Reaching underserved South Africans with integrated chronic disease screening and mobile HIV counselling and testing: A retrospective, longitudinal study conducted in Cape Town.

BACKGROUND: Community-based, mobile HIV counselling and testing (HCT) and screening for non-communicable diseases (NCDs) may improve early diagnosis and referral for care in underserved populations. We evaluated HCT/NCD data and described population characteristics of those visiting a mobile clinic in high HIV disease burden settings in Cape Town, South Africa, between 2008 and 2016. METHODS: Trained counsellors registered patients ≥12 years old at a mobile clinic, which offered HCT and blood pressure, diabetes (glucose testing) and obesity (body mass index) screening. A nurse referred patients who required HIV treatment or NCD care. Using multivariable logistic regression, we estimated correlates of new HIV diagnoses adjusting for gender, age and year. RESULTS: Overall, 43,938 individuals (50% male; 29% <25 years; median age = 31 years) tested for HIV at the mobile clinic, where 27% of patients (66% of males, 34% of females) reported being debut HIV testers. Males not previously tested for HIV had higher rates of HIV positivity (11%) than females (7%). Over half (55%, n = 1,343) of those previously diagnosed HIV-positive had not initiated ART. More than one-quarter (26%) of patients screened positive for hypertension (males 28%, females 24%, p<0.001). Females were more likely overweight (25% vs 20%) or obese (43% vs 9%) and presented with more diabetes symptoms than males (8% vs 4%). Females (3%) reported more symptoms of STIs than males (1%). Reporting symptoms of sexually transmitted infections (aOR = 3.45, 95% CI = 2.84, 4.20), diabetes symptoms (aOR = 1.61, 95% 1.35, 1.92), and TB symptoms (aOR = 4.40, 95% CI = 3.85, 5.01) were associated with higher odds of a new HIV diagnosis after adjusting for covariates. CONCLUSION: Findings demonstrate that mobile clinics providing integrated HCT and NCD screening may offer the opportunity of early diagnosis and referral for care for those who delay screening, including men living with HIV not previously tested.

Selenium-dependent metabolic reprogramming during inflammation and resolution.

Trace element selenium (Se) is incorporated as the 21st amino acid, selenocysteine, into selenoproteins through tRNA[Ser]Sec. Selenoproteins act as gatekeepers of redox homeostasis and modulate immune function to effect anti-inflammation and resolution. However, mechanistic underpinnings involving metabolic reprogramming during inflammation and resolution remain poorly understood. Bacterial endotoxin lipopolysaccharide (LPS) activation of murine bone marrow-derived macrophages cultured in the presence or absence of Se (as selenite) was used to examine temporal changes in the proteome and metabolome by multiplexed tandem mass tag-quantitative proteomics, metabolomics, and machine-learning approaches. Kinetic deltagram and clustering analysis indicated that addition of Se led to extensive reprogramming of cellular metabolism upon stimulation with LPS enhancing the pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation, to aid in the phenotypic transition toward alternatively activated macrophages, synonymous with resolution of inflammation. Remodeling of metabolic pathways and consequent metabolic adaptation toward proresolving phenotypes began with Se treatment at 0 h and became most prominent around 8 h after LPS stimulation that included succinate dehydrogenase complex, pyruvate kinase, and sedoheptulokinase. Se-dependent modulation of these pathways predisposed bone marrow-derived macrophages to preferentially increase oxidative phosphorylation to efficiently regulate inflammation and its timely resolution. The use of macrophages lacking selenoproteins indicated that all three metabolic nodes were sensitive to selenoproteome expression. Furthermore, inhibition of succinate dehydrogenase complex with dimethylmalonate affected the proresolving effects of Se by increasing the resolution interval in a murine peritonitis model. In summary, our studies provide novel insights into the role of cellular Se via metabolic reprograming to facilitate anti-inflammation and proresolution.

Comparative effectiveness of ustekinumab or vedolizumab after one year in 130 patients with anti-TNF-refractory Crohn's disease.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in Crohn's disease but some patients lose response and require alternative biologic therapy. There are few data on comparative effectiveness of vedolizumab and ustekinumab in this setting. AIM: To compare the effectiveness of ustekinumab and vedolizumab in anti-TNF-refractory Crohn's disease over 12 months. METHODS: Patients commencing ustekinumab or vedolizumab for anti-TNF-refractory Crohn's disease with minimum follow-up of 12 months were included. The primary outcome measure was the difference in steroid-free remission rates at end of induction (2 months) and at 12 months. We also assessed rates of clinical response and remission, treatment persistence, surgery and adverse events in both groups. We performed logistic regression analysis to assess factors associated with steroid-free remission and clinical response and remission. RESULTS: We included 85 patients commencing vedolizumab and 45 commencing ustekinumab. In an unadjusted model, rates of steroid-free and clinical remission were significantly higher among ustekinumab-treated patients. After adjusting for confounders, steroid-free remission was higher among ustekinumab-treated patients at 2 months (odds ratio, OR 2.79, 95% confidence interval, CI 1.06-7.39, P = 0.038) and 12 months (OR 2.01, 95% CI 0.89-4.56, P = 0.095). More patients treated with ustekinumab remained on therapy at the end of 12 months (84.4% vs 61.5%, P = 0.007). CONCLUSIONS: Ustekinumab appeared more effective in treating anti-TNF-refractory Crohn's disease and more patients persisted with therapy.

British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

Isolation and Identification of Aryl Hydrocarbon Receptor Modulators in White Button Mushrooms (Agaricus bisporus).

Natural aryl hydrocarbon (AHR) ligands have been identified in food and herbal medicines, and they may exhibit beneficial activity in humans. In this study, white button (WB) feeding significantly decreased AHR target gene expression in the small intestine of both conventional and germ-free mice. High-performance liquid chromatography (HPLC) fractionation and ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) combined with an AHR-responsive cell-based luciferase gene reporter assay were used to isolate and characterize benzothiazole (BT) derivatives and 6-methylisoquinoline (6-MIQ) as AHR modulators from WB mushrooms. The study showed dose-dependent changes of AHR transformation determined by the cell-based luciferase gene reporter assay and transcription of CYP1A1 in human Caco-2 cells by BT derivatives and 6-MIQ. These findings suggested that WB mushroom contains new classes of natural AHR modulators and demonstrated HPLC fractionation and UHPLC-MS/MS combined with a cell-based luciferase gene reporter assay as a useful approach for isolation and characterization of the previously unidentifed AHR modulators from natural products.

Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ2 = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Principal cells of the brainstem's interaural sound level detector are temporal differentiators rather than integrators.

The brainstem's lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating 'chopper' responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit.

Gender differences in the real-world effectiveness of smoking cessation medications: Findings from the 2010-2011 Tobacco Use Supplement to the Current Population Survey.

BACKGROUND: Meta-analyses of clinical trial data have identified clinically relevant gender differences in the efficacy of smoking cessation pharmacotherapy. It is unclear whether these findings are generalizable to smokers quitting in real-world contexts. METHODS: Using Tobacco Use Supplement to the Current Population Survey (TUS-CPS) 2010-2011 cross-sectional data, we generated propensity score matched samples of smokers who quit either unassisted by medication, using only varenicline, or using only transdermal nicotine patch (TNP). We used generalized estimating equations to estimate gender differences in the comparative effectiveness of these cessation options for achieving 30-days of abstinence, adjusting for potential confounders. RESULTS: When stratified by gender, TNP was significantly more effective than unassisted quit attempts for men (OR=1.37; 95%CI=1.02,1.83; p=0.03), but not for women (OR=0.96; 95%CI=0.71,1.31; p=0.82). Varenicline was significantly more effective than unassisted quit attempts for women (OR=1.63; 95%CI=1.16, 2.31; p=0.005), but not men (OR=1.35; 95%CI=0.94,1.96; p=0.11). Varenicline was also more effective than TNP for women (OR=1.51; 95%CI=0.12,2.05; p=0.007) but not men (OR=0.92; 95%CI=0.65,1.31; p=0.64). A significant gender by medication interaction was found only for the comparison of varenicline to TNP (OR=1.64; 95%CI=1.04,2.61; p=0.04). CONCLUSIONS: Findings for varenicline vs. TNP were consistent with clinical trial data, showing greater differences in effectiveness for women compared to men. Results lend support to the generalizability of clinical trial findings, highlighting the importance of considering gender when offering treatment for smoking cessation.

Surface water mitigates the anti-metamorphic effects of elevated perchlorate concentrations in New Mexico spadefoot toad larvae (Spea multiplicata).

Perchlorate (ClO4-) has potential to negatively impact amphibian populations by inhibiting thyroid hormone production, and thus metamorphosis in developing larvae. However, variability exists in species sensitivity, and there is evidence suggesting that natural surface waters can mitigate the anti-metamorphic potential of perchlorate. New Mexico spadefoot toad tadpoles, Spea multiplicata, were exposed to natural surface waters spiked with nominal concentrations of 0, 1000, 1350, 1710, 3000, 5110, and 8000 µg/L perchlorate ion for up to 42 days. No consistent dose-response trends were observed in mortality, rate of metamorphosis, Gosner stage, mass, or length. This study suggests that perchlorate exposure to concentrations as high as 8000 µg/L in natural surface waters does not result in adverse effects on New Mexico spadefoot tadpoles and emphasizes the importance of using site-specific conditions and species when evaluating ecological risks in perchlorate-impacted areas.

Lipid Emulsion Added to a Liquid High-Carbohydrate Diet and Voluntary Running Exercise Reduce Lipogenesis and Ameliorate Early-Stage Hepatic Steatosis in Mice.

Background: The use of parenteral nutrition formulas is often associated with the development of hepatic steatosis. We have shown previously that the addition of a lipid emulsion (LE) rich in n-6 (ω-6) fatty acids (FAs) ameliorated triglyceride (TG) accumulation in the livers of nonobese mice fed a high-carbohydrate diet (HCD) for 5 wk. However, it remains unclear how rapidly this condition develops and whether it can be prevented by LE with or without a running wheel for voluntary exercise (Exe).Objective: We investigated in an 8-d study whether mice develop steatosis and whether the administration of LE with or without Exe reduces the concentration of total FAs and prevents an increase in the expression of genes in the liver associated with lipogenesis.Methods: Male C57BL/6 mice aged 5 wk were randomized into 5 groups: standard feed pellet (SFP); a liquid HCD (77% of total energy from carbohydrates and 0.5% from fat); HCD + Exe; HCD + 13.5% LE (67% carbohydrates and 13.5% fat); or HCD + 13.5% LE + Exe. Hepatic TG concentration, lipogenic genes, and total FAs were measured on day 8.Results: Oil Red O staining and TG quantification showed hepatic TG accumulation on day 8; the addition of 13.5% LE either with or without Exe suppressed the TG accumulation compared with HCD (P < 0.005). With the use of quantitative reverse transcriptase-polymerase chain reaction analysis, the expression concentrations of lipogenic genes [ATP-citrate lyase, acetyl coenzyme A carboxylase 1, FA synthase (Fasn), and stearoyl coenzyme A desaturase 1 (Scd1)] in the HCD + 13.5% LE group were 26-60% of HCD (P < 0.01) and 11-38% of HCD in the HCD + 13.5% LE + Exe group (P < 0.001), with interactions for Fasn and Scd1 (P < 0.05). With the use of gas chromatography-mass spectrometry analysis, the HCD + 13.5% LE group had lower monounsaturated fatty acids (38.7% of HCD) but higher polyunsaturated fatty acids (164% of HCD) (P < 0.001).Conclusions: In short-term studies designed to resemble the early dynamic stage of the development of hepatic steatosis, the addition of 13.5% LE to a liquid HCD reduced hepatic lipogenesis. Exe exerted an independent protective effect and interacted with LE to further reduce the expression of Scd1.

Impact of Cannabis Use on Treatment Outcomes among Adults Receiving Cognitive-Behavioral Treatment for PTSD and Substance Use Disorders.

BACKGROUND: Research has demonstrated a strong link between trauma, posttraumatic stress disorder PTSD and substance use disorders (SUDs) in general and cannabis use disorders in particular. Yet, few studies have examined the impact of cannabis use on treatment outcomes for individuals with co-occurring PTSD and SUDs. METHODS: Participants were 136 individuals who received cognitive-behavioral therapies for co-occurring PTSD and SUD. Multivariate regressions were utilized to examine the associations between baseline cannabis use and end-of-treatment outcomes. Multilevel linear growth models were fit to the data to examine the cross-lagged associations between weekly cannabis use and weekly PTSD symptom severity and primary substance use during treatment. RESULTS: There were no significant positive nor negative associations between baseline cannabis use and end-of-treatment PTSD symptom severity and days of primary substance use. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa. Moreover, results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. CONCLUSION: Cannabis use was not associated with adverse outcomes in end-of-treatment PTSD and primary substance use, suggesting independent pathways of change. The theoretical and clinical implications of the reciprocal associations between weekly cannabis use and subsequent PTSD and primary substance use symptoms during treatment are discussed.

Procedural outcomes of fluoroless catheter ablation outside the traditional catheterization lab.

AIMS: Non-fluoroscopic catheter ablation is becoming routine. In experienced centres, fluoroscopy is rarely required. The use of a traditional catheterization lab (cath lab) may no longer be necessary. We began performing catheter ablations at a paediatric centre outside the traditional cardiac cath lab in 2013. The purpose of this study was to compare procedural features of paediatric catheter ablation performed outside the cath lab to those performed within a cath lab. METHODS AND RESULTS: We prospectively looked at patients presenting to the paediatric centre with supraventricular tachycardia (SVT) undergoing catheter ablation outside the cath lab in a standard operating room (OR group). We compared retrospectively to a control group matched for age, type, and location of arrhythmia who had ablations in a traditional cath lab (CL group). Catheter visualization was exclusively by electro-anatomic mapping. Fifty-nine patients with SVT underwent catheter ablation in the OR from October 2013 to December 2015. Thirty-three patients had accessory pathways, 29 were manifest, and 13 of those were left sided. Twenty-six had atrioventricular nodal re-entrant tachycardia. Transseptal puncture with transoesophageal echocardiography guidance was used for 10 left-sided pathways, whereas the other 3 had patent foramen ovales. Procedure time did not differ significantly between groups (OR group mean 131 min, range 57-408; CL group mean 152 min, range 68-376; P = 0.12). Acute success was similar in both groups [OR group: 58/59 (98.3%) and CL group: 57/59 (96.6%)]. There were no major complications in either group. There was no fluoroscopy used in either group. CONCLUSION: Although performing paediatric catheter ablations outside the traditional cath lab is early in our experience, we produced similar outcomes and results without encountering procedural difficulties of performing ablations in a non-conventional setting. Larger multi-centred trials will be essential to determine the feasibility of this practice.

Editor's Highlight: Perfluorooctane Sulfonate-Choline Ion Pair Formation: A Potential Mechanism Modulating Hepatic Steatosis and Oxidative Stress in Mice.

The mechanisms underlying perfluorooctane sulfonate (PFOS)-induced steatosis remain unclear. The hypothesis that PFOS causes steatosis and other hepatic effects by forming an ion pair with choline was examined. C57BL/6 mice were fed either a control diet or a marginal methionine/choline-deficient (mMCD) diet, with and without 0.003, 0.006, or 0.012% potassium PFOS. Dietary PFOS caused a dose-dependent decrease in body weight, and increases in the relative liver weight, hepatic triglyceride concentration and serum markers of liver toxicity and oxidative stress. Some of these effects were exacerbated in mice fed the mMCD diet supplemented with 0.012% PFOS compared with those fed the control diet supplemented with 0.012% PFOS. Surprisingly, serum PFOS concentrations were higher while liver PFOS concentrations were lower in mMCD-fed mice compared with corresponding control-fed mice. To determine if supplemental dietary choline could prevent PFOS-induced hepatic effects, C57BL/6 mice were fed a control diet, or a choline supplemental diet (1.2%) with or without 0.003% PFOS. Lipidomic analysis demonstrated that PFOS caused alterations in hepatic lipid metabolism in the PFOS-fed mice compared with controls, and supplemental dietary choline prevented these PFOS-induced changes. Interestingly, dietary choline supplementation also prevented PFOS-induced oxidative damage. These studies are the first to suggest that PFOS may cause hepatic steatosis and oxidative stress by effectively reducing the choline required for hepatic VLDL production and export by forming an ion pair with choline, and suggest that choline supplementation may prevent and/or treat PFOS-induced hepatic steatosis and oxidative stress.

Antileishmanial Activity of Compounds Derived from the Medicines for Malaria Venture Open Access Box Against Intracellular Leishmania major Amastigotes.

Leishmaniasis is a complex tropical disease caused by kinetoplastid parasitic protozoa of the genus Leishmania and is transmitted by the sand fly insect vector. Cutaneous leishmaniasis (CL) is the most common form of this disease, and CL infections often result in serious skin lesions and scars. CL remains a public health problem in many endemic countries worldwide because of the absence of effective, safe, and cost-effective drugs for treatment. One of the strategies we chose to use to find novel chemical entities worthy of further development as antileishmanials involved screening synthetic and natural products libraries. In our study, we developed a Leishmania major intracellular amastigote assay that uses the activity of luciferase as a measure of parasite proliferation and used this assay to screen a collection of 400 compounds obtained from Medicines for Malaria Venture (MMV) for their antileishmanial activity. Our results showed that 14 compounds identified by MMV as antimalarial drugs have antileishmanial activity and can potentially be optimized for CL drug development.

Planning and response to Ebola virus disease: An integrated approach.

The care of patients with Ebola virus disease (EVD) requires the application of critical care medicine principles under conditions of stringent infection control precautions. The care of patients with EVD requires a number of elements in terms of physical layout, personal protective apparel, and other equipment. Provision of care is demanding in terms of depth of staff and training. The key to safely providing such care is a system that brings many valuable skills to the table, and allows communication between these individuals. We present our approach to leadership structure and function--a variation of incident command--in providing care to 3 patients with EVD.

Inorganic elements in green sea turtles (Chelonia mydas): relationships among external and internal tissues.

Inorganic elements from anthropogenic sources have entered marine environments worldwide and are detectable in marine organisms, including sea turtles. Threatened and endangered classifications of sea turtles have heretofore made assessments of contaminant concentrations difficult because of regulatory restrictions on obtaining samples using nonlethal techniques. In the present study, claw and skin biopsy samples were examined as potential indicators of internal tissue burdens in green sea turtles (Chelonia mydas). Significant relationships were observed between claw and liver, and claw and muscle concentrations of mercury, nickel, arsenic, and selenium (p < 0.05). Similarly, significant relationships were observed between skin biopsy concentrations and those in liver, kidney, and muscle tissues for mercury, arsenic, selenium, and vanadium (p < 0.05). Concentrations of arsenic, barium, chromium, nickel, strontium, vanadium, and zinc in claws and skin biopsies were substantially elevated when compared with all other tissues, indicating that these highly keratinized tissues may represent sequestration or excretion pathways. Correlations between standard carapace length and cobalt, lead, and manganese concentrations were observed (p < 0.05), indicating that tissue concentrations of these elements may be related to age and size. Results suggest that claws may indeed be useful indicators of mercury and nickel concentrations in liver and muscle tissues, whereas skin biopsy inorganic element concentrations may be better suited as indicators of mercury, selenium, and vanadium concentrations in liver, kidney, and muscle tissues of green sea turtles.

Electrical stimulation of the hypoglossal nerve: a potential therapy.

Obstructive sleep apnea is characterized by recurrent episodes of pharyngeal collapse, which result from a decrease in pharyngeal dilator muscle tone. The genioglossus is a major pharyngeal dilator that maintains airway patency during sleep. Early studies in animal and humans have demonstrated that electrical stimulation of this muscle reduces pharyngeal collapsibility, increases airflow, and mitigates obstructive sleep apnea. These findings impelled the development of fully implantable hypoglossal nerve stimulating systems (HGNS), for which feasibility trial results are now available. These pilot studies have confirmed that hypoglossal nerve stimulation can prevent pharyngeal collapse without arousing patients from sleep. Potentially, a substantial segment of the patient population with obstructive sleep apnea can be treated with this novel approach. Furthermore, the feasibility trial findings suggest that the therapeutic potential of HGNS can be optimized by selecting patients judiciously, titrating the stimulus intensity optimally, and characterizing the underlying function and anatomy of the pharynx. These strategies are currently being examined in ongoing pivotal trials of HGNS.

Embryotoxicity of mixtures of weathered crude oil collected from the Gulf of Mexico and Corexit 9500 in mallard ducks (Anas platyrhynchos).

Dispersants are applied to marine crude oil spills to enhance microbial degradation and reduce impacts of crude oils on ecosystems. In summer 2010, the dispersant Corexit 9500 was applied to crude oil in the Gulf of Mexico. The co-occurrence of the Deepwater Horizon oil spill with nesting efforts of birds in the Gulf region may have resulted in exposure of adult birds, and subsequently bird eggs, to combinations of crude oil and Corexit 9500. The objective of this study was to examine the embryotoxicity of 50:1 and 10:1 mixtures of weathered crude oil collected from the Gulf of Mexico and Corexit 9500 applied to mallard duck eggs. Combinations of weathered crude oil and Corexit 9500 were applied to eggshells of mallard ducks via paintbrush in varying masses ranging from 0.1 to 59.9 mg and 0.1 to 44.9 mg for 50:1 and 10:1 mixtures, respectively. Conservatively derived median lethal applications for 50:1 and 10:1 mixtures of weathered crude oil and Corexit 9500 were 21.3±4.9 mg/egg (321.8 µg/g egg) and 33.1±11.8 mg/egg (517.0 µg/g egg), respectively. Spleen mass of hatchlings exposed to the 50:1 mixture was the only physiological measure significantly different from controls of both mixtures. Results indicated that decreasing ratios of dispersant relative to weathered crude oil decreased toxicity to mallard embryos. In comparison to treatments of eggs with weathered crude oil alone, toxicity increased when the oil to dispersant ratio was 50:1, but decreased with the mixture that contained more dispersant (10:1).

Thalamocortical projections to rat auditory cortex from the ventral and dorsal divisions of the medial geniculate nucleus.

The ventral and dorsal medial geniculate (MGV and MGD) constitute the major auditory thalamic subdivisions providing thalamocortical inputs to layer IV and lower layer III of auditory cortex. No quantitative evaluation of this projection is available. Using biotinylated dextran amine (BDA)/biocytin injections, we describe the cortical projection patterns of MGV and MGD cells. In primary auditory cortex the bulk of MGV axon terminals are in layer IV/lower layer III with minor projections to supragranular layers and intermediate levels in infragranular layers. MGD axons project to cortical regions designated posterodorsal (PD) and ventral (VA) showing laminar terminal distributions that are quantitatively similar to the MGV-to-primary cortex terminal distribution. At the electron microscopic level MGV and MGD terminals are non-γ-aminobutyric acid (GABA)ergic with MGD terminals in PD and VA slightly but significantly larger than MGV terminals in primary cortex. MGV/MGD terminals synapse primarily onto non-GABAergic spines/dendrites. A small number synapse on GABAergic structures, contacting large dendrites or cell bodies primarily in the major thalamocortical recipient layers. For MGV projections to primary cortex or MGD projections to PD or VA, the non-GABAergic postsynaptic structures at each site were the same size regardless of whether they were in supragranular, granular, or infragranular layers. However, the population of MGD terminal-recipient structures in VA were significantly larger than the MGD terminal-recipient structures in PD or the MGV terminal-recipient structures in primary cortex. Thus, if terminal and postsynaptic structure size indicate strength of excitation then MGD to VA inputs are strongest, MGD to PD intermediate, and MGV to primary cortex the weakest.

Acute upper airway responses to hypoglossal nerve stimulation during sleep in obstructive sleep apnea.

RATIONALE: Hypoglossal nerve stimulation (HGNS) recruits lingual muscles, reduces pharyngeal collapsibility, and treats sleep apnea. OBJECTIVES: We hypothesized that graded increases in HGNS relieve pharyngeal obstruction progressively during sleep. METHODS: Responses were examined in 30 patients with sleep apnea who were implanted with an HGNS system. Current (milliampere) was increased stepwise during non-REM sleep. Frequency and pulse width were fixed. At each current level, stimulation was applied on alternating breaths, and responses in maximal inspiratory airflow (V(I)max) and inspiratory airflow limitation (IFL) were assessed. Pharyngeal responses to HGNS were characterized by the current levels at which V(I)max first increased and peaked (flow capture and peak flow thresholds), and by the V(I)max increase from flow capture to peak (ΔV(I)max). MEASUREMENTS AND MAIN RESULTS: HGNS produced linear increases in V(I)max from unstimulated levels at flow capture to peak flow thresholds (215 ± 21 to 509 ± 37 ml/s; mean ± SE; P < 0.001) with increasing current from 1.05 ± 0.09 to 1.46 ± 0.11 mA. V(I)max increased in all patients and IFL was abolished in 57% of patients (non-IFL subgroup). In the non-IFL compared with IFL subgroup, the flow response slope was greater (1241 ± 199 vs. 674 ± 166 ml/s/mA; P < 0.05) and the stimulation amplitude at peak flow was lower (1.23 ± 0.10 vs. 1.80 ± 0.20 mA; P < 0.05) without differences in peak flow. CONCLUSIONS: HGNS produced marked dose-related increases in airflow without arousing patients from sleep. Increases in airflow were of sufficient magnitude to eliminate IFL in most patients and IFL and non-IFL subgroups achieved normal or near-normal levels of flow, suggesting potential HGNS efficacy across a broad range of sleep apnea severity.