Gradients of response latencies and temporal precision of auditory neurons extend across the whole inferior colliculus.

Neural responses to acoustic stimulation have long been studied throughout the auditory system to understand how sound information is coded for perception. Within the inferior colliculus (IC), a majority of the studies have focused predominantly on characterizing neural responses within the central region (ICC), as it is viewed as part of the lemniscal system mainly responsible for auditory perception. In contrast, the responses of outer cortices (ICO) have largely been unexplored, though they also function in auditory perception tasks. Therefore, we sought to expand on previous work by completing a three-dimensional (3-D) functional mapping study of the whole IC. We analyzed responses to different pure tone and broadband noise stimuli across all IC subregions and correlated those responses with over 2,000 recording locations across the IC. Our study revealed there are well-organized trends for temporal response parameters across the full IC that do not show a clear distinction at the ICC and ICO border. These gradients span from slow, imprecise responses in the caudal-medial IC to fast, precise responses in the rostral-lateral IC, regardless of subregion, including the fastest responses located in the ICO. These trends were consistent at various acoustic stimulation levels. Weaker spatial trends could be found for response duration and spontaneous activity. Apart from tonotopic organization, spatial trends were not apparent for spectral response properties. Overall, these detailed acoustic response maps across the whole IC provide new insights into the organization and function of the IC.NEW & NOTEWORTHY Study of the inferior colliculus (IC) has largely focused on the central nucleus, with little exploration of the outer cortices. Here, we systematically assessed the acoustic response properties from over 2,000 locations in different subregions of the IC. The results revealed spatial trends in temporal response patterns that span all subregions. Furthermore, two populations of temporal response types emerged for neurons in the outer cortices that may contribute to their functional roles in auditory tasks.

Visual observation of extraction of a Micra leadless pacemaker from a human cadaver.

INTRODUCTION: In this article we present the extraction of a Micra from a human cadaver implanted 3 years previously with both visual and X-ray imaging taken during the removal. METHODS: A Micra pacemaker was extracted from a human cadaver with endoscopy and fluoroscopy using a Micra delivery tool. Histological analysis was performed on slices from the tissue surrounding the Micra. RESULTS: The fully encapsulated Micra was easily retrieved with a maximum force of 1.9 pounds. CONCLUSIONS: Even though the Micra was implanted almost 3 years previously, the snaring and extraction of the Micra was performed relatively easily and with minimal force required.

Glucagon therapy in canines with an insulinoma: A retrospective descriptive study of 11 dogs.

Canine insulinomas are uncommon neoplasms, which often result in refractory hypoglycemia. Glucagon is one readily available treatment for insulin-induced hypoglycemia. The primary objective of this study was to evaluate blood glucose trends and outcome (survival to discharge versus death or euthanasia) for dogs with insulinoma that were treated with glucagon. Secondary objectives included the description and influence of other variables such as abnormalities on diagnostic tests, physical examination abnormalities, concurrent administration of dextrose and/or glucocorticoids, and seizures. The median glucagon constant rate infusion dose was significantly higher for the non-survivors than for survivors. No other correlation was found between any of the independent variables evaluated when comparing blood glucose trends, length of hospitalization, and outcome. The main conclusion of the study is that glucagon therapy in insulinomas is an effective treatment to manage hypoglycemia.

Thérapie au glucagon de chiens avec un insulinome: étude rétrospective descriptive de 11 chiens. Les insulinomes canins sont des néoplasmes peu fréquents, qui résultent souvent en hypoglycémie réfractaire. Le glucagon est un traitement facilement disponible pour l'hypoglycémie induite par l'insuline. L'objectif primaire de la présente étude était d'évaluer les tendances du glucose sanguin et l'issu (survie jusqu'au congé versus décès ou euthanasie) de chiens avec insulinome qui furent traités avec du glucagon. Les objectifs secondaires incluaient la description et l'influence d'autres variables telles que des anomalies lors des tests diagnostiques et des examens physiques, l'administration concomitante de dextrose et/ou de glucocorticoïdes, et des convulsions. La dose médiane de perfusion à taux constant de glucagon était significativement plus élevée pour les non-survivants que pour les survivants. Aucune autre corrélation ne fut trouvée entre l'une ou l'autre des variables indépendantes évaluées lors de comparaisons avec les tendances du glucose sanguin, la durée de l'hospitalisation, et l'issu. La principale conclusion de cette étude est que la thérapie au glucagon lors d'insulinomes est un traitement efficace pour gérer l'hypoglycémie.(Traduit par Dr Serge Messier).

A Framework for Evaluating Vendor Procurement in a Digital Health Project.

The eHealth Centre of Excellence, a Waterloo, Ontario-based organization that advances and promotes digital health initiatives in clinical care, developed and assessed an innovative evaluation procurement framework. The purpose of the framework was to assess and support long-term vendor-organization procurement partnerships to develop, improve and expand electronic referral (eReferral) solutions. The framework focused on six criteria: the quality of the eReferral solution, its implementation, the service provided, the extent of training and knowledge transfer, the quality of the vendor's team and the vendor's project experience. These domains were further defined by components and key performance indicators unique to the eReferral solution to accommodate the stakeholders' specified needs as well as change management challenges to create value for users and organizations in long-term relationships. The evaluation used both qualitative and quantitative methodologies. The framework used data from three sources: (1) the System Coordinated Access program and vendor team experience surveys that focused on the six criteria mentioned earlier; (2) key stakeholder interviews that focused on system quality, user satisfaction and perception of net benefits; and (3) a vendor scorecard that focused on deliverables and efficiencies. Vendor procurement should be viewed not as a process that ends when a vendor is selected but rather as a continuing and evolving relationship. Evaluation should assess the ability and willingness of vendors to support stakeholders and meet their needs, stimulate new ideas and adapt to changing environments and expanding systems. The model enabled recording of factors necessary for successful outcomes and provided a strategy to help select vendors for successful long-term partnerships.

The experiences of medical students with ADHD: A phenomenological study.

Attention Deficit/Hyperactivity 'Disorder' (ADHD) is a form of neurodivergence, characterised by lifelong differences in attention, impulsivity, and hyperactivity. University students with ADHD underachieve academically and tend to have lower levels of self-esteem. Medical schools have an obligation to minimise barriers for students with ADHD. Understanding the experiences of medical students with ADHD is vital to promote inclusive approaches. Our exploratory research question was: "What are the experiences of medical students with ADHD?" This was an interpretive phenomenological study. Loosely structured interviews were conducted with participants (medical students with ADHD) over Zoom. Subsequent transcripts were analysed using interpretive phenomenological analysis. Six people participated. Our analysis identified the following themes: Identity and diagnosis; ADHD profile; system issues; conflict, competition and compensation; improving the experience. Participants reported experiences of bullying and isolation at medical school, perpetrated by doctors and peers, as well as feelings of alienation when unable to conform on placement and in exams. From this, participants adopted survival strategies, such as masking, to avoid being ostracised. All recognised their ADHD status when their mental health deteriorated during their medical studies. Of those who disclosed their diagnosis, none were offered personalised support. Participants feared disclosure, largely due to weaponised professionalism and the effects of toxic competitiveness in medicine. They yearned for a sense of belonging. Participants reported strengths associated with ADHD such as empathy and working well under pressure, which are highly desirable aptitudes for doctors. This study has highlighted areas where medical schools can be instrumental in cultivating an environment where medical students with ADHD can thrive, not just survive. This may take the form of peer support groups, alongside reasonable adjustments throughout medical school-particularly for Objective Structured Clinical Examinations, for example. Enabling these students to thrive may help to prevent early burnout and subsequent attrition from medicine.

Quantifying Cardiothoracic Variation with Posture and Respiration to Inform Cardiac Device Design.

PURPOSE: With extravascular implantable cardioverter defibrillator leads placed beneath the sternum, it is important to quantify heart motion relative to the rib cage with postural changes and respiration. METHODS: MRI scans from five males and five females were collected in upright and supine postures at end inspiration [n = 10 each]. Left and right decubitus [n = 8 each] and prone [n = 5] MRIs at end inspiration and supine MRIs at end expiration [n = 5] were collected on a subset. Four cardiothoracic measurements, six cardiac measurements, and six cardiac landmarks were collected to measure changes across different postures and stages of respiration. RESULTS: The relative location of the LV apex to the nearest intercostal space was significantly different between the supine and decubitus postures (average ± SD difference: - 15.7 ± 11.4 mm; p < 0.05). The heart centroid to xipho-sternal junction distance was 9.7 ± 7.9 mm greater in the supine posture when compared to the upright posture (p < 0.05). Cardiac landmark motion in the lateral direction was largest due to postural movement (range 23-50 mm) from the left decubitus to the right decubitus posture, and less influenced by respiration (5-17 mm). Caudal-cranial displacement was generally larger due to upright posture (13-23 mm caudal) and inspiration (7-20 mm cranial). CONCLUSIONS: This study demonstrates that the location of the heart with respect to the rib cage varies with posture and respiration. The gravitational effects of postural shifts on the heart position are roughly 2-3 times larger than the effects of normal respiration.

Development and application of loop-mediated isothermal amplification assays on rapid detection of various types of staphylococci strains.

A loop-mediated isothermal amplification (LAMP) method for rapid detection of various Staphylococcus strains and associated antibiotic resistance determinant had been developed and evaluated in this study. Six primers, including outer primers, inner primers and loop primers, were specially designed for recognizing eight distinct sequences on three targets: 16SrRNA, femA and mecA.. Forty-one reference strains, including various species of gram-negative and -positive isolates, were included in this study to evaluate and optimize LAMP assays. The optimal reaction condition was found to be 65 °C for 45 min, with detection limits at 100 fg DNA/tube and 10 CFU/reaction for 16S rRNA, 100 fg DNA/tube and 10 CFU/reaction for femA, 1 pg DNA/tube and 100 CFU/reaction for mecA, respectively. Application of LAMP assays were performed on 118 various types of Staphylococcus isolates, the detection rate of LAMP assays for the 16SrRNA, femA and mecA was 100% (118/118), 98.5% (64/65) and 94.3% (66/70), and the negative predictive value (NPV) was 100%, 98.1% and 92.3% respectively; with a 100% positive predictive value (PPV) for all three targets. In conclusion, LAMP assays were demonstrated to be useful and powerful tools for rapid detection of various Staphylococcus strains, and undoubtedly, the rapidness, technical simplicity, and cost-effectiveness of LAMP assays will demonstrate broad application for bacteriological detection of food-borne Methicillin-resistant Staphylococcus (MRS) isolates.

Allogeneic Hematopoietic Stem Cell Transplant for Acute Lymphoblastic Leukemia in a Pediatric Patient After COVID-19 Infection Complicated by MIS-C.

The COVID-19 pandemic has impacted the care of countless individuals, including pediatric oncology patients. The initial lack of knowledge about the disease course and implications of infection led to delays in treatment to minimize additional harm. In pediatric oncology, unnecessary delays in chemotherapy or hematopoietic stem cell transplantation may increase the risk of disease relapse. This case report describes one high-risk pediatric oncology patient's clinical course through hematopoietic stem cell transplantation immediately following COVID-19 infection complicated by multisystem inflammatory syndrome in children. The disease course, monitoring, long-term outcome, and recommendations for future research are reviewed.

Faculty, Preceptor, and Students' Perceptions of the Need for Trauma-Informed Education: Recommendations for Implementation.

BACKGROUND: The widespread physical, mental, and emotional health impacts of trauma are well established. Trauma-informed care (TIC) is an approach that uses knowledge about trauma and its effects to create safe care environments. PURPOSE: Using a concurrent mixed-methods design, this study assessed faculty, preceptor, and students' perceptions about the need for TIC content in nursing education. METHODS: Semistructured interviews were conducted with 15 faculty, and cross-sectional survey data were collected from a nonprobability sample of 99 nursing students at a large Midwestern university to evaluate the need for education on TIC. RESULTS: Faculty and preceptors stressed the importance of education on TIC and discussed barriers and facilitators to implementation. Nursing students reported that it is important to learn about TIC, yet do not feel prepared to provide TIC. CONCLUSIONS: The results illustrate the need for nursing content on TIC and provide recommendations for trauma-informed educational practices.

COVID-19 vaccination intention and behavior in a large, diverse, U.S. refugee population.

INTRODUCTION: Refugees often face increased risk of exposure to COVID-19 due to their disproportionate representation in the essential workforce and crowded household conditions. There is a paucity of data about risk factors for under-immunization for COVID-19 among refugees. METHODS: Refugees were surveyed in two phases that corresponded to before and after wide availability of COVID-19 vaccines. Participants were asked about their attitudes, and perceptions about COVID-19, previous acceptance of vaccines, sources utilized to obtain trusted health information, and intent to get vaccinated. The overall participant vulnerability was assessed using the social vulnerability index. In-depth semi-structured interviews were completed with key stakeholders through snowball sampling. RESULTS: Of 247 refugees, 244 agreed to participate in the initial survey. Among those, 140 (57.4%) intended to get vaccinated, 43 (17.6%) were unsure, and 61 (25%) did not intend to get vaccinated. In the follow up survey, all 215 who were reached, agreed to provide information about their vaccination status. Among those respondents, 141 (65.6%) were either vaccinated or expressed intent to do so, and 74 (34.4%) remained hesitant. We did not observe any significant correlation between socio-demographic variables, country of origin, and vaccination status/intent. Among those who initially intended to get vaccinated, nearly 1 in 5 changed their mind and decided to forego vaccination, and among those who initially did not plan getting vaccinated, 1 in 3 changed their mind and got vaccinated. Fears related to the vaccine, concerns that the vaccine is religiously prohibited, "wait and see" how others did with the vaccine, communication and transportation barriers were commonly cited as reason not to get vaccinated. CONCLUSIONS: Over a third of refugees in our study were hesitant to get vaccinated. Refugees desired additional education about the benefits and safety of vaccines along with easier access to vaccination clinics in their communities.

Murine immune response to a chronic Staphylococcus aureus biofilm infection.

Staphylococcus aureus has reemerged as an important human pathogen in recent decades. Although many infections caused by this microbial species persist through a biofilm mode of growth, little is known about how the host's adaptive immune system responds to these biofilm infections. In this study, S. aureus cells adhered to pins in culture and were subsequently inserted into the tibiae of C57BL/6 mice, with an infecting dose of 2 × 105 CFU. This model was utilized to determine local cytokine levels, antibody (Ab) function, and T cell populations at multiple time points throughout infection. Like human hosts, S. aureus implant infection was chronic and remained localized in 100% of C57BL/6 mice at a consistent level of approximately 10(7) CFU/gram bone tissue after day 7. This infection persisted locally for >49 days and was recalcitrant to clearance by the host immune response and antimicrobial therapy. Local inflammatory cytokines of the Th1 (interleukin-2 [IL-2], IL-12 p70, tumor necrosis factor alpha [TNF-α], and IL-1ß) and Th17 (IL-6 and IL-17) responses were upregulated throughout the infection, except IL-12 p70, which dwindled late in the infection. In addition, Th1 Ab subtypes against a biofilm antigen (SA0486) were upregulated early in the infection, while Th2 Abs and anti-inflammatory regulatory T cells (Tregs) were not upregulated until later. These results indicate that early Th1 and Th17 inflammatory responses and downregulated Th2 and Treg responses occur during the development of a chronic biofilm implant infection. This unrestrained inflammatory response may cause tissue damage, thereby enabling S. aureus to attach and thrive in a biofilm mode of growth.

Integrated Care Management to Improve Diabetes Outcomes in Refugee and Immigrant Patients (I-Care).

Purpose: Refugee and immigrant patients face significant barriers to health care and are more likely to have poorly controlled chronic disease than the general U.S. population. I-Care aims to improve health equity for refugees and immigrants who face a disproportionate burden of chronic disease. Methods: Refugees and immigrants with uncontrolled diabetes and associated cardiovascular risk factors were enrolled in a care management program within an academic adult medicine clinic. The program utilized a care manager to coordinate care and services between designated primary care providers, affiliated clinical teams, and community partners. Health literacy, chronic disease parameters, and care utilization were assessed at enrollment and 8-12 months later. Results: A total of 50 refugees and immigrants were followed for 8 to 12 months. Clinical parameters found a reduced mean HbA1c from 9.32 to 8.60 (p=0.05) and reduced low-density lipoprotein mean from 96.22 to 86.60 (p=0.01). The frequency of normal blood pressures was 9 (18%) at enrollment and 16 (32%) at 1 year. The cumulative frequency of emergency room visits decreased from 66% to 36% and hospitalizations from 22% to 8%. Rates of comprehensive care monitoring, including monofilament testing and one-time ophthalmology visits, increased from 60% to 82% and from 32% to 42%, respectively. Cumulative frequency of interdisciplinary support engagement with pharmacy and nutrition visits increased from 58% to 78% and from 26% to 38%, respectively. Conclusion: This program highlights the importance of a multidisciplinary community-engaged care model that has demonstrated improvement in quality metrics and health care costs for refugees and immigrants.

Imaging-Based Localization of His Bundle Pacing Electrodes: Results From the Prospective IMAGE-HBP Study.

OBJECTIVES: This study sought to evaluate the correlation between His bundle (HB) pacing (HBP) implantation characteristics, lead-tip location, and association of intraprocedural His recordings with approximated HB anatomic landmarks using computed tomography (CT) imaging. BACKGROUND: HBP continues to grow in clinical practice due to offering true physiological pacing. However, a clear understanding of HB anatomy and the lead-tip location's influence on pacing characteristics is lacking. METHODS: The IMAGE-HBP study (Imaging Study of Lead Implant for His Bundle Pacing) was a prospective, multicenter study designed to assess implantation characteristics of the SelectSecure Model 3830 lead placed at the HB, evaluate protocol-specified HBP success (His recording present on electrogram and HBP threshold ≤2.5 V at 1 ms), and correlation between lead-tip location by CT imaging and HBP characteristics as well as lead-related complications through 12 months. RESULTS: Sixty-nine patients underwent a lead implantation attempt at the HB. Of these, 61 patients (88%) had a lead successfully implanted at the HB, and 52 patients (75%) met the pre-specified definition of successful HBP. In 51 patients with CT imaging, 11 leads (22%) were placed in the atrial aspect of the HB region (36% selective HBP), and 40 leads (78%) were placed in the ventricular aspect (28% selective HBP). Four of the 51 patients had P-wave oversensing, all with leads in the atrium. Freedom from lead-related complication at 12 months was 93%. CONCLUSIONS: Successful HBP could be achieved at lead-tip locations in the atrium or ventricle but is preferable in the ventricle to eliminate risk of oversensing. The IMAGE-HBP study offers better insight into approximated HB anatomic landmarks, lead-tip location, and correlation with pacing characteristics. (Imaging Study of Lead Implant for His Bundle Pacing [IMAGE-HBP]; NCT03294317).

The Seniors Health Research Transfer Network Knowledge Network Model: system-wide implementation for health and healthcare of seniors.

The Ontario Seniors Health Research Transfer Network (SHRTN) aims to improve the health of older adults through increasing the knowledge capacity of 850 community care agencies and 620 long-term care homes. The SHRTN includes caregivers, researchers, policy makers, administrators, educators, and organizations. The SHRTN comprises communities of practice, a library service, a network of 7 research institutes, and local implementation teams. The SHRTN combines face-to-face meetings with information technology to promote change at the client care level in organizational and provincial policies and in the promotion of health services research.

Severity Index for Suspected Arbovirus (SISA): Machine learning for accurate prediction of hospitalization in subjects suspected of arboviral infection.

BACKGROUND: Dengue, chikungunya, and Zika are arboviruses of major global health concern. Decisions regarding the clinical management of suspected arboviral infection are challenging in resource-limited settings, particularly when deciding on patient hospitalization. The objective of this study was to determine if hospitalization of individuals with suspected arboviral infections could be predicted using subject intake data. METHODOLOGY/PRINCIPAL FINDINGS: Two prediction models were developed using data from a surveillance study in Machala, a city in southern coastal Ecuador with a high burden of arboviral infections. Data were obtained from subjects who presented at sentinel medical centers with suspected arboviral infection (November 2013 to September 2017). The first prediction model-called the Severity Index for Suspected Arbovirus (SISA)-used only demographic and symptom data. The second prediction model-called the Severity Index for Suspected Arbovirus with Laboratory (SISAL)-incorporated laboratory data. These models were selected by comparing the prediction ability of seven machine learning algorithms; the area under the receiver operating characteristic curve from the prediction of a test dataset was used to select the final algorithm for each model. After eliminating those with missing data, the SISA dataset had 534 subjects, and the SISAL dataset had 98 subjects. For SISA, the best prediction algorithm was the generalized boosting model, with an AUC of 0.91. For SISAL, the best prediction algorithm was the elastic net with an AUC of 0.94. A sensitivity analysis revealed that SISA and SISAL are not directly comparable to one another. CONCLUSIONS/SIGNIFICANCE: Both SISA and SISAL were able to predict arbovirus hospitalization with a high degree of accuracy in our dataset. These algorithms will need to be tested and validated on new data from future patients. Machine learning is a powerful prediction tool and provides an excellent option for new management tools and clinical assessment of arboviral infection.

Distinct insulin granule subpopulations implicated in the secretory pathology of diabetes types 1 and 2.

Insulin secretion from ß-cells is reduced at the onset of type-1 and during type-2 diabetes. Although inflammation and metabolic dysfunction of ß-cells elicit secretory defects associated with type-1 or type-2 diabetes, accompanying changes to insulin granules have not been established. To address this, we performed detailed functional analyses of insulin granules purified from cells subjected to model treatments that mimic type-1 and type-2 diabetic conditions and discovered striking shifts in calcium affinities and fusion characteristics. We show that this behavior is correlated with two subpopulations of insulin granules whose relative abundance is differentially shifted depending on diabetic model condition. The two types of granules have different release characteristics, distinct lipid and protein compositions, and package different secretory contents alongside insulin. This complexity of ß-cell secretory physiology establishes a direct link between granule subpopulation and type of diabetes and leads to a revised model of secretory changes in the diabetogenic process.

Diabetes is a disease that occurs when sugar levels in the blood can no longer be controlled by a hormone called insulin. People with type 1 diabetes lose the ability to produce insulin after their immune system attacks the ß-cells in their pancreas that make this hormone. People with type 2 diabetes develop the disease when ß-cells become exhausted from increased insulin demand and stop producing insulin. ß-cells store insulin in small compartments called granules. When blood sugar levels rise, these granules fuse with the cell membrane allowing ß-cells to release large quantities of insulin at once. This fusion is disrupted early in type 1 diabetes, but later in type 2: the underlying causes of these disruptions are unclear. In the laboratory, signals that trigger inflammation and molecules called fatty acids can mimic type 1 or type 2 diabetes respectively when applied to insulin-producing cells. Kreutzberger, Kiessling et al. wanted to know whether pro-inflammatory molecules and fatty acids affect insulin granules differently at the molecular level. To do this, insulin-producing cells were grown in the lab and treated with either fatty acids or pro-inflammatory molecules. The insulin granules of these cells were then isolated. Next, the composition of the granules and how they fused to lab-made membranes that mimic the cell membrane was examined. The experiments revealed that healthy ß-cells have two types of granules, each with a different version of a protein called synaptotagmin. Cells treated with molecules mimicking type 1 diabetes lost granules with synaptotagmin-7, while granules with synaptotagmin-9 were lost in cells treated with fatty acids to imitate type 2 diabetes. Each type of granule responded differently to calcium levels in the cell and secreted different molecules, indicating that each elicits a different diabetic response in the body. These findings suggest that understanding how insulin granules are formed and regulated may help find treatments for type 1 and 2 diabetes, possibly leading to therapies that reverse the loss of different types of granules. Additionally, the molecules of these granules may also be used as markers to determine the stage of diabetes. More broadly, these results show how understanding how molecule release changes with disease in different cell types may help diagnose or stage a disease.

Farnesol-induced apoptosis in Candida albicans.

Farnesol, a precursor in the isoprenoid/sterol pathway, was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. Farnesol is involved in the inhibition of germination and biofilm formation by C. albicans and can be cytotoxic at certain concentrations. In addition, we have shown that farnesol can trigger apoptosis in mammalian cells via the classical apoptotic pathways. In order to elucidate the mechanism behind farnesol cytotoxicity in C. albicans, the response to farnesol was investigated, using proteomic analysis. Global protein expression profiles demonstrated significant changes in protein expression resulting from farnesol exposure. Among the downregulated proteins were those involved in metabolism, glycolysis, protein synthesis, and mitochondrial electron transport and the respiratory chain, whereas proteins involved in folding, protection against environmental and oxidative stress, actin cytoskeleton reorganization, and apoptosis were upregulated. Cellular changes that accompany apoptosis (regulated cell death) were further analyzed using fluorescent microscopy and gene expression analysis. The results indicated reactive oxygen species accumulation, mitochondrial degradation, and positive terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) in the farnesol-exposed cells concurrent with increased expression of antioxidant-encoding and drug response genes. More importantly, the results demonstrated farnesol-induced upregulation of the caspase gene MCA1 and the intracellular presence of activated caspases. In conclusion, this study demonstrated that farnesol promotes apoptosis in C. albicans through caspase activation, implying an important physiological role for farnesol in the fungal cell life cycle with important implications for adaptation and survival.

Sitagliptin and Simvastatin Interaction Causing Rhabdomyolysis and AKI.

We report a case of rhabdomyolysis and severe acute kidney injury (AKI) requiring dialysis in a 69-year-old male who was recently started on sitagliptin while on chronic simvastatin therapy. This potential interaction is not included in the package insert for sitagliptin. A comprehensive literature review revealed six previous reports of rhabdomyolysis due to drug interaction between sitagliptin and statins including simvastatin, lovastatin, and atorvastatin. Of these six cases, only two had developed rhabdomyolysis-associated AKI, none of which were severe enough to require dialysis. As patients are commonly prescribed statins and sitagliptin for treatment of dyslipidemia and diabetes, health care professionals should be aware of this potential drug interaction and closely monitor their patients for signs and symptoms of rhabdomyolysis and AKI. This case highlights the importance of conducting further studies on the risk of muscular toxicity of sitagliptin especially when administered concurrently with statins.

Reinterpretation of the localization of the ATP binding cassette transporter ABCG1 in insulin-secreting cells and insights regarding its trafficking and function.

The ABC transporter ABCG1 contributes to the regulation of cholesterol efflux from cells and to the distribution of cholesterol within cells. We showed previously that ABCG1 deficiency inhibits insulin secretion by pancreatic beta cells and, based on its immunolocalization to insulin granules, proposed its essential role in forming granule membranes that are enriched in cholesterol. While we confirm elsewhere that ABCG1, alongside ABCA1 and oxysterol binding protein OSBP, supports insulin granule formation, the aim here is to clarify the localization of ABCG1 within insulin-secreting cells and to provide added insight regarding ABCG1's trafficking and sites of function. We show that stably expressed GFP-tagged ABCG1 closely mimics the distribution of endogenous ABCG1 in pancreatic INS1 cells and accumulates in the trans-Golgi network (TGN), endosomal recycling compartment (ERC) and on the cell surface but not on insulin granules, early or late endosomes. Notably, ABCG1 is short-lived, and proteasomal and lysosomal inhibitors both decrease its degradation. Following blockade of protein synthesis, GFP-tagged ABCG1 first disappears from the ER and TGN and later from the ERC and plasma membrane. In addition to aiding granule formation, our findings raise the prospect that ABCG1 may act beyond the TGN to regulate activities involving the endocytic pathway, especially as the amount of transferrin receptor is increased in ABCG1-deficient cells. Thus, ABCG1 may function at multiple intracellular sites and the plasma membrane as a roving sensor and modulator of cholesterol distribution, membrane trafficking and cholesterol efflux.

Control of insulin granule formation and function by the ABC transporters ABCG1 and ABCA1 and by oxysterol binding protein OSBP.

In pancreatic ß-cells, insulin granule membranes are enriched in cholesterol and are both recycled and newly generated. Cholesterol's role in supporting granule membrane formation and function is poorly understood. ATP binding cassette transporters ABCG1 and ABCA1 regulate intracellular cholesterol and are important for insulin secretion. RNAi inter-ference-induced depletion in cultured pancreatic ß-cells shows that ABCG1 is needed to stabilize newly made insulin granules against lysosomal degradation; ABCA1 is also involved but to a lesser extent. Both transporters are also required for optimum glucose-stimulated insulin secretion, likely via complementary roles. Exogenous cholesterol addition rescues knockdown-induced granule loss (ABCG1) and reduced secretion (both transporters). Another cholesterol transport protein, oxysterol binding protein (OSBP), appears to act proximally as a source of endogenous cholesterol for granule formation. Its knockdown caused similar defective stability of young granules and glucose-stimulated insulin secretion, neither of which were rescued with exogenous cholesterol. Dual knockdowns of OSBP and ABC transporters support their serial function in supplying and concentrating cholesterol for granule formation. OSBP knockdown also decreased proinsulin synthesis consistent with a proximal endoplasmic reticulum defect. Thus, membrane cholesterol distribution contributes to insulin homeostasis at production, packaging, and export levels through the actions of OSBP and ABCs G1 and A1.