19%; after imaging, +15%;; P; < 0.001). Decision curve analysis documented incremental value across the full range of pretest probabilities. A clinical judgment/interleukin-6 algorithm ruled out UAP with a sensitivity of 97% and ruled in UAP with a specificity of 93%.; Interleukin-6 significantly improves the early diagnosis of UAP in the ED.
Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery
Comparison of high-sensitivity cardiac troponin I and T for the prediction of cardiac complications after non-cardiac surgery: We aimed to directly compare preoperative high-sensitivity cardiac troponin (hs-cTn) I and T concentration for the prediction of major cardiac complications after non-cardiac surgery.; We measured hs-cTnI and hs-cTnT preoperatively in a blinded fashion in 1022 patients undergoing non-cardiac surgery. The primary endpoint was a composite of major cardiac complications including cardiac death, cardiac arrest, myocardial infarction, clinically relevant arrhythmias, and acute heart failure within 30 days. We hypothesized that the type of surgery may impact on the predictive accuracy of hs-cTnI/T and stratified all analyses according to the type of surgery.; Major cardiac complications occurred in 108 (11%) patients, 58/243 (24%) patients undergoing vascular surgery and 50/779 (6%, P < .001) patients undergoing non-vascular surgery. Using regulatory-approved 99th percentile cut-off concentrations, preoperative hs-cTnI elevations were less than one-fifth as common as preoperative hs-cTnT elevations (P < .001). Among patients undergoing vascular surgery, preoperative hs-cTnI concentrations, but not hs-cTnT, was an independent predictor of cardiac complications (adjusted odds ratio (aOR) 1.5, 95% confidence interval (95% CI) 1.0-2.1). The area under the receiver-operating characteristics curve (AUC) was 0.67 (95% CI, 0.59-0.75) for hs-cTnI versus 0.59 (95% CI 0.51-0.67, P = .012) for hs-cTnT. In contrast, among patients undergoing non-vascular surgery both preoperative hs-cTnI and hs-cTnT were independent predictors of the primary endpoint (aOR 1.6, 95% CI 1.3-2.0, and aOR 3.0, 95% CI 2.0-4.6, respectively) and showed higher predictive accuracy (AUC 0.77, 95% CI, 0.71-0.83, and 0.79, 95% CI 0.73-0.85, P = ns).; Preoperative hs-cTnI and hs-cTnT concentrations predict major cardiac complications after non-vascular surgery, while, in patients undergoing vascular surgery, hs-cTnI may have better accuracy.
Evaluation of Two 3D Printers for Guided Implant Surgery
Evaluation of Two 3D Printers for Guided Implant Surgery: To compare the suitability of a fused filament fabrication (FFF) consumer 3D printer with a professional digital light processing (DLP) printer for the production of surgical templates for guided oral implant surgery.; Eight virtual templates were printed with two different 3D printers. These were optically scanned and the incongruences between virtual and printed templates were determined after alignment of the surface scans and the virtual data. Minimum, maximum, and mean incongruences were determined, and a t test between both groups was performed to determine statistically significant differences in accuracy.; Templates printed with the professional DLP printer showed statistically significantly less incongruence (P = .001) than those fabricated by the consumer FFF 3D printer.; The accuracy of manufactured templates is strongly dependent on the printing device and method. At this time, the tested consumer 3D FFF printer is not suitable for the fabrication of templates for implant guided surgery. Minimum requirements regarding printers' features and 3D-printed templates need to be assessed in future studies.
StarD13: a potential star target for tumor therapeutics
StarD13: a potential star target for tumor therapeutics:
Abstract
StarD13 is a tumor suppressor and a GTPase activating protein (GAP) for Rho GTPases. Thus, StarD13 regulates cell survival pathways and induces apoptosis in a p53-dependent and independent manners. In tumors, StarD13 is either downregulated or completely inhibited, depending on the tumor type. As such, and through the dysregulation of Rho GTPases, this affects adhesion dynamics, actin dynamics, and leads to an increase or a decrease in tumor metastasis depending on the tumor grade and type. Being a key regulatory protein, StarD13 is a potential promising candidate for therapeutic approaches. This paper reviews the key characteristics of this protein and its role in tumor malignancies.Time-space Fourier κ ω ′ filter for motion artifacts compensation during transcranial fluorescencebrain imaging
Time-space Fourier κ ω ′ filter for motion artifacts compensation during transcranial fluorescence
brain imaging:
Intravital imaging of brain vasculature through the intact cranium in vivo is based on the evolution
of the fluorescence intensity and provides an ability to characterize various physiological
processes in the natural context of cellular resolution. The involuntary motions of the examined
subjects often limit in vivo non-invasive functional optical imaging. Conventional imaging
diagnostic modalities encounter serious difficulties in correction of artificial motions, associated
with fast high dynamics of the intensity values in the collected image sequences, when a common
reference cannot be provided. In the current report, we introduce an alternative solution based on a
time-space Fourier transform method so-called K-Omega. We demonstrate that the proposed approach is
effective for image stabilization of fast dynamic image sequences and can be used autonomously
without supervision and assignation of a reference image.
brain imaging:
Intravital imaging of brain vasculature through the intact cranium in vivo is based on the evolution
of the fluorescence intensity and provides an ability to characterize various physiological
processes in the natural context of cellular resolution. The involuntary motions of the examined
subjects often limit in vivo non-invasive functional optical imaging. Conventional imaging
diagnostic modalities encounter serious difficulties in correction of artificial motions, associated
with fast high dynamics of the intensity values in the collected image sequences, when a common
reference cannot be provided. In the current report, we introduce an alternative solution based on a
time-space Fourier transform method so-called K-Omega. We demonstrate that the proposed approach is
effective for image stabilization of fast dynamic image sequences and can be used autonomously
without supervision and assignation of a reference image.
Reducing 4D CT imaging artifacts at the source: first experimental results from the respiratoryadaptive computed tomography (REACT) system
Reducing 4D CT imaging artifacts at the source: first experimental results from the respiratory
adaptive computed tomography (REACT) system: Breathing variations during 4D CT imaging often manifest as geometric irregularities known as
respiratory-induced image artifacts and ultimately effect radiotherapy treatment efficacy. To reduce
such image artifacts we developed Respiratory Adaptive Computed Tomography (REACT) to trigger CT
acquisition during periods of regular breathing. For the first time, we integrate REACT with
clinical hardware and hypothesize that REACT will reduce respiratory-induced image artifacts ≥ 4 mm
compared to conventional 4D CT. 4D image sets were acquired using REACT and conventional 4D CT on a
Siemens Somatom scanner. Scans were taken for 13 respiratory traces (12 patients) that were
reproduced on a lung-motion phantom. Motion was observed by the Varian RPM system and sent to the
REACT software where breathing irregularity was evaluated in real-time and used to trigger the
imaging beam. REACT and conventional 4D CT images were compared to a ground truth static-phantom
image and compared ...
adaptive computed tomography (REACT) system: Breathing variations during 4D CT imaging often manifest as geometric irregularities known as
respiratory-induced image artifacts and ultimately effect radiotherapy treatment efficacy. To reduce
such image artifacts we developed Respiratory Adaptive Computed Tomography (REACT) to trigger CT
acquisition during periods of regular breathing. For the first time, we integrate REACT with
clinical hardware and hypothesize that REACT will reduce respiratory-induced image artifacts ≥ 4 mm
compared to conventional 4D CT. 4D image sets were acquired using REACT and conventional 4D CT on a
Siemens Somatom scanner. Scans were taken for 13 respiratory traces (12 patients) that were
reproduced on a lung-motion phantom. Motion was observed by the Varian RPM system and sent to the
REACT software where breathing irregularity was evaluated in real-time and used to trigger the
imaging beam. REACT and conventional 4D CT images were compared to a ground truth static-phantom
image and compared ...
Patient-Specific Surgical Implants Made of 3D Printed PEEK: Material, Technology, and Scope of Surgical Application
Patient-Specific Surgical Implants Made of 3D Printed PEEK: Material, Technology, and Scope of Surgical Application: Additive manufacturing (AM) is rapidly gaining acceptance in the healthcare sector. Three-dimensional (3D) virtual surgical planning, fabrication of anatomical models, and patient-specific implants (PSI) are well-established processes in the surgical fields. Polyetheretherketone (PEEK) has been used, mainly in the reconstructive surgeries as a reliable alternative to other alloplastic materials for the fabrication of PSI. Recently, it has become possible to fabricate PEEK PSI with Fused Filament Fabrication (FFF) technology. 3D printing of PEEK using FFF allows construction of almost any complex design geometry, which cannot be manufactured using other technologies. In this study, we fabricated various PEEK PSI by FFF 3D printer in an effort to check the feasibility of manufacturing PEEK with 3D printing. Based on these preliminary results, PEEK can be successfully used as an appropriate biomaterial to reconstruct the surgical defects in a "biomimetic" design.
Retrospective Evaluation of Changes in Gait Patterns in Children and Adolescents With Cerebral Palsy After Multilevel Surgery
Retrospective Evaluation of Changes in Gait Patterns in Children and Adolescents With Cerebral Palsy After Multilevel Surgery: The purpose of this study was to retrospectively investigate changes in gait patterns after single-event multilevel surgery in children and adolescents with bilateral cerebral palsy. Three-dimensional instrumented pre- and postoperative gait data of 12 patients were compared to data of 12 healthy control subjects using principal component analysis to reduce the dimensionality of kinematic and kinetic gait data and detect gait differences. The differences between pre- and postoperative data and between postoperative data and data of control subjects were calculated using a linear mixed model. The results revealed 14 significant effects for pre- and postoperative waveforms and 11 significant effects for postoperative and control waveforms. Patients after single-event multilevel surgery walked with smaller internal foot progression angle throughout the gait cycle, lower knee flexion at initial swing, and earlier knee extension during terminal swing. Retained gait deviations included excessive pelvic tilt and internally rotated and flexed hips over the entire gait cycle. Contrary to our hypothesis, postoperative waveforms in the sagittal plane differed more from control waveforms than from preoperative waveforms. These results emphasize the importance of carefully planning further conservative therapy 2 years after single-event multilevel surgery.
Removal of pharmaceutical compounds from aqueous solution by novel activated carbon synthesized from lovegrass ( Poaceae )
Removal of pharmaceutical compounds from aqueous solution by novel activated carbon synthesized from lovegrass ( Poaceae ):
Abstract
In this work, lovegrass (Cpa), an abundant grass of the Poaceae family, was employed as feedstock for the production of activated carbon in a conventional furnace using ZnCl2 as a chemical activator. The prepared material (Cpa-AC) was characterized by pH of the point of zero charges (pHpzc), Boehm’s titration method, CHN/O elemental analysis, ATR-FTIR, N2 adsorption/desorption curves, and SEM. This carbon material was used for adsorption of acetylsalicylic acid (ASA) and sodium diclofenac (DFC). FTIR analysis identified the presence of O-H, N-H, O-C=O), C-O, and aromatic ring bulk and surface of (Cpa-AC) adsorbent. The quantification of the surface functional groups showed the presence of a large amount of acidic functional groups on the surface of the carbon material. The isotherms of adsorption and desorption of N2 confirm that the Cpa-AC adsorbent is mesopore material with a large surface area of 1040 m2 g−1. SEM results showed that the surface of Cpa-AC is rugous. The kinetic study indicates that the system followed the pseudo-second-order model (pH 4.0). The equilibrium time was achieved at 45 (ASA) and 60 min (DCF). The Liu isotherm model best fitted the experimental data. The maxima sorption capacities (Qmax) for ASA and DFC at 25 °C were 221.7 mg g−1 and 312.4 mg g−1, respectively. The primary mechanism of ASA and DFC adsorption was justified considering electrostatic interactions and π-π interactions between the Cpa-AC and the adsorbate from the solution.Cancers, Vol. 12, Pages 924: PD-L1–PD-1 Pathway in the Pathophysiology of Multiple Myeloma
Cancers, Vol. 12, Pages 924: PD-L1–PD-1 Pathway in the Pathophysiology of Multiple Myeloma:
Cancers, Vol. 12, Pages 924: PD-L1–PD-1 Pathway in the Pathophysiology of Multiple Myeloma
Cancers doi: 10.3390/cancers12040924
Authors:
Hideto Tamura
Mariko Ishibashi
Mika Sunakawa-Kii
Koiti Inokuchi
PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.
Cancers, Vol. 12, Pages 924: PD-L1–PD-1 Pathway in the Pathophysiology of Multiple Myeloma
Cancers doi: 10.3390/cancers12040924
Authors:
Hideto Tamura
Mariko Ishibashi
Mika Sunakawa-Kii
Koiti Inokuchi
PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1+ patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.
A 24-year-old Immigrant With Rash
A 24-year-old Immigrant With Rash:
A 24-year-old woman was evaluated 12 weeks after normal vaginal delivery for recurrent painful nodular skin rash present on and off for the last 2 years. Two days before presentation, red, painful, and nonpruritic rash had appeared on her upper and lower extremities. The patient denied fever, weight loss, night sweat, cough, shortness of breath, or any other symptoms. Upon physical examination, multiple tender violaceous nodules with no fluctuation, ulceration, or drainage were seen (Figure 1). During the patient’s last pregnancy she was noted to have latent tuberculosis infection with a positive QuantiFERON test results and negative findings at chest radiography. She had immigrated from Vietnam to the United States 6 years before her current presentation, and she denied any previous testing or treatment for tuberculosis.
A 24-year-old woman was evaluated 12 weeks after normal vaginal delivery for recurrent painful nodular skin rash present on and off for the last 2 years. Two days before presentation, red, painful, and nonpruritic rash had appeared on her upper and lower extremities. The patient denied fever, weight loss, night sweat, cough, shortness of breath, or any other symptoms. Upon physical examination, multiple tender violaceous nodules with no fluctuation, ulceration, or drainage were seen (Figure 1). During the patient’s last pregnancy she was noted to have latent tuberculosis infection with a positive QuantiFERON test results and negative findings at chest radiography. She had immigrated from Vietnam to the United States 6 years before her current presentation, and she denied any previous testing or treatment for tuberculosis.
Repeatability of spatiotemporal, plantar pressure and force parameters during treadmill walking and running
Repeatability of spatiotemporal, plantar pressure and force parameters during treadmill walking and running: Instrumented treadmills with integrated pressure mats measure spatiotemporal, pressure and force parameters and are often used to investigate changes in gait patterns due to injury or rehabilitation.; What is the within- and between-day repeatability of such an instrumented treadmill for spatiotemporal parameters, peak pressures and forces during walking and running?; Treadmill gait and running analysis were performed at 5.0, 6.5, and 9.0 km/h in 33 healthy adults (age: 31.6 ± 7.4 years; body mass index: 23.8 ± 3.2 kg/m; 2; ) once on day 1 and twice on day 7. For all three speeds, intraclass correlation coefficents (ICC) and smallest detectable differences (SDC) corresponding to 95% limits of agreement were calculated for spatiotemporal parameters and peak pressures and forces in the heel, midfoot, and forefoot regions.; All spatiotemporal parameters and peak forces in the heel, midfoot, and forefoot regions showed a good within- and between-day repeatability (ICCs > 0.878) for all gait speeds with within-day repeatability being generally higher. For peak pressures, only the heel and forefoot regions but not the midfoot region, showed good repeatability (ICC > 0.9) at all gait speeds. SDCs ranged from 1.5 to 2.5° for foot rotation, 4.4 to 6.6 cm for stride length, 0.7 to 2.5% for length of stance phases, and 2.8 to 9.2 N/cm; 2; for peak pressures in all foot regions. For walking, SDCs of peak forces in the heel, midfoot and forefoot regions were below 60 N, and for running below 135 N.; Except for peak pressures in the midfoot, spatiotemporal and kinetic gait parameters during walking and running showed a good within- and between-day repeatability. Hence, the investigated treadmill is suitable to analyze gait patterns and changes in gait patterns due to interventions.
Decompression surgery improves gait quality in patients with symptomatic lumbar spinal stenosis
Decompression surgery improves gait quality in patients with symptomatic lumbar spinal stenosis: We aimed to fully understand the extent of limitations associated with symptomatic lumbar spinal stenosis (LSS) and the functional outcome of its treatment, including not only function during daily activities (eg, using the 6-minute walk test [6MWT]) but also the quality of function that should be objectively assessed.; This study was performed to test the hypothesis that the Oswestry Disability Index (ODI) score, the walking distance during the 6MWT (6-minute walking distance [6MWD]), and gait quality (spatiotemporal parameters and gait asymmetry) will improve postoperatively and achieve normal values; to determine if changes in gait parameters correlate with changes in Oswestry Disability Index (ODI) score; and to ascertain if patients' gait quality will diminish during the 6MWT, reflected by changes in gait parameters during the 6MWT.; This is a prospective observational study with intervention.; The sample comprised patients with symptomatic LSS.; The ODI score, gait quality (spatiotemporal and asymmetry), and walking performance (walking distance during the 6MWT) were the outcome measures.; Patients with symptomatic LSS were analyzed on the day before surgery and 10 weeks and 12 months postoperatively. Functional disability in daily life was assessed by the ODI. Spatiotemporal and kinematic gait parameters were recorded with an inertial sensor system during the 6MWT, and the 6MWD was determined. Gait asymmetry was defined as 100*|right-left|/(0.5*(|right+left|)).; The ODI decreased by 17.9% and 23.9% and 6MWD increased by 21 m and 26 m from baseline to 10-week and 12-month follow-up, respectively. Gait quality did not change during the 6MWT at any assessment or between assessments. Compared with the control group, patients walked less during the 6MWT, and gait quality differed between patients and the control group at baseline and 10-week follow-up but not at 12-month follow-up. Change in gait quality explained 39% and 73% of variance in change in ODI from baseline to 10-week and to 12-month follow-up, respectively.; Changes in gait quality explained a large portion of variance in changes in the ODI, indicating that patients with symptomatic LSS perceive their compromised gait quality as functional limitations. Gait data obtained by instrumented gait analysis contain information on gait quality that can be helpful for evaluating functional limitations in patients with LSS, the outcome of decompression surgery, and the development of patient-specific rehabilitation regimens.
Artificial Intelligence in Ophthalmology: A Meta-Analysis of Deep Learning Models for Retinal Vessels Segmentation.
Artificial Intelligence in Ophthalmology: A Meta-Analysis of Deep Learning Models for Retinal Vessels Segmentation.:
Artificial Intelligence in Ophthalmology: A Meta-Analysis of Deep Learning Models for Retinal Vessels Segmentation.
J Clin Med. 2020 Apr 03;9(4):
Authors: Islam MM, Poly TN, Walther BA, Yang HC, Li YJ
Abstract
BACKGROUND AND OBJECTIVE: Accurate retinal vessel segmentation is often considered to be a reliable biomarker of diagnosis and screening of various diseases, including cardiovascular diseases, diabetic, and ophthalmologic diseases. Recently, deep learning (DL) algorithms have demonstrated high performance in segmenting retinal images that may enable fast and lifesaving diagnoses. To our knowledge, there is no systematic review of the current work in this research area. Therefore, we performed a systematic review with a meta-analysis of relevant studies to quantify the performance of the DL algorithms in retinal vessel segmentation.
METHODS: A systematic search on EMBASE, PubMed, Google Scholar, Scopus, and Web of Science was conducted for studies that were published between 1 January 2000 and 15 January 2020. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) procedure. The DL-based study design was mandatory for a study's inclusion. Two authors independently screened all titles and abstracts against predefined inclusion and exclusion criteria. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for assessing the risk of bias and applicability.
RESULTS: Thirty-one studies were included in the systematic review; however, only 23 studies met the inclusion criteria for the meta-analysis. DL showed high performance for four publicly available databases, achieving an average area under the ROC of 0.96, 0.97, 0.96, and 0.94 on the DRIVE, STARE, CHASE_DB1, and HRF databases, respectively. The pooled sensitivity for the DRIVE, STARE, CHASE_DB1, and HRF databases was 0.77, 0.79, 0.78, and 0.81, respectively. Moreover, the pooled specificity of the DRIVE, STARE, CHASE_DB1, and HRF databases was 0.97, 0.97, 0.97, and 0.92, respectively.
CONCLUSION: The findings of our study showed the DL algorithms had high sensitivity and specificity for segmenting the retinal vessels from digital fundus images. The future role of DL algorithms in retinal vessel segmentation is promising, especially for those countries with limited access to healthcare. More compressive studies and global efforts are mandatory for evaluating the cost-effectiveness of DL-based tools for retinal disease screening worldwide.
PMID: 32260311 [PubMed]
| Related Articles |
J Clin Med. 2020 Apr 03;9(4):
Authors: Islam MM, Poly TN, Walther BA, Yang HC, Li YJ
Abstract
BACKGROUND AND OBJECTIVE: Accurate retinal vessel segmentation is often considered to be a reliable biomarker of diagnosis and screening of various diseases, including cardiovascular diseases, diabetic, and ophthalmologic diseases. Recently, deep learning (DL) algorithms have demonstrated high performance in segmenting retinal images that may enable fast and lifesaving diagnoses. To our knowledge, there is no systematic review of the current work in this research area. Therefore, we performed a systematic review with a meta-analysis of relevant studies to quantify the performance of the DL algorithms in retinal vessel segmentation.
METHODS: A systematic search on EMBASE, PubMed, Google Scholar, Scopus, and Web of Science was conducted for studies that were published between 1 January 2000 and 15 January 2020. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) procedure. The DL-based study design was mandatory for a study's inclusion. Two authors independently screened all titles and abstracts against predefined inclusion and exclusion criteria. We used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for assessing the risk of bias and applicability.
RESULTS: Thirty-one studies were included in the systematic review; however, only 23 studies met the inclusion criteria for the meta-analysis. DL showed high performance for four publicly available databases, achieving an average area under the ROC of 0.96, 0.97, 0.96, and 0.94 on the DRIVE, STARE, CHASE_DB1, and HRF databases, respectively. The pooled sensitivity for the DRIVE, STARE, CHASE_DB1, and HRF databases was 0.77, 0.79, 0.78, and 0.81, respectively. Moreover, the pooled specificity of the DRIVE, STARE, CHASE_DB1, and HRF databases was 0.97, 0.97, 0.97, and 0.92, respectively.
CONCLUSION: The findings of our study showed the DL algorithms had high sensitivity and specificity for segmenting the retinal vessels from digital fundus images. The future role of DL algorithms in retinal vessel segmentation is promising, especially for those countries with limited access to healthcare. More compressive studies and global efforts are mandatory for evaluating the cost-effectiveness of DL-based tools for retinal disease screening worldwide.
PMID: 32260311 [PubMed]
miR-155 inhibits oxidized low-density lipoprotein–induced apoptosis in different cell models by targeting the p85α/AKT pathway
miR-155 inhibits oxidized low-density lipoprotein–induced apoptosis in different cell models by targeting the p85α/AKT pathway:
Abstract
The apoptosis of vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), and macrophages directly causes the instability or rupture of atherosclerotic plaques. Accumulating evidence suggests that oxidized low-density lipoprotein (OxLDL) could induce apoptosis via endogenous or exogenous pathways. Interestingly, it has been reported that microRNA155 (miR-155) plays a pivotal role in the regulation of apoptosis. Here, we hypothesized that overexpression of miR-155 could inhibit OxLDL-induced apoptosis by targeting the p85α/AKT pathway. In this study, we established models of OxLDL-induced apoptosis in mouse VECs, VSMCs, and macrophages. Furthermore, we explored the effects of miR-155 expression on the apoptosis of different cells, and ultimately revealed whether miR-155 regulated apoptosis by targeting the p85α/AKT pathway. The results demonstrated that miR-155 inhibited p85α expression and attenuated VEC, VSMC, and macrophage apoptosis, at least in part by suppressing the expression of p85α-activated AKT to inhibit apoptosis. Our findings collectively suggested that miR-155 attenuated OxLDL-mediated apoptosis in different cells by targeting p85α, supporting its possible therapeutic role in atherosclerosis.Good vibrations: Itch induction by whole body vibration exercise without the need of a pruritogen
Good vibrations: Itch induction by whole body vibration exercise without the need of a pruritogen: Mechanically induced itch is an important cofactor in many patients with chronic itch. However, studying mechanical itch in a controlled environment is challenging because it is difficult to evoke. We investigated the use of whole body vibration (WBV) exercise, a training method used for musculoskeletal rehabilitation, to experimentally evoke mechanical itch. Mild to severe itch ascending from the soles to the groins was evoked in 16 of 20 healthy participants. We observed a characteristic on/off itch crescendo pattern reflecting the alternating intervals of vibration and no vibration. Wheals or an angioedema was absent, and serum mast cell tryptase was not increased by the exercise. Participants described the evoked sensation primarily as "itching" with some nociceptive components. Itch intensity correlated with the intensity of a concomitant erythema (R = 0.45, P = 0.043) and with the rise in skin temperature (R = 0.54, P = 0.017). Hence, WBV can be used as an easily applicable, noninvasive, investigator- and user-friendly framework for studying mechanical itch. Moreover, WBV allows to "switch itch on and off" rapidly and to simultaneously study interactions between itch, skin blood flow and skin temperature.
Preclinical human models and emerging therapeutics for advanced systemic mastocytosis
Preclinical human models and emerging therapeutics for advanced systemic mastocytosis: Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, the neoplastic cells carry activating mutations in; KIT; Progress in mastocytosis research has long been hindered by the lack of suitable; in vitro; models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC-1, LAD1/2, LUVA, ROSA and MCPV-1. The HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34; +; cells of non-mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSA; KIT WT; and MCPV-1) do not harbor; KIT; mutations, HMC-1 and ROSA; KIT D816V; cells exhibit activating; KIT; mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSA; KIT D816V; subclone has been successfully used to generate a unique; in vivo; model of advanced mastocytosis by injection into immunocompromised mice. Such a model may allow; in vivo; validation of data obtained; in vitro; with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSA; KIT D816V; cells in preclinical therapeutic research in mastocytosis.
The role of mast cells in autoimmune bullous dermatoses
The role of mast cells in autoimmune bullous dermatoses: Skin mast cells (MCs), a resident immune cell type with broad regulatory capacity, play an important role in sensing danger signals as well as in the control of the local immune response. It is conceivable to expect that skin MCs regulate autoimmune response and are thus involved in autoimmune diseases in the skin, e.g., autoimmune bullous dermatoses (AIBD). Therefore, exploring the role of MCs in AIBD will improve our understanding of the disease pathogenesis and the search for novel therapeutic targets. Previously, in clinical studies with AIBD, particularly bullous pemphigoid, patients' samples have demonstrated that MCs are likely involved in the development of the diseases. However, using MC-deficient mice, studies with mouse models of AIBD have obtained inconclusive or even discrepant results. Therefore, it is necessary to clarify the observed discrepancies and to elucidate the role of MCs in AIBD. Here, in this review, we aim to clarify discrepant findings and finally elucidate the role of MCs in AIBD by summarizing and discussing the findings in both clinical and experimental studies.
Although abundant in tumor tissue, mast cells have no effect on immunological micro-milieu or growth of HPV-induced or transplanted tumors
Although abundant in tumor tissue, mast cells have no effect on immunological micro-milieu or growth of HPV-induced or transplanted tumors: High numbers of mast cells populate the stroma of many types of neoplasms, including human papilloma virus-induced benign and malignant tumors in man and mouse. Equipped with numerous pattern recognition receptors and capable of executing important pro-inflammatory responses, mast cells are considered innate sentinels that significantly impact tumor biology. Mast cells were reported to promote human papilloma virus (HPV)-induced epithelial hyperproliferation and neo-angiogenesis in an HPV-driven mouse model of skin cancer. We analyzed HPV-induced epithelial hyperplasia and squamous cell carcinoma formation, as well as growth of tumors inoculated into the dermis, in mice lacking skin mast cells. Unexpectedly, the absence of mast cells had no effect on HPV-induced epithelial growth or angiogenesis, on growth kinetics of inoculated tumors, or on the immunological tumor micro-milieu. Thus, the conspicuous recruitment of mast cells into tumor tissues cannot necessarily be equated with important mast cell functions in tumor growth.
Variability of PD-L1 expression in mastocytosis
Variability of PD-L1 expression in mastocytosis: Mastocytosis is a rare disease with heterogeneous clinical manifestations and few effective therapies. Programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) protect tissues from immune-mediated damage and permit tumors to evade immune destruction. Therapeutic antibodies against PD-1 and PD-L1 are effective in the treatment of a variety of neoplasms. In the present study, we sought to systematically analyze expression of PD-1 and PD-L1 in a large number of patients with mastocytosis using immunohistochemistry and multiplex fluorescence staining. PD-L1 showed membrane staining of neoplastic mast cells (MCs) in 77% of systemic mastocytosis (SM) cases including 3 of 3 patients with MC leukemia, 2 of 2 with aggressive SM, 1 of 2 with smoldering SM, 3 of 4 with indolent SM, and 9 of 12 with SM with an associated hematologic neoplasm (SM component only). Ninety-two percent (23 of 25) of cutaneous mastocytosis (CM) cases and 1 of 2 with myelomastocytic leukemia expressed PD-L1, with no expression found in 15 healthy/reactive marrows, 18 myelodysplastic syndromes (MDSs), 16 myeloproliferative neoplasms (MPNs), 5 MDS/MPNs, and 3 monoclonal MC activation syndromes. Variable PD-L1 expression was observed between and within samples, with PD-L1 staining of MCs ranging from 10% to 100% (mean, 50%). PD-1 dimly stained 4 of 27 CM cases (15%), with no expression in SM or other neoplasms tested; PD-1 staining of MCs ranged from 20% to 50% (mean, 27%). These results provide support for the expression of PD-L1 in SM and CM, and PD-1 expression in CM. These data support the exploration of agents with anti-PD-L1 activity in patients with advanced mastocytosis.
Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat:
Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
Cancers doi: 10.3390/cancers12040929
Authors:
Mohannad Ashtar
Hirofumi Tenshin
Jumpei Teramachi
Ariunzaya Bat-Erdene
Masahiro Hiasa
Asuka Oda
Kotaro Tanimoto
So Shimizu
Yoshiki Higa
Takeshi Harada
Masahiro Oura
Kimiko Sogabe
Shingen Nakamura
Shiro Fujii
Ryohei Sumitani
Hirokazu Miki
Kengo Udaka
Mamiko Takahashi
Kumiko Kagawa
Itsuro Endo
Eiji Tanaka
Toshio Matsumoto
Masahiro Abe
Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.
Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
Cancers doi: 10.3390/cancers12040929
Authors:
Mohannad Ashtar
Hirofumi Tenshin
Jumpei Teramachi
Ariunzaya Bat-Erdene
Masahiro Hiasa
Asuka Oda
Kotaro Tanimoto
So Shimizu
Yoshiki Higa
Takeshi Harada
Masahiro Oura
Kimiko Sogabe
Shingen Nakamura
Shiro Fujii
Ryohei Sumitani
Hirokazu Miki
Kengo Udaka
Mamiko Takahashi
Kumiko Kagawa
Itsuro Endo
Eiji Tanaka
Toshio Matsumoto
Masahiro Abe
Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.
Cancers, Vol. 12, Pages 927: Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells
Cancers, Vol. 12, Pages 927: Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells:
Cancers, Vol. 12, Pages 927: Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells
Cancers doi: 10.3390/cancers12040927
Authors:
Abdulaziz B. Hamid
Ruben C. Petreaca
Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.
Cancers, Vol. 12, Pages 927: Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells
Cancers doi: 10.3390/cancers12040927
Authors:
Abdulaziz B. Hamid
Ruben C. Petreaca
Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.
Cancers, Vol. 12, Pages 928: Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
Cancers, Vol. 12, Pages 928: Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells:
Cancers, Vol. 12, Pages 928: Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
Cancers doi: 10.3390/cancers12040928
Authors:
Andrea Abate
Elisa Rossini
Sara Anna Bonini
Martina Fragni
Deborah Cosentini
Guido Albero Massimo Tiberio
Diego Benetti
Constanze Hantel
Marta Laganà
Salvatore Grisanti
Massimo Terzolo
Maurizio Memo
Alfredo Berruti
Sandra Sigala
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.
Cancers, Vol. 12, Pages 928: Cytotoxic Effect of Trabectedin In Human Adrenocortical Carcinoma Cell Lines and Primary Cells
Cancers doi: 10.3390/cancers12040928
Authors:
Andrea Abate
Elisa Rossini
Sara Anna Bonini
Martina Fragni
Deborah Cosentini
Guido Albero Massimo Tiberio
Diego Benetti
Constanze Hantel
Marta Laganà
Salvatore Grisanti
Massimo Terzolo
Maurizio Memo
Alfredo Berruti
Sandra Sigala
Mitotane is the only drug approved for the treatment of adrenocortical carcinoma (ACC). The regimen to be added to mitotane is a chemotherapy including etoposide, doxorubicin, and cisplatin. This pharmacological approach, however, has a limited efficacy and significant toxicity. Evidence indicates that ACC seems to be sensitive to alkylating agents. Trabectedin is an anti-tumor drug that acts as an alkylating agent with a complex mechanism of action. Here, we investigated whether trabectedin could exert a cytotoxic activity in in vitro cell models of ACC. Cell viability was evaluated by MTT assay on ACC cell lines and primary cell cultures. The gene expression was evaluated by q-RT-PCR, while protein expression and localization were studied by Western blot and immunocytochemistry. Combination experiments were performed to evaluate their interaction on ACC cell line viability. Trabectedin demonstrated high cytotoxicity at sub-nanomolar concentrations in ACC cell lines and patient-derived primary cell cultures. The drug was able to reduce /β catenin nuclear localization, although it is unclear whether this effect is involved in the observed cytotoxicity. Trabectedin/mitotane combination exerted a synergic cytotoxic effect in NCI-H295R cells. Trabectedin has antineoplastic activity in ACC cells. The synergistic cytotoxic activity of trabectedin with mitotane provides the rationale for testing this combination in a clinical study.
Eosinophils are a major source of interleukin-31 in bullous pemphigoid
Eosinophils are a major source of interleukin-31 in bullous pemphigoid: Bullous pemphigoid (BP) is characterized by substantial skin and blood eosinophilia as well as intensive pruritus. Since the pruritogenic cytokine interleukin (IL)-31 is increased in inflammatory skin diseases the aim of this study was to determine whether IL-31 plays a role in BP. Using immunofluorescence, IL-31 expression was analysed in eosinophils derived from blister fluids and skin from patients with BP and IL-31 levels in blister fluids, serum and culture supernatants were determined by enzyme-linked immunoassay (ELISA). High levels of IL-31 expression were observed in BP blister fluids, but they were only marginally elevated in BP serum compared with healthy controls. Eosinophils from either BP blister fluids or skin biopsies showed strong expression of IL-31. Furthermore, peripheral blood eosinophils from patients with BP, but not healthy controls, released high levels of IL-31, reflecting those in blister fluids. In conclusion, eosinophils are a major source of IL-31 in BP and this cytokine may contribute to itch in patients with BP.
Normocomplementaemic urticarial vasculitis: effective treatment with omalizumab
Normocomplementaemic urticarial vasculitis: effective treatment with omalizumab: We report two patients with normocomplementaemic urticarial vasculitis with impressive response to omalizumab. This contrasts recent reports on hypocomplementaemic urticarial vasculitis syndrome, highlighting the need for clinical trials of omalizumab in normocomplementaemic urticarial vasculitis.
Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin
Mouse mast cells and mast cell proteases do not play a significant role in acute tissue injury pain induced by formalin: Subcutaneous formalin injections are used as a model for tissue injury-induced pain where formalin induces pain and inflammation indirectly by crosslinking proteins and directly through activation of the transient receptor potential A1 receptor on primary afferents. Activation of primary afferents leads to both central and peripheral release of neurotransmitters. Mast cells are found in close proximity to peripheral sensory nerve endings and express receptors for neurotransmitters released by the primary afferents, contributing to the neuro/immune interface. Mast cell proteases are found in large quantities within mast cell granules and are released continuously in small amounts and upon mast cell activation. They have a wide repertoire of proposed substrates, including Substance P and calcitonin gene-related peptide, but knowledge of their in vivo function is limited. We evaluated the role of mouse mast cell proteases (mMCPs) in tissue injury pain responses induced by formalin, using transgenic mice lacking either mMCP4, mMCP6, or carboxypeptidase A3 (CPA3), or mast cells in their entirety. Further, we investigated the role of mast cells in heat hypersensitivity following a nerve growth factor injection. No statistical difference was observed between the respective mast cell protease knockout lines and wild-type controls in the formalin test. Mast cell deficiency did not have an effect on formalin-induced nociceptive responses nor nerve growth factor-induced heat hypersensitivity. Our data thus show that mMCP4, mMCP6, and CPA3 as well as mast cells as a whole, do not play a significant role in the pain responses associated with acute tissue injury and inflammation in the formalin test. Our data also indicate that mast cells are not essential to heat hypersensitivity induced by nerve growth factor.
Mast cell-specific expression of human Siglec-8
Mast cell-specific expression of human Siglec-8 in conditional knock-in mice: Sialic acid-binding Ig-like lectin 8 (Siglec-8) is expressed on the surface of human eosinophils, mast cells, and basophils-cells that participate in allergic and other diseases. Ligation of Siglec-8 by specific glycan ligands or antibodies triggers eosinophil death and inhibits mast cell degranulation; consequences that could be leveraged as treatment. However, Siglec-8 is not expressed in murine and most other species, thus limiting preclinical studies in vivo. Based on a ROSA26 knock-in vector, a construct was generated that contains the CAG promoter, a LoxP-floxed-Neo-STOP fragment, and full-length Siglec-8 cDNA. Through homologous recombination, this Siglec-8 construct was targeted into the mouse genome of C57BL/6 embryonic stem (ES) cells, and chimeric mice carrying the ROSA26-Siglec-8 gene were generated. After cross-breeding to mast cell-selective Cre-recombinase transgenic lines (CPA3-Cre, and Mcpt5-Cre), the expression of Siglec-8 in different cell types was determined by RT-PCR and flow cytometry. Peritoneal mast cells (dual FcεRI⁺ and c-Kit⁺) showed the strongest levels of surface Siglec-8 expression by multicolor flow cytometry compared to expression levels on tissue-derived mast cells. Siglec-8 was seen on a small percentage of peritoneal basophils, but not other leukocytes from CPA3-Siglec-8 mice. Siglec-8 mRNA and surface protein were also detected on bone marrow-derived mast cells. Transgenic expression of Siglec-8 in mice did not affect endogenous numbers of mast cells when quantified from multiple tissues. Thus, we generated two novel mouse strains, in which human Siglec-8 is selectively expressed on mast cells. These mice may enable the study of Siglec-8 biology in mast cells and its therapeutic targeting in vivo.
Gamma band oscillations in the early phase of psychosis: A systematic review
Gamma band oscillations in the early phase of psychosis: A systematic review: Abnormal gamma oscillations, measured by electroencephalography (EEG), have been associated with chronic psychotic disorders, but their prevalence in the early phase of psychosis is less clear. We sought to address this by systematically reviewing the relevant literature. We searched for EEG studies of gamma band oscillations in subjects at high risk for psychosis and in patients with first episode psychosis. The following measures of gamma oscillations were extracted: resting power, evoked power, induced power, connectivity and peak frequency. Forty-five studies with a total of 3099 participants were included. There were potential sources of bias in the study designs and potential artefacts. Although there were few consistent findings, several studies reported decreased evoked or induced power in both high risk subjects and first episode patients. Studies using larger samples with serial EEG measurements, and designs that minimise artefacts that occur at the gamma frequency may advance work in this area.
Regulated nuclear accumulation of a histone methyltransferase times the onset of heterochromatin formation in; C. elegans; embryos
Regulated nuclear accumulation of a histone methyltransferase times the onset of heterochromatin formation in; C. elegans; embryos: Heterochromatin formation during early embryogenesis is timed precisely, but how this process is regulated remains elusive. We report the discovery of a histone methyltransferase complex whose nuclear accumulation and activation establish the onset of heterochromatin formation in; Caenorhabditis elegans; embryos. We find that the inception of heterochromatin generation coincides with the accumulation of the histone H3 lysine 9 (H3K9) methyltransferase MET-2 (SETDB) into nuclear hubs. The absence of MET-2 results in delayed and disturbed heterochromatin formation, whereas accelerated nuclear localization of the methyltransferase leads to precocious H3K9 methylation. We identify two factors that bind to and function with MET-2: LIN-65, which resembles activating transcription factor 7-interacting protein (ATF7IP) and localizes MET-2 into nuclear hubs, and ARLE-14, which is orthologous to adenosine 5'-diphosphate-ribosylation factor-like 14 effector protein (ARL14EP) and promotes stable association of MET-2 with chromatin. These data reveal that nuclear accumulation of MET-2 in conjunction with LIN-65 and ARLE-14 regulates timing of heterochromatin domains during embryogenesis.
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