Timepoint for return to occupations post-burn injury using the Canadian Occupational Performance Measure (COPM).

INTRODUCTION: The Canadian Occupational Performance Measure (COPM) was implemented at a state-wide burns service to ensure compliance with current best evidence as outlined by the Australian and New Zealand Burns Association 'burn trauma rehabilitation: allied health practice guidelines'- Chapter 7 Measuring Post-Burn Recovery, as a standard outcome measure for individuals with an admission time greater than 24 h. The primary aim of this study is to determine if individuals have a minimal important change in performance and satisfaction with activities that were identified as problematic on the COPM prior to their acute discharge. Previous research confirmed the feasibility of using the COPM in the acute burn ward and recommended the most appropriate timepoint for re-measurement be confirmed, which is the secondary objective of this study. The benefits of confirming this timepoint include ensuring efficient use of clinicians' time without compromising the accuracy of the assessment and ensuring effective translation of the guidelines' recommendation. METHODS: A prospective longitudinal study was undertaken, where all individuals who previously completed a COPM prior to acute discharge were sought to complete a re-assessment while accessing outpatient services. Time frames for re-assessment were open. Only individuals who were actively receiving occupational therapy outpatient services were included. COPM assessments were completed in person where possible, particularly for participants who required an interpreter, with phone and video calls also used when needed. RESULTS: A total of 37 participants were included, with the timeframe between initial and post-COPM assessment ranging from 2 to 643 days. Outcomes plateaued at approximately 12 months (365 days) post-initial measurement (prior to discharge from acute ward). The most common occupational performance goals that participants identified were returning to work, sport, and driving. 86.5% of participants increased their satisfaction with these activities. The results of this study demonstrate improvements across the domains of performance and satisfaction occur for individuals with burns at approximately 3 months and 12 months post-injury. CONCLUSION: Based on this study, it is suggested that when using the COPM assessment in a tertiary burn setting, re-measurement be completed no earlier than 3 months and later than 12 months from burn injury, or upon discharge from the service. The findings from this study will be translated into clinical practice at this facility.

Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction.

Although therapeutic interventions of signal-transduction cascades with targeted kinase inhibitors are a well-established strategy, drug-discovery efforts to identify targeted phosphatase inhibitors have proven challenging. Herein we report a series of allosteric, small-molecule inhibitors of wild-type p53-induced phosphatase (Wip1), an oncogenic phosphatase common to multiple cancers. Compound binding to Wip1 is dependent on a 'flap' subdomain located near the Wip1 catalytic site that renders Wip1 structurally divergent from other members of the protein phosphatase 2C (PP2C) family and that thereby confers selectivity for Wip1 over other phosphatases. Treatment of tumor cells with the inhibitor GSK2830371 increases phosphorylation of Wip1 substrates and causes growth inhibition in both hematopoietic tumor cell lines and Wip1-amplified breast tumor cells harboring wild-type TP53. Oral administration of Wip1 inhibitors in mice results in expected pharmacodynamic effects and causes inhibition of lymphoma xenograft growth. To our knowledge, GSK2830371 is the first orally active, allosteric inhibitor of Wip1 phosphatase.

Altered significance of D'Amico risk classification in patients with prostate cancer linked to a familial breast cancer (kConFab) cohort.

OBJECTIVE: To ascertain whether D'Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort. PATIENTS AND METHODS: From family cancer pedigrees of patients evaluated through a familial breast cancer cohort all related men with a diagnosis of prostate cancer were identified. Genotyping of each patient or of the dominant familial BRCA2 mutation was undertaken in each instance. Prostate cancers were analysed by BRCA2 carrier vs non-carrier status for their clinical progression and survival according to their D'Amico risk groups. RESULTS: For patients who were BRCA2-mutation positive, there was no significant difference in cancer-specific survival (CSS) between those patients who were graded as having D'Amico high- or intermediate-risk disease. For patients who were BRCA2-mutation negative, but were identified via a family cancer pedigree, there was no statistically significant difference in CSS between D'Amico high- and intermediate-risk prostate cancers. Patients with D'Amico high-risk disease who were BRCA2-mutation carriers had substantially increased disease-specific mortality compared with high-risk non-carriers (hazard ratio 2.94, P = 0.004). CONCLUSION: D'Amico risk classification has limitations in predicting variations in prostate cancer-specific mortality for this group of patients.

A data management and publication workflow for a large-scale, heterogeneous sensor network.

It is common for hydrology researchers to collect data using in situ sensors at high frequencies, for extended durations, and with spatial distributions that produce data volumes requiring infrastructure for data storage, management, and sharing. The availability and utility of these data in addressing scientific questions related to water availability, water quality, and natural disasters relies on effective cyberinfrastructure that facilitates transformation of raw sensor data into usable data products. It also depends on the ability of researchers to share and access the data in useable formats. In this paper, we describe a data management and publication workflow and software tools for research groups and sites conducting long-term monitoring using in situ sensors. Functionality includes the ability to track monitoring equipment inventory and events related to field maintenance. Linking this information to the observational data is imperative in ensuring the quality of sensor-based data products. We present these tools in the context of a case study for the innovative Urban Transitions and Aridregion Hydrosustainability (iUTAH) sensor network. The iUTAH monitoring network includes sensors at aquatic and terrestrial sites for continuous monitoring of common meteorological variables, snow accumulation and melt, soil moisture, surface water flow, and surface water quality. We present the overall workflow we have developed for effectively transferring data from field monitoring sites to ultimate end-users and describe the software tools we have deployed for storing, managing, and sharing the sensor data. These tools are all open source and available for others to use.

Cardiac R2* values are independent of the image analysis approach employed.

PURPOSE: To determine whether systematic differences were present between myocardial R2* values obtained with two different decay models: truncation and exponential + constant (Exp-C). METHODS: Single-center cohorts were used to compare black and bright blood sequences separately, and a multicenter cohort of mixed bright and black blood studies was used to assess the generalizability. Truncated exponential estimates were calculated with CMRtools, which uses a single region of interest (ROI) method. Exp-C estimates were calculated using a pixelwise approach. RESULTS: No differences could be distinguished based upon whether a white or black blood sequence was examined. The two fitting algorithms yielded similar R2* values, with R-squared values exceeding 0.997 and a coefficient of variation of 3% to 4%. Results using the pixelwise method yielded a small systematic bias (∼3%) that became apparent in patients with severe iron deposition. This disparity disappeared when Exp-C fitting was used on a single ROI, suggesting that the use of pixelwise mapping was responsible for the bias. In the multicenter cohort, the strong agreement between the two fitting approaches was reconfirmed. CONCLUSION: Cardiac R2* values are independent of the signal model used for its calculation over clinically relevant ranges. Clinicians can compare results among centers using these disparate approaches with confidence.

A phase 2 study of the safety, tolerability, and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload.

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Incidental finding of Cowper's syringocele in traumatic blunt injury: a case report.

Cowper's syringocele is a cystic dilation of the bulbourethral duct or gland. This rare pathology has historically been diagnosed in the pediatric population, with recent literature reporting an increased incidence in adults. Attempts have been made to classify Cowper's syringoceles by their appearance on imaging and endoscopy, however a simpler classification of unobstructed versus obstructed may be of more utility in directing management. Herein, we present a novel case of a Cowper's syringocele developed in adulthood that supports the suspicion for underdiagnosis, as well as one proposed mechanism of acquired etiology of Cowper's syringoceles involving incomplete or intermittent obstruction secondary to the application of external force of the leading to asymptomatic cystic dilation.

Surgical correction of multiple renoduodenal fistulas due to chronic pyelonephritis: a case report and literature review.

Renoduodenal fistulas are a rare and uncommon phenomenon that account for ˂1% of those found between the urinary and intestinal tracts. Precipitation of this pathologic tract can be caused by chronic inflammation, necrosis, or ischemia. This case illustrates a 72-year-old man presenting with flank pain discovered to have multiple renoduodenal fistulas and our approach that led to the resolution of his symptoms. We review the pathophysiology, management, and effects of these fistulous tracts on renal function. Patients with staghorn calculi should undergo immediate evaluation for removal of the stone. In cases complicated by fistula formation, need for radical nephrectomy should be investigated and surgical repair should be pursued.

Effects of pH on Olfactory Behaviours in Male Shore Crabs, Carcinus maenas.

The effects of climate change are becoming more apparent, predominantly concerning the impacts of ocean acidification on calcifying species. Many marine organisms rely on chemical signals for processes such as foraging for food, predator avoidance, or locating mates. The process of how chemical cues in marine invertebrates function, and how this sensory mode is affected by pH levels, is less researched. We tested the impact of reduced pH (7.6), simulating end-of-the-century predicted average ocean pH, against current oceanic pH conditions (8.2), on the behavioural response of male shore crabs Carcinus maenas to the female sex pheromone bouquet consisting of Uridine-diphosphate (UDP) and Uridine-triphosphate (UTP). While in current pH conditions (8.2), there was a significant increase in sexual interactions in the presence of female pheromone, males showed reduced sexual behaviours at pH 7.6. The crab weight-pH relationship, in which larger individuals respond more intensely sexually in normal pH (8.2), is reversed for both the initial detection and time to locate the cue. These results indicate that lowered pH alters chemical signalling in C. maenas also outside the peak reproductive season, which may need to be taken into account when considering the future management of this globally invasive species.

Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities.

Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined. Therefore, we sought to understand the ability of TTFields to disrupt the growth patterns of and induce kinomic landscape shifts in TMZ-sensitive and -resistant GBM cells. We determined that TTFields significantly decreased the growth of TMZ-sensitive and -resistant cells. Kinomic profiling predicted kinases that were induced or repressed by TTFields, suggesting possible therapy-specific vulnerabilities. Serving as a potential pro-survival mechanism for TTFields, kinomics predicted the increased activity of platelet-derived growth-factor receptor alpha (PDGFRα). We demonstrated that the addition of the PDGFR inhibitor, crenolanib, to TTFields further reduced cell growth in comparison to either treatment alone. Collectively, our data suggest the efficacy of TTFields in vitro and identify common signaling responses to TTFields in TMZ-sensitive and -resistant populations, which may support more personalized medicine approaches.

Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells.

Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death. One tumor type that exhibits a shift in the sphingolipid balance towards S1P is glioblastoma (GBM), a highly aggressive brain tumor. GBMs almost always recur despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Understanding sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target dysregulation of sphingolipid metabolism in GBM. Carmofur, a derivative of 5-fluorouracil, inhibits acid ceramidase (ASAH1), a key enzyme in the production of S1P, and is in use outside the USA to treat colorectal cancer. We find that the mRNA for ASAH1, but not other ceramidases, is elevated in recurrent GBM. When TMZ-resistant GBM cells were treated with carmofur, decreased cell growth and increased apoptosis were observed along with cell cycle perturbations. RNA-sequencing identified decreases in cell cycle control pathways that were specific to TMZ-resistant cells. Furthermore, the transcription factor and G1 to S phase regulator, E2F8, was upregulated in TMZ-resistant versus parental GBM cells and inhibited by carmofur treatment in TMZ-resistant GBM cells, specifically. These data suggest a possible role for E2F8 as a mediator of carmofur effects in the context of TMZ resistance. These data suggest the potential utility of normalizing the sphingolipid balance in the context of recurrent GBM.

High grade prostatic intraepithelial neoplasia does not display loss of heterozygosity at the mutation locus in BRCA2 mutation carriers with aggressive prostate cancer.

UNLABELLED: What's known on the subject? and What does the study add? The risk of developing aggressive prostate cancer is increased for men carrying a pathogenic germline mutation in BRCA2. An earlier study by the Kathleen Cuningham Consortium for Research into Familial Breast Cancer showed that BRCA2 mutation carriers displayed a loss of heterozygosity (LOH) within their prostate cancer tissue in the majority of cases, thus implying that the prostate cancer in these men occurred as a result of LOH for BRCA2. High grade prostatic intraepithelial neoplasia (HGPIN) has been considered a precursor to prostate adenocarcinoma in some, but not all, cases of prostate adenocarcinoma. The study found that there was no LOH for BRCA2 in HGPIN. From this small cohort of BRCA2-positive men, we suggest HGPIN is not necessarily a precursor to their prostate cancer development. The presence of HGPIN in a TRUS biopsy in these men at risk of high risk disease is not an indication for prostatectomy. OBJECTIVES: • To determine if high grade prostatic intraepithelial neoplasia (HGPIN), which is considered a precursor to the development of prostate adenocarcinoma, displays the same genetic hallmarks as adenocarcinoma. • To identify, using molecular genetic techniques, if HGPIN is a precursor of tumour development and progression in men carrying a pathogenic germline mutation in BRCA2. PATIENTS AND METHODS: • Ten participants from the Kathleen Cuningham Consortium for Research into Familial Breast Cancer cohort of high-risk breast cancer families were identified, with (i) a diagnosis of aggressive prostate cancer and presence of HGPIN, (ii) a pathogenic BRCA2 mutation, and (iii) access to archival prostate tissue specimens. • Loss of heterozygosity (LOH) at the BRCA2 gene was examined using mutation-specific PCR and sequencing of DNA from laser microdissected HGPIN. RESULTS: • Within this cohort of 10 pathogenic BRCA2 carriers, no patient displayed LOH at the mutation locus within HGPIN, irrespective of whether or not corresponding adenocarcinoma DNA displayed LOH. CONCLUSIONS: • Although HGPIN is considered a precursor to cancer, as no LOH was observed, this assay does not provide a genetic marker that may be considered a positive predictor of tumorigenesis in BRCA2 carriers. • In this group of high-risk men, early screening via prostate-specific antigen testing, rectal examination and prostate biopsy may be prudent to permit the detection and the optimum clinical management of prostate cancer.

Outcomes of a Stroke Response Team on the Emergent Management of Intracerebral Hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage results in high patient mortality or poor functional outcomes. Early access to specialty care allows for rapid implementation of evidence-based strategies that improve the patient's long-term outcomes. OBJECTIVES: The aim of this study was to determine the impact of a dedicated stroke response team on timeliness of blood pressure control, administration of anticoagulation reversal agents, and emergency department arrival to a critical care bed. METHODS: A stroke response team was developed from the neuro intensive care unit that compliments the hospital's current rapid response team. Development of an algorithm guides the implementation of key interventions for intracerebral hemorrhages. Widespread education targeting care of patients with hemorrhagic stroke provided the stroke response team and emergency department staff with knowledge to implement the plan of care. RESULTS: Baseline time interval data were collected on 70 consecutive patients with intracerebral hemorrhage. After implementation of a dedicated stroke response team, time interval data on 70 consecutive patients with intracerebral hemorrhage were collected for comparison with the baseline measurement. A significant decrease was seen in the time to control the patient's systolic blood pressure (median of 130 to 56 minutes, P = .000) and emergency department arrival to a critical care bed (240 to 132 minutes, P = .000). Patient arrival to anticoagulation reversal agent administration decreased from a mean of 98 to 72 minutes (P = .32). DISCUSSION: Implementation of a stroke response team increased the knowledge of the care team, improved the timeliness of blood pressure control, and decreased the time for emergency department arrival to a critical care bed, and to anticoagulation reversal agent administration.

A feasibility study of the Canadian Occupational Performance Measure (COPM) in the burn cohort in an acute tertiary facility.

BACKGROUND: Retrospective auditing identified the need to implement a client centered tool to measure occupational performance and re engagement in activities after burn injury. The Canadian Occupational Performance Measure (COPM) was chosen as it has a broad focus on occupational performance across the lifespan. However, given the time constraints that acute care clinicians work within in a tertiary teaching hospital, a feasibility study was warranted to identify the time to complete the COPM and any potential barriers which may arise in order to evaluate the appropriateness of using this tool. METHODS: This project was a prospective cohort study. All patients presenting to the ward and the Specialist Burns Outpatient Clinic were consecutively enrolled in this study. Information was collected regarding administration of the COPM including administration time, number of interruptions and reasons for non-completion of the outcome measure e.g. wound dressing procedures, surgery, scheduling conflicts. A survey method was used to explore the perceptions of Occupational Therapy clinicians regarding use of the COPM in clinical practice. RESULTS: Over the course of the study period 70 COPM's were administered. The average time for administration across both settings was 9 min. Individually the average time taken for administration of the COPM with inpatients was 11.21 min, in the outpatient setting 7.85 min. The Survey Monkey questionnaire was emailed to 58 occupational therapy clinicians working at the facility associated with the study. The response rate was 41.4% (24). DISCUSSION: Patient reported outcome measures are central to patient centred care which is a core element of health care provision. Results from this study found that the COPM took approximately 9 min to administer, which is suitable within the time constraints of an acute tertiary environment and would be feasible in our setting. Fifty one percent of the participants identified return to work as the activity of daily living most impacted by their burn injury. As burn injuries impact all domains of daily life the use of patient reported outcome measures to direct goal orientated care is imperative. CONCLUSION: This study found that the time to administer the COPM is feasible within the acute tertiary setting. Perceived barriers identified can be overcome with increased knowledge of client centred practice and the importance of goal directed care. The use of patient reported outcome measures in clinical practice empowers consumers to identify what goals they would like to achieve.

Regulation of NKG2D Stress Ligands and Its Relevance in Cancer Progression.

Under cellular distress, multiple facets of normal homeostatic signaling are altered or disrupted. In the context of the immune landscape, external and internal stressors normally promote the expression of natural killer group 2 member D (NKG2D) ligands that allow for the targeted recognition and killing of cells by NKG2D receptor-bearing effector populations. The presence or absence of NKG2D ligands can heavily influence disease progression and impact the accessibility of immunotherapy options. In cancer, tumor cells are known to have distinct regulatory mechanisms for NKG2D ligands that are directly associated with tumor progression and maintenance. Therefore, understanding the regulation of NKG2D ligands in cancer will allow for targeted therapeutic endeavors aimed at exploiting the stress response pathway. In this review, we summarize the current understanding of regulatory mechanisms controlling the induction and repression of NKG2D ligands in cancer. Additionally, we highlight current therapeutic endeavors targeting NKG2D ligand expression and offer our perspective on considerations to further enhance the field of NKG2D ligand biology.

Insights Into Persistent HIV-1 Infection and Functional Cure: Novel Capabilities and Strategies.

Although HIV-1 replication can be efficiently suppressed to undetectable levels in peripheral blood by combination antiretroviral therapy (cART), lifelong medication is still required in people living with HIV (PLWH). Life expectancies have been extended by cART, but age-related comorbidities have increased which are associated with heavy physiological and economic burdens on PLWH. The obstacle to a functional HIV cure can be ascribed to the formation of latent reservoir establishment at the time of acute infection that persists during cART. Recent studies suggest that some HIV reservoirs are established in the early acute stages of HIV infection within multiple immune cells that are gradually shaped by various host and viral mechanisms and may undergo clonal expansion. Early cART initiation has been shown to reduce the reservoir size in HIV-infected individuals. Memory CD4+ T cell subsets are regarded as the predominant cellular compartment of the HIV reservoir, but monocytes and derivative macrophages or dendritic cells also play a role in the persistent virus infection. HIV latency is regulated at multiple molecular levels in transcriptional and post-transcriptional processes. Epigenetic regulation of the proviral promoter can profoundly regulate the viral transcription. In addition, transcriptional elongation, RNA splicing, and nuclear export pathways are also involved in maintaining HIV latency. Although most proviruses contain large internal deletions, some defective proviruses may induce immune activation by expressing viral proteins or producing replication-defective viral-like particles. In this review article, we discuss the state of the art on mechanisms of virus persistence in the periphery and tissue and summarize interdisciplinary approaches toward a functional HIV cure, including novel capabilities and strategies to measure and eliminate the infected reservoirs and induce immune control.

Prioritising enhancements across allied health telehealth services in a metropolitan hospital: Using a concept mapping approach.

INTRODUCTION: A prior study examining perceptions of Allied Health Professions (AHP) telehealth services at a metropolitan hospital highlighted multiple issues impacting service uptake, operationalisation, and delivery. Concept mapping methodology was utilised to address these issues and prioritise actionable telehealth service improvements. METHODS: Representatives (n = 22) from seven AHP departments and consumers generated statements addressing the question: 'What do we need to do to enhance and sustain telehealth services?' Statements were synthesised and then clinicians and managers sorted them into similar groups and assigned each statement a ranking of perceived (a) importance and (b) changeability. Multivariate and multidimensional scaling was undertaken to develop a final prioritised set of goals for change. RESULTS: Ninety-six unique statements were generated as actionable goals for change. Statements were grouped into 13 clusters relating to improvements in staff support, infrastructure, consumer support and organisational processes. All clusters were rated >50% for importance (range 3.3-2.4 out of 4) and changeability (range 2.6-2.1 out of 4). Twenty-six statements were ranked highest for importance and changeability. Key prioritised areas were staff training, consumer advocacy and engagement, telehealth operations and workflow. CONCLUSION: Concept mapping was an effective process for generating a prioritised list of actions to enhance AHP telehealth services.

Targeting Acid Ceramidase Inhibits Glioblastoma Cell Migration through Decreased AKT Signaling.

Glioblastoma (GBM) remains one of the most aggressive cancers, partially due to its ability to migrate into the surrounding brain. The sphingolipid balance, or the balance between ceramides and sphingosine-1-phosphate, contributes to the ability of GBM cells to migrate or invade. Of the ceramidases which hydrolyze ceramides, acid ceramidase (ASAH1) is highly expressed in GBM samples compared to non-tumor brain. ASAH1 expression also correlates with genes associated with migration and focal adhesion. To understand the role of ASAH1 in GBM migration, we utilized shRNA knockdown and observed decreased migration that did not depend upon changes in growth. Next, we inhibited ASAH1 using carmofur, a clinically utilized small molecule inhibitor. Inhibition of ASAH1 by carmofur blocks in vitro migration of U251 (GBM cell line) and GBM cells derived from patient-derived xenografts (PDXs). RNA-sequencing suggested roles for carmofur in MAPK and AKT signaling. We found that carmofur treatment decreases phosphorylation of AKT, but not of MAPK. The decrease in AKT phosphorylation was confirmed by shRNA knockdown of ASAH1. Our findings substantiate ASAH1 inhibition using carmofur as a potential clinically relevant treatment to advance GBM therapeutics, particularly due to its impact on migration.

Coccidioidal Peritonitis: A Review of 17 Cases.

Coccidioidomycosis is the second most common endemic fungal infection in the United States. Prior descriptions of coccidioidal peritonitis include only single cases. We describe 17 new cases previously unreported from healthcare institutions in California. The majority of cases presented with nonspecific abdominal complaints. PubMed and Google Scholar were searched for additional case series and only single case reports and reviews of single cases were found. The diagnosis was confirmed by culture or histopathology and/or serology in each patient. All patients were treated with anti-fungal therapy. This case series demonstrates that coccidioidal peritonitis may be asymptomatic or present with only subtle abdominal symptoms. In a minority of our patients, the diagnosis was established incidentally during surgery. Based on this series, the overall outcome of coccidioidal peritonitis is favorable with long-term triazole treatment. The term cure is not usually used in disseminated coccidioidal disease because of the risk of late relapse.

Understanding the origins of time-dependent inhibition by polypeptide deformylase inhibitors.

The continual bacterial adaptation to antibiotics creates an ongoing medical need for the development of novel therapeutics. Polypeptide deformylase (PDF) is a highly conserved bacterial enzyme, which is essential for viability. It has previously been shown that PDF inhibitors represent a promising new area for the development of antimicrobial agents, and that many of the best PDF inhibitors demonstrate slow, time-dependent binding. To improve our understanding of the mechanistic origin of this time-dependent inhibition, we examined in detail the kinetics of PDF catalysis and inhibition by several different PDF inhibitors. Varying pH and solvent isotope led to clear changes in time-dependent inhibition parameters, as did inclusion of NaCl, which binds to the active site metal of PDF. Quantitative analysis of these results demonstrated that the observed time dependence arises from slow binding of the inhibitors to the active site metal. However, we also found several metal binding inhibitors that exhibited rapid, non-time-dependent onset of inhibition. By a combination of structural and chemical modification studies, we show that metal binding is only slow when the rest of the inhibitor makes optimal hydrogen bonds within the subsites of PDF. Both of these interactions between the inhibitor and enzyme were found to be necessary to observe time-dependent inhibition, as elimination of either leads to its loss.