Sulfhydryl compounds and antioxidants inhibit cytotoxicity to outer hair cells of a gentamicin metabolite in vitro

Aminoglycoside antibiotics such as gentamicin have long been known to destroy cochlear and vestibular hair cells in vivo. In the cochlea outer hair cells are preferentially affected. In contrast, gentamicin will not damage outer hair cells in vitro unless it has been enzymatically converted to a cytotoxic metabolite. Several potential inhibitors of this enzymatic reaction were tested in an in vitro assay against outer hair cells isolated from the guinea pig cochlea. Viability of hair cells (viable cells as per cent of total number of cells observed) averaged about 70% under control conditions. Addition of metabolized gentamicin significantly reduced viability to less than 50% in one hour. Sulfhydryl compounds (glutathione, dithioerythritol) and antioxidants (vitamin C, phenylene diamine, trolox) prevented the cytotoxic actions of the gentamicin metabolite. Inhibitors of aminc oxidases and compounds reportedly protective against renal and acute lethal toxicity of aminoglycosides (poly--aspartate and pyridoxal phosphate, respectively) were ineffective as protectants. The results reinforce the hypothesis that gentamicin is enzymatically converted to a cytotoxin and imply the participation of sulfhydryl-sensitive groups or free radicals in this reaction. Alternatively or additionally, sulfhydryl compounds or antioxidants may participate in detoxification reactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31500/1/0000422.pd

The Role of Attention-Deficit/hyperactivity Disorder in the Association between Verbal Ability and Conduct Disorder

Although there is clear evidence that low verbal ability is a risk factor for conduct disorder (CD), some researchers have questioned whether this association is due to the common comorbidity between attention-deficit/hyperactivity disorder (ADHD) and CD. The present study examined the association among verbal ability, ADHD, and CD in a genetically informative sample in order to examine the role of genes and/or environmental influences shared in common with ADHD on the covariation between verbal ability and CD. Participants were 2744 adolescents from the Center for Antisocial Drug Dependence (CADD), and included 360 monozygotic (MZ) female twin pairs, 221 dizygotic (DZ) female twin pairs, 297 MZ male twin pairs, 220 DZ male twin pairs, and 274 opposite-sex DZ twin pairs. The Diagnostic Interview Schedule for Children (DISC-IV) was used to assess lifetime symptoms of ADHD and CD. Verbal ability was assessed via the Vocabulary subtest of the Wechsler Adult Intelligence Scale III (WAIS-III) for individuals over the age of 16 and the Vocabulary subtest of the Wechsler Intelligence Scale for Children III (WISC-III) for individuals under the age of 16. There was a small but significant negative covariance between verbal ability and CD and between verbal ability and ADHD. Results also suggest that the covariation between verbal ability and CD is due to influences shared in common with ADHD

Natural variation of HIV-1 group M integrase: Implications for a new class of antiretroviral inhibitors

HIV-1 integrase is the third enzymatic target of antiretroviral (ARV) therapy. However, few data have been published on the distribution of naturally occurring amino acid variation in this enzyme. We therefore characterized the distribution of integrase variants among more than 1,800 published group M HIV-1 isolates from more than 1,500 integrase inhibitor (INI)-naïve individuals. Polymorphism rates equal or above 0.5% were found for 34% of the central core domain positions, 42% of the C-terminal domain positions, and 50% of the N-terminal domain positions. Among 727 ARV-naïve individuals in whom the complete pol gene was sequenced, integrase displayed significantly decreased inter- and intra-subtype diversity and a lower Shannon's entropy than protease or RT. All primary INI-resistance mutations with the exception of E157Q – which was present in 1.1% of sequences – were nonpolymorphic. Several accessory INI-resistance mutations including L74M, T97A, V151I, G163R, and S230N were also polymorphic with polymorphism rates ranging between 0.5% to 2.0%

Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations

Objectives:We characterized pairwise and higher order patterns of non-nucleoside reverse transcriptase inhibi-tor (NNRTI)-selected mutations because multiple mutations are usually required for clinically significant resist-ance to second-generation NNRTIs. Patients and methods: We analysed viruses from 13039 individuals with sequences containing at least one of 52 published NNRTI-selected mutations, including 1133 viruses from individuals who received efavirenz but no other NNRTI and 1510 viruses from individuals who received nevirapine but no other NNRTI. Of the 17 reported etravirine resistance-associated mutations (RAMs), Y181C/I/V, L100I, K101P and M230L were considered major based on published in vitro susceptibility data

A Case of Novel Coronavirus Disease 19 in a Chronic Hemodialysis Patient Presenting with Gastroenteritis and Developing Severe Pulmonary Disease.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease with an alarming case fatality rate up to 5%. The risk factors for severe presentations are concentrated in patients with chronic kidney disease, particularly patients with end-stage renal disease (ESRD) who are dialysis dependent. We report the first US case of a 56-year-old nondiabetic male with ESRD secondary to IgA nephropathy undergoing thrice-weekly maintenance hemodialysis for 3 years, who developed COVID-19 infection. He has hypertension controlled with angiotensin receptor blocker losartan 100 mg/day and coronary artery disease status-post stent placement. During the first 5 days of his febrile disease, he presented to an urgent care, 3 emergency rooms, 1 cardiology clinic, and 2 dialysis centers in California and Utah. During this interval, he reported nausea, vomiting, diarrhea, and low-grade fevers but was not suspected of COVID-19 infection until he developed respiratory symptoms and was admitted to the hospital. Imaging studies upon admission were consistent with bilateral interstitial pneumonia. He was placed in droplet-eye precautions while awaiting COVID-19 test results. Within the first 24 h, he deteriorated quickly and developed acute respiratory distress syndrome (ARDS), requiring intubation and increasing respiratory support. Losartan was withheld due to hypotension and septic shock. COVID-19 was reported positive on hospital day 3. He remained in critical condition being treated with hydroxychloroquine and tocilizumab in addition to the standard medical management for septic shock and ARDS. Our case is unique in its atypical initial presentation and highlights the importance of early testing

The Etiology of Observed Negative Emotionality from 14 to 24 Months

We examined the magnitude of genetic and environmental influences on observed negative emotionality at age 14, 20, and 24 months. Participants were 403 same-sex twin pairs recruited from the Longitudinal Twin Study whose emotional responses to four different situations were coded by independent raters. Negative emotionality showed significant consistency across settings, and there was evidence of a latent underlying negative emotionality construct. Heritability decreased, and the magnitude of shared environmental influences increased, for the latent negative emotionality construct from age 14 to 24 months. There were significant correlations between negative emotionality assessed at age 14, 20, and 24 months, and results suggested common genetic and shared environmental influences affecting negative emotionality across age, and that age-specific influences are limited to non-shared environmental influences, which include measurement error

HIV-1 Protease, Reverse Transcriptase, and Integrase Variation

ABSTRACT HIV-1 protease (PR), reverse transcriptase (RT), and integrase (IN) variability presents a challenge to laboratories performing genotypic resistance testing. This challenge will grow with increased sequencing of samples enriched for proviral DNA such as dried blood spots and increased use of next-generation sequencing (NGS) to detect low-abundance HIV-1 variants. We analyzed PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to characterize variation at each amino acid position, identify mutations indicating APOBEC-mediated G-to-A editing, and identify mutations resulting from selective drug pressure. Forty-seven percent of PR, 37% of RT, and 34% of IN positions had one or more amino acid variants with a prevalence of ≥1%. Seventy percent of PR, 60% of RT, and 60% of IN positions had one or more variants with a prevalence of ≥0.1%. Overall 201 PR, 636 RT, and 346 IN variants had a prevalence of ≥0.1%. The median intersubtype prevalence ratios were 2.9-, 2.1-, and 1.9-fold for these PR, RT, and IN variants, respectively. Only 5.0% of PR, 3.7% of RT, and 2.0% of IN variants had a median intersubtype prevalence ratio of ≥10-fold. Variants at lower prevalences were more likely to differ biochemically and to be part of an electrophoretic mixture compared to high-prevalence variants. There were 209 mutations indicative of APOBEC-mediated G-to-A editing and 326 mutations nonpolymorphic treatment selected. Identification of viruses with a high number of APOBEC-associated mutations will facilitate the quality control of dried blood spot sequencing. Identifying sequences with a high proportion of rare mutations will facilitate the quality control of NGS. IMPORTANCE Most antiretroviral drugs target three HIV-1 proteins: PR, RT, and IN. These proteins are highly variable: many different amino acids can be present at the same position in viruses from different individuals. Some of the amino acid variants cause drug resistance and occur mainly in individuals receiving antiretroviral drugs. Some variants result from a human cellular defense mechanism called APOBEC-mediated hypermutation. Many variants result from naturally occurring mutation. Some variants may represent technical artifacts. We studied PR and RT sequences from >100,000 individuals and IN sequences from >10,000 individuals to quantify variation at each amino acid position in these three HIV-1 proteins. We performed analyses to determine which amino acid variants resulted from antiretroviral drug selection pressure, APOBEC-mediated editing, and naturally occurring variation. Our results provide information essential to clinical, research, and public health laboratories performing genotypic resistance testing by sequencing HIV-1 PR, RT, and IN

Computer simulation as a component of catheter-based training

IntroductionComputer simulation has been used in a variety of training programs, ranging from airline piloting to general surgery. In this study we evaluate the use of simulation to train novice and advanced interventionalists in catheter-based techniques.MethodsTwenty-one physicians underwent evaluation in a simulator training program that involved placement of a carotid stent. Five participants were highly experienced in catheter-based techniques (>300 percutaneous cases), including carotid angioplasty and stenting (CAS); the remaining 16 participants were interventional novices (<5 percutaneous cases). The Procedicus VIST simulator, composed of real-time vascular imaging simulation software and a tactile interface coupled to angiographic catheters and guide wires, was used. After didactic instruction regarding CAS and use of the simulator, each participant performed a simulated CAS procedure. The participant's performance was supervised and evaluated by an expert interventionalist on the basis of 50 specific procedural steps with a maximal score of 100. Specific techniques of guide wire and catheter manipulation were subjectively assessed on a scale of 0 to 5 points based on ability. After evaluation of the initial simulated CAS procedure, each participant received a minimum of 2 hours of individualized training by the expert interventionalist, with the VIST simulator. Each participant then performed a second simulated CAS procedure, which was graded with the same scale. After completion, participants assessed the training program and its utility via survey questionnaire.ResultsThe average simulated score for novice participants after the training program improved significantly from 17.8 ± 15.6 to 69.8 ± 9.8 (P < .01), time to complete simulation decreased from 44 ± 10 minutes to 30 ± 8 minutes (P < .01), and fluoroscopy time decreased from 31 ± 7 minutes to 23 ± 7 minutes (P < .01). No statistically significant difference in score, total time, or fluoroscopy time was noted for experienced interventionalists. Improvement was noted in guide wire and catheter manipulation skills in novices.. Analysis of survey data from experienced interventionalists indicated that the simulated clinical scenarios were realistic and that the simulator could be a valuable tool if clinical and tactile feedback were improved. Novices also thought the simulated training was a valuable experience, and desired further training time.ConclusionsAn endovascular training program using the Procedicus VIST haptic simulator resulted in significant improvement in trainee facility with catheter-based techniques in a simulated clinical setting. Novice participants derived the greatest benefit from simulator training in a mentored program, whereas experienced interventionalists did not seem to derive significant benefit