First penicillin-binding protein occupancy patterns for 15 {beta}-lactams and {beta}-lactamase inhibitors in Mycobacterium abscessus [Pharmacology]

a.lsfakia shared this article with you from Inoreader First penicillin-binding protein occupancy patterns for 15 {beta}-lactams and {beta}-lactamase inhibitors in Mycobacterium abscessus [Pharmacology] Via AAC Accepts: Articles Published Ahead of Print Mycobacterium abscessus (Mab) causes serious infections that often require over 18 months of antibiotic combination therapy. There is no standard regimen for the treatment of Mab infections and the multitude of combinations that have been used clinically have had low success rates and high rates for toxicities. With β-lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving treatment of Mab infections and minim izing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in Mab. We determined the preferred PBP targets of 13 β-lactams and two β-lactamase inhibitors in two Mab strains and identified PBP sequences by proteomics. The Bocillin FL binding assay was used to determine the β-lactam concentrations (IC50) that half-maximally inhibited Bocillin binding. Principal component analysis identified four clusters of PBP occupancy patterns. Carbapenems inactivated all PBPs at low concentrations (0.016-0.5mg/L; cluster 1). Cephalosporins (cluster 2) inactivated PonA2, PonA1, and PbpA at low (0.031-1mg/L; ceftriaxone and cefotaxime) or intermediate concentrations (0.35-16mg/L; ceftazidime and cefoxitin). Sulbactam, aztreonam, carumonam, mecillinam and avibactam (cluster 3) inactivated the same PBPs as cephalosporins , but required higher concentrations. Other penicillins (cluster 4) specifically targeted PbpA at 2-16mg/L. Carbapenems, ceftriaxone and cefotaxime were the most promising β-lactams since they inactivated most or all PBPs at clinically relevant concentrations. These first PBP occupancy patterns in Mab provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Ciprofloxacin pharmacokinetics/pharmacodynamics (PKPD) against susceptible and low level resistant Escherichia coli in an experimental ascending urinary tract infection model in mice. [Experimental Therapeutics]

a.lsfakia shared this article with you from Inoreader Ciprofloxacin pharmacokinetics/pharmacodynamics (PKPD) against susceptible and low level resistant Escherichia coli in an experimental ascending urinary tract infection model in mice. [Experimental Therapeutics] Via AAC Accepts: Articles Published Ahead of Print The mouse ascending urinary tract infection model was used to study the pharmacokinetic/pharmacodynamic (PKPD) relationship with effect of ciprofloxacin in treatment s.c. for three days varying doses and dosing intervals against a susceptible Escherichia coli (MIC, 0.032 mg/L). Further, a humanized dose of ciprofloxacin was administered for three days against three E. coli with low level resistance, i.e. MIC' s of 0.06, 0.25 and 1 mg/L, respectively. Against the susceptible isolate ciprofloxacin was highly effective in clearing the urine with daily doses from 10 mg/kg, but the dosing regimen had to be divided in at least two doses for optimal effect. Ciprofloxacin could not clear the urine or kidneys for the low level resistant strains. PKPD correlations with all strains combined showed for AUC24/MIC a slightly higher correlation with effect in urine and kidneys (R2, 0.71 and 0.69, respectively) than the %T>MIC (R2, 0.41 and 0.61, respectively). Equal correlations for the two PKPD indices were found for reduction of colony counts (CFUs) in the bladder tissue, but not even the highest dose of 28 mg/kg x 6 could clear the bladder tissue. In conclusion, ciprofloxacin is highly effective in clearing the urine and kidney tissue for fully susceptible E. coli, while even low level resistance in E.coli obscures this effect. While the effect of ciprofloxacin is mostly AUC/MIC driven against E. coli infection in the urinary tr act, the effect in urine depends on presence of ciprofloxacin in the urine during most of 24 hours. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Molecular evaluation of fluoroquinolone resistance in serial Mycobacterium tuberculosis isolates from individuals diagnosed with multidrug-resistant tuberculosis [Mechanisms of Resistance]

a.lsfakia shared this article with you from Inoreader Molecular evaluation of fluoroquinolone resistance in serial Mycobacterium tuberculosis isolates from individuals diagnosed with multidrug-resistant tuberculosis [Mechanisms of Resistance] Via AAC Accepts: Articles Published Ahead of Print Fluoroquinolones (FQ) are crucial components of multidrug-resistant tuberculosis (MDR TB) treatment. Varying levels of resistance are associated with specific mutations within the Quinolone Resistance Determining Region (QRDR) of gyrA. We sequenced the QRDR from serial isolates of MDR TB patients in the Preserving Effective TB Treatment Study (PETTS) with baseline (FQR) or acquired FQ resistance (FQACQR) using the IonTorrent™ Personal Genome Machine to a depth of 10,000x and rep orted single nucleotide polymorphisms in ≥1% of reads. FQR isolates harbored 15 distinct alleles with 1.3 (max=6) on average per isolate. Eighteen alleles were identified in FQACQR isolates with an average of 1.6 (max=9) per isolate. Isolates from 78% of FQACQR individuals had mutant alleles identified within 6 months of treatment initiation. Asp94Gly followed by Ala90Val were the predominant alleles in initial FQ-resistant isolates. Seventy-seven percent (36/47) of FQACQR group patients had isolates with FQ resistance alleles prior to changes to the FQ component of their treatment. Unlike individuals treated initially with other FQs, none of the 21 individuals treated initially with levofloxacin developed genotypic or phenotypic FQ resistance, although, country of residence is likely a contributing factor since 69% of these individuals were from a single country. Initial detection of phenotypic and genotypic resistance occurred simultan eously for most; however, phenotypic resistance occurred earlier in isolates harboring mixtures of very low-abundance (<1% of reads) alleles while genotypic resistance often occurred earlier for low-level resistance-associated alleles. Understanding factors influencing acquisition and evolution of FQ resistance could reveal strategies for improved treatment success. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Safety of laser-generated shockwave treatment for bacterial biofilms in a cutaneous rodent model

a.lsfakia shared this article with you from Inoreader Safety of laser-generated shockwave treatment for bacterial biofilms in a cutaneous rodent model Via Latest Results Abstract Bacterial biofilms are often found in chronically infected wounds. Biofilms protect bacteria from antibiotics and impair wound healing. Surgical debridement is often needed to remove the biofilm from an infected wound. Laser-generated shockwave (LGS) treatment is a novel tissue-sparing treatment for biofilm disruption. Previous studies have demonstrated that LGS is effective in disrupting biofilms in vitro. In this study, we aim to determine the safety threshold of the LGS technology in an in vivo rodent model. To understand the in vivo effects of LGS on healthy cutaneous tissue, the de-haired dorsal skin of Sprague-Dawley rats were treated with LGS at three different peak pressures (118, 296, 227 MPa). These pressures were generated using a 1064 nm Nd/YAG laser (pulse duration 5 ns and laser fluence of 777.9 mJ) with laser spot size diameters of 2.2, 3.0, and 4.2 mm, respectively. Following treatment, the animals were observed for 72 h, and a small subset was eu thanized at 1-h, 24-h, and 72-h post-treatment and assessed for tissue injury or inflammation under histology. Each treatment group consisted of 9 rats (n = 3/time point for 1-h, 24-h, 72-h post-treatment). An additional 4 control (untreated) rats were included in the analysis, for a total of 31 animals. Gross injuries occurred in 21 (77%) animals and consisted of minor erythema, with prevalence positively correlated with peak pressure (p < 0.05). Of injuries under gross observation, 94% resolved within 24 h. Under histological analysis, the injuries and tissue inflammation were found to be localized to the epidermis and superficial dermis. LGS appears to be well tolerated by cutaneous tissue for the laser energy settings shown to be effective against bacterial biofilm in vitro. All injuries incurred, at even the highest peak pressures, were clinically mild and resolved within 1 day. This lends further support to the overall safety of LGS and serves to translate LGS towards in vivo efficacy studies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Red Marrow Absorbed Dose Calculation in Thyroid Cancer Patient Using a Simplified Excel Spreadsheet

gnorimies20.15 shared this article with you from Inoreader Red Marrow Absorbed Dose Calculation in Thyroid Cancer Patient Using a Simplified Excel Spreadsheet Via pubmed: thyroid cancer Red Marrow Absorbed Dose Calculation in Thyroid Cancer Patient Using a Simplified Excel Spreadsheet Mol Imaging Radionucl Ther. 2020 10 19;29(3):124-131 Authors: Songprakhon R, Roysri K, Charoenphun P, Chuamsaamarkkee K Abstract Objectives: Absorbed dose to red marrow (Drm) can be calculated using blood dosimetry. However, this method is laborious and invasive. Therefore, image-based dosimetry is the method of choice. Nonetheless, the commercial software is expensive. The goal of this work was to develop a simplified excel spreadsheet for image-based radioiodine red marrow dosimetry. Methods: The serial whole-body images (acquired at 2nd, 6th, 24th, 48th, and 72th hours) of 29 patients from the routine pretherapeutic dosimetry protocol were retrospectively reanalyzed. The commercial OLINDA/EXM image-based dosimetry software was used to calculate the whole-body time-integrated activity coefficient (TIACWB) and Drm [in terms of absorbed dose coefficient (drm)]. For the simplified excel spreadsheet, the wholebody count was obtained from the vendor-supplied software. Then, the TIACWB was computed by a fitting time-activity curve using an Excel function. S factor was taken from other publications and scaled according to the patient-specific mass. A comparison of the TIACWB and drm from both methods was done using a non-inferiority test using a paired t-test or the Wilcoxon signed-rank test. Results: The TIACWB showed no significant difference between both methods (p=0.243). The calculated Drm from a simplified Excel spreadsheet was assumed to be statistically non-inferior to the commercial OLINDA/EXM image-based dosimetry software with the non-inferiority margin of 0.02 (p<0.05). Conclusion: The dose assessment from a simplified Excel spreadsheet is feasible and relatively low cost compared to the commercial OLINDA/EXM image-based dosimetry software. PMID: 33094576 [PubMed] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer.

gnorimies20.15 shared this article with you from Inoreader Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer. Via pubmed: thyroid cancer Immortalization up-regulated protein promotes tumorigenesis and inhibits apoptosis of papillary thyroid cancer. J Cell Mol Med. 2020 Oct 23;: Authors: Lin L, Wen J, Lin B, Bhandari A, Zheng D, Kong L, Wang Y, Wang O, Chen Y Abstract The incidence of thyroid cancer is increasing in recent years worldwide, but the underlying mechanisms await further exploration. We utilized the bioinformatic analysis to discover that Immortalization up-regulated protein (IMUP) could be a potential oncogene in the papillary thyroid cancer (PTC). We verified this finding in several databases and locally validated cohorts. Clinicopathological features analyses showed that high expression of IMUP is positively related to malignant clinicopathological features in PTC. Braf-like PTC patients with higher IMUP expression had shorter disease-free survival. The biological function of IMUP in PTC cell lines (KTC-1 and TPC-1) was investigated using small interfering RNA. Our results showed that silencing IMUP suppresses proliferation, migration and invasion while inducing apoptosis in PTC cell lines. Changes of the expression of apoptosis-related molecules were identified by real-time quantitative polymerase chain reaction and Western blotting. We also found that YAP1 and TAZ, the critical effectors in the Hippo pathway, were down-regulated when the IMUP is silenced. Rescue experiments showed that overexpression of YAP1 reverses the tumour inhibitory effect caused by IMUP knockdown. Our study demonstrated that IMUP has an oncogenic function in PTC and might be a new target gene in the treatment of PTC. PMID: 33094920 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

FAM172A promotes follicular thyroid carcinogenesis and may be a marker of FTC.

gnorimies20.15 shared this article with you from Inoreader FAM172A promotes follicular thyroid carcinogenesis and may be a marker of FTC. Via pubmed: thyroid cancer FAM172A promotes follicular thyroid carcinogenesis and may be a marker of FTC. Endocr Relat Cancer. 2020 Nov;27(11):657-669 Authors: Xu PP, Zeng S, Xia XT, Ye ZH, Li MF, Chen MY, Xia T, Xu JJ, Jiao Q, Liu L, Li LX, Guo MG Abstract Our aims were to uncover the role of FAM172A (Family with sequence similarity 172 member A) in the pathogenesis of follicular thyroid carcinoma (FTC) and to evaluate its value in the differential diagnosis between malignant and benign thyroid follicular lesions. FAM172A expression was evaluated by q-PCR, immunoblotting and immunohistochemistry (IHC). The ability of proliferation, migration and invasion of cells were assessed by Cell Counting Kit-8 assay (CCK8), clone-formation and Transwell assays. Nude mouse tumorigenicity assays were used to investigate the role of FAM172A in the pathogenesis of FTC in vivo. The value of FAM172A in the differential diagnosis for FTC was assessed using 120 formalin-fixed paraffin-embedded (FFPE) tissues after the operation and 81 fine-needle aspiration biopsy (FNAB) samples before the operation. FAM172A was highly expressed in FTC tissues and FTC cell lines. Downregulation of FAM172A inhibited the proliferation, invasion and migration of FTC cells through Erk1/2 and JNK pathways. Subcutaneous tumorigenesis in nude mice showed that knockdown of FAM172A inhibited tumor growth and progression in vivo. The FAM172A IHC scores of 3.5 had 92% sensitivity and 63% specificity to separate FTC from benign/borderline thyroid follicular lesions, and 92% sensitivity and 80% specificity to discriminate FTC from benign thyroid follicular lesions in postoperative FFPE samples. The corresponding values were 75 and 78%, and 75 and 89% in preoperative FNA samples, respectively. FAM172A plays an important role in the pathogenesis of FTC through Erk1/2 and JNK pathways. FAM172A may be a potential marker for the preoperative diagnosis of FTC based on the IHC results of thyroid FNAB samples. PMID: 33095186 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Nitrate contamination of drinking water, common in agricultural areas, increases the risk of certain cancers and impacts fetal development during pregnancy.

gnorimies20.15 shared this article with you from Inoreader Health and economic impact of nitrate pollution in drinking water: a Wisconsin case study. Via pubmed: thyroid cancer Health and economic impact of nitrate pollution in drinking water: a Wisconsin case study. Environ Monit Assess. 2020 Oct 23;192(11):724 Authors: Mathewson PD, Evans S, Byrnes T, Joos A, Naidenko OV Abstract Nitrate contamination of drinking water, common in agricultural areas, increases the risk of certain cancers and impacts fetal development during pregnancy. Building on previously published methodology, this study evaluates nitrate-attributable disease cases and adverse birth outcomes as well as their economic costs for Wisconsin, USA. Nitrate is the most common contaminant in groundwater in Wisconsin. Two-thirds of the state's residents use groundwater as the primary source of drinking water. Here, we analyze nitrate exposure from drinking water in Wisconsin based on nitrate test results for community water systems for the period of 2010-2017 and a novel methodology for estimating nitrate exposure for the 28% of state's residents who use private wells. We estimate that annually, 111-298 combined cases of colorectal, ovarian, thyroid, bladder, and kidney cancer in Wisconsin may be due to nitrate contamination of drinking water. Each year, up to 137-149 cases of very low birth weight, 72-79 cases of very preterm birth, and two cases of neural tube defects could be due to nitrate exposure from drinking water. The direct medical cost estimates for all nitrate-attributable adverse health outcomes range between $23 and $80 million annually. Simulating targeted reductions in the counties with the highest current drinking water nitrate concentrations resulted in similar reductions in adverse health outcomes as statewide reduction efforts, up to nitrate reductions of 20%. Time trend analysis suggests that groundwater nitrate concentrations are overall increasing. Thus, nitrate contamination of water supplies in Wisconsin is a public health problem that needs to be addressed. PMID: 33095309 [PubMed - as supplied by publisher] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Incidence of respiratory syncytial virus infection in children with congenital heart disease undergoing immunoprophylaxis with palivizumab in Pará state, north region of Brazil.

gnorimies20.15 shared this article with you from Inoreader Incidence of respiratory syncytial virus infection in children with congenital heart disease undergoing immunoprophylaxis with palivizumab in Pará state, north region of Brazil. Via pubmed: flu treatment Related Articles Incidence of respiratory syncytial virus infection in children with congenital heart disease undergoing immunoprophylaxis with palivizumab in Pará state, north region of Brazil. BMC Pediatr. 2019 08 28;19(1):299 Authors: de Souza RP, Ribeiro ALR, de Menezes SAF, Machado LFA Abstract BACKGROUND: Palivizumab prophylaxis for the human respiratory syncytial virus (HRSV) has been reported to reduce the risk of hospital admissions related to HRSV in children with congenital heart disease (CHD). These children are at high risk of developing severe lower respiratory tract infection (LRTI) due to HRSV infection. Our goal was to evaluate the incidence of HRSV infection in children with CHD after being submitted to immunoprophylaxis with palivizumab in Pará state, North region of Brazil. METHODS: A prospective and observational cohort study was performed in children ≤2 years of age with CHD who received palivizumab immunoprophylaxis between January 1 and June 31, 2016. A questionnaire about basic non-medical care measures was applied to parents/legal representatives. Data on patients' demographic characteristics, household environment, and respiratory infections were evaluated. HRSV infection was determined by qPCR. RESULTS: There were 104 children enrolled in this investigation and the results showed a mean age of 10.6 months, an average weight of 7.3 kg and 3.5 doses of palivizumab per children during seasonality of HRSV. Respiratory infection was observed in 27.9% of cases, of which 9.6% were LRTI. No case of children who received palivizumab immunoprophylaxis and developed influenza-like symptoms tested positive for HRSV. CONCLUSION: Although the lack of a control group doesn't allow to affirm the effectiveness of HRSV passive immunization, the immunoprophylaxis with palivizumab appeared to be totally efficient in preventing respiratory infection by HRSV in children up to two years of age with CHD. PMID: 31462289 [PubMed - indexed for MEDLINE] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Influenza and respiratory syncytial virus infections in the oldest-old continent.

gnorimies20.15 shared this article with you from Inoreader Influenza and respiratory syncytial virus infections in the oldest-old continent. Via pubmed: flu treatment Related Articles Influenza and respiratory syncytial virus infections in the oldest-old continent. Eur J Clin Microbiol Infect Dis. 2020 Nov;39(11):2085-2090 Authors: Boattini M, Almeida A, Christaki E, Cruz L, Antão D, Moreira MI, Bianco G, Iannaccone M, Tsiolakkis G, Khattab E, Kasapi D, Charrier L, Tosatto V, Marques TM, Cavallo R, Costa C Abstract SARS-CoV-2 dramatically revealed the sudden impact of respiratory viruses in our lives. Influenza and respiratory syncytial virus (RSV) infections are associated with high rates of morbidity, mortality, and an important burden on healthcare systems worldwide, especially in elderly patients. The aim of this study was to identify severity predictors in the oldest-old admitted with influenza and/or RSV infections. This is a multicenter, retrospective study of all oldest-old patients (≥ 85 years old) admitted for laboratory-confirmed influenza and/or RSV infection in three tertiary hospitals in Portugal, Italy, and Cyprus over two consecutive winter seasons. The outcomes included the following: pneumonia on infection presentation, use of non-invasive ventilation (NIV), and in-hospital death (IHD). The association with possible predictors, including clinical features and type of virus infection, was assessed using uni- and multivariable analyses. A total of 251 oldes t-old patients were included in the study. Pneumonia was evident in 32.3% (n = 81). NIV was implemented in 8.8% (n = 22), and IHD occurred in 13.9% (n = 35). Multivariable analyses revealed that chronic obstructive pulmonary disease (COPD) or asthma was associated with pneumonia (OR 1.86; 95% CI 1.02-3.43; p = 0.045). COPD or asthma (OR 4.4; 95% CI 1.67-11.6; p = 0.003), RSV (OR 3.12; 95% CI 1.09-8.92; p = 0.023), and influenza B infections (OR 3.77; 95% CI 1.06-13.5; p = 0.041) were associated with NIV use, respectively, while chronic kidney disease was associated with IHD (OR 2.50; 95% CI 1.14-5.51; p = 0.023). Among the oldest-old, chronic organ failure, such as COPD or asthma, and CKD predicted pneumonia and IHD, respectively, beyond the importance of viral virulence itself. These findings could impact on public health policies, such as fostering influenza immunization campaigns, home-based care programs, and end-of-life care. Filling knowledge ga ps is crucial to set priorities and advise on transition model of care that best fits the oldest-old. PMID: 32594325 [PubMed - indexed for MEDLINE] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Pharyngodynia, nasal congestion, rhinorrhea, smell, and taste dysfunctions could be the presenting symptoms of coronavirus disease

gnorimies20.15 shared this article with you from Inoreader Clinical Presentation of COVID-19: A Systematic Review Focusing on Upper Airway Symptoms. Via pubmed: pharyngitis[all fiel... Related Articles Clinical Presentation of COVID-19: A Systematic Review Focusing on Upper Airway Symptoms. Ear Nose Throat J. 2020 Nov;99(9):569-576 Authors: Lovato A, de Filippis C Abstract AIM: Pharyngodynia, nasal congestion, rhinorrhea, smell, and taste dysfunctions could be the presenting symptoms of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2. The aim was to perform a systematic review of current evidences on clinical presentation of COVID-19, focusing on upper airway symptoms in order to help otolaryngologists identifying suspected cases. METHODS: We searched PubMed and Web of Science electronic databases. RESULTS: We included 5 retrospective clinical studies for a total of 1556 hospitalized patients with COVID-19, 57.5% were male and mean age was 49.1 years. Pooled data revealed that pharyngodynia was present in 12.4% of patients, nasal congestion in 3.7%, and rhinorrhea was rare. No reports on COVID-19 and olfactory/gustative disorders matched inclusion criteria but preliminary evidences suggested they could be present. Common symptoms were fever (85.6%), cough (68.7%), and fatigue (39.4%). Frequent comorbidities were hypertension (17.4%), diabetes (3.8%), and coronary heart disease (3.8%); 83% of patients had alterations on chest computed tomography that were bilateral in 89.5% of cases. Ground-glass opacity was the most common finding (50%). Lymphopenia (77.2%) and leucopenia (30.1%) were common. Critical cases with complications were 9%, intensive care unit admission was required in 7.3%, invasive ventilation in 3.4%, and mortality was 2.4%. CONCLUSION: Otolaryngologists should know that pharyngodynia, nasal congestion, olfactory, and gustative disorders could be the presenting symptoms of COVID-19. Clinical presentation together with radiological and laboratory findings could help to identify suspected cases. PMID: 32283980 [PubMed - indexed for MEDLINE] View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.