High risk of malnutrition among hospitalised coronavirus disease 2019 (COVID-19) patients is associated with mortality and other clinical outcomes.

INTRODUCTION: Increasing evidence indicates an association between nutritional status and Coronavirus disease 2019 (COVID-19) disease severity. The aim of the study was to describe the risk of malnutrition, body mass index (BMI) and vitamin D status of hospitalised COVID-19 patients and assess whether they are associated with duration of hospital stay, intensive care unit (ICU) admission, mechanical ventilation, and mortality. METHODS: The study is a descriptive retrospective study of 273 patients with COVID-19 admitted to Hospital from February 2020 to March 2021. Patients were screened for risk of malnutrition using a validated screening tool. BMI was calculated from height and weight. Insufficient Vitamin D status was defined as 25(OH)vitD <50 nmol/L. Logistic regression analysis was used to assess the association between indicators of nutritional status of patients with COVID-19, and outcomes such as duration of stay >7 days, ICU admission, mechanical ventilation, and mortality. Interaction between risk of malnutrition and BMI of ≥30 kg/m2 was assessed using the likelihood ratio test with hospital stay, ICU admission, mechanical ventilation, and mortality as outcomes. RESULTS: Screening for risk of malnutrition identified 201 (74%) patients at a medium to high risk of malnutrition. Patients defined as being at a medium or high risk of malnutrition were more likely to be hospitalised for >7 days compared to those defined as low risk (OR: 10.72; 95% CI: 3.9-29.46; p < 0.001 and OR: 61.57; 95% CI: 19.48-194.62; p < 0.001, respectively). All patients who were admitted to ICU (n = 41) and required mechanical ventilation (n = 27) were defined as having medium or high risk of malnutrition. High risk of malnutrition was also associated with increased odds of mortality (OR: 8.87; 955 CI 1.08-72,96; p = 0.042). BMI of ≥30 kg/m2 (43%) and 25(OH)vitD <50 nmol/L (20%) were not associated with duration of stay >7 days or mortality, although BMI ≥30 kg/m2 was associated with increased risk of ICU admission (OR: 7.12; 95% CI: 1.59-31.94; p = 0.010) and mechanical ventilation (OR: 8.86; 95% CI: 1.12-69.87; p = 0.038). Interactions between risk of malnutrition and BMI ≥30 kg/m2 were not significant to explain the outcomes of hospital stay >7 days, ICU admission, mechanical ventilation, or mortality. CONCLUSION: High risk of malnutrition among hospitalised COVID-19 patients was associated with longer duration of hospital stay, ICU admission, mechanical ventilation and mortality, and BMI ≥30 kg/m2 was associated with ICU admission and mechanical ventilation. Insufficient Vitamin D status was not associated with duration of hospital stay, ICU admission, mechanical ventilation, or mortality.

Incidence of cirrhosis in Iceland-impact of the TraP HepC nationwide HCV elimination program.

OBJECTIVE: In 2016, a nationwide elimination program for hepatitis C virus (HCV) was initiated in Iceland, entitled Treatment as Prevention for Hepatitis C (TraP HepC), providing unrestricted access to antiviral treatment. The aims were to describe the changes in etiology and epidemiology of cirrhosis in Iceland and to assess the trends in HCV-related cirrhosis following TraP HepC. METHODS: The study included all patients newly diagnosed with cirrhosis in 2016-2022. Diagnosis was based on liver elastography, histology, or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, or elevated international normalized ratio (INR). RESULTS: Over the study period, 342 new cirrhosis patients were identified, 223 (65%) males, median age 62 years. The crude overall incidence was 13.8 cases per 100,000 inhabitants annually. The most common etiologies were alcohol-related liver disease (ALD) (40%), metabolic dysfunction-associated steatotic liver disease (MASLD) (28%), and HCV with or without alcohol overconsumption (15%). The number of HCV cirrhosis cases was unusually high in 2016 (n = 23) due to intensified case-finding, but decreased significantly over the study period (p < 0.001) to n = 1 (2021) and n = 2 (2022). The overall 5-year survival was 55% (95% CI 48.9-62.3%). The most common causes of death were hepatocellular carcinoma (26%) and liver failure (25%). CONCLUSION: During the past two decades, the incidence of cirrhosis has increased extraordinarily in Iceland, associated with increased alcohol consumption, obesity, and HCV. ALD and MASLD now collectively make up two thirds of cases in Iceland. Following a nationwide elimination program, incidence of HCV cirrhosis has dropped rapidly in Iceland.

NaX Channel Is a Physiological [Na+] Detector in Oxytocin- and Vasopressin-Releasing Magnocellular Neurosecretory Cells of the Rat Supraoptic Nucleus.

The Scn7A gene encodes NaX, an atypical noninactivating Na+ channel, whose expression in sensory circumventricular organs is essential to maintain homeostatic responses for body fluid balance. However, NaX has also been detected in homeostatic effector neurons, such as vasopressin (VP)-releasing magnocellular neurosecretory cells (MNCVP) that secrete VP (antidiuretic hormone) into the bloodstream in response to hypertonicity and hypernatremia. Yet, the physiological relevance of NaX expression in these effector cells remains unclear. Here, we show that rat MNCVP in males and females is depolarized and excited in proportion with isosmotic increases in [Na+]. These responses were caused by an inward current resulting from a cell-autonomous increase in Na+ conductance. The Na+-evoked current was unaffected by blockers of other Na+-permeable ion channels but was significantly reduced by shRNA-mediated knockdown of Scn7A expression. Furthermore, reducing the density of NaX channels selectively impaired the activation of MNCVP by systemic hypernatremia without affecting their responsiveness to hypertonicity in vivo These results identify NaX as a physiological Na+ sensor, whose expression in MNCVP contributes to the generation of homeostatic responses to hypernatremia.SIGNIFICANCE STATEMENT In this study, we provide the first direct evidence showing that the sodium-sensing channel encoded by the Scn7A gene (NaX) mediates cell-autonomous sodium detection by MNCs in the low millimolar range and that selectively reducing the expression of these channels in MNCs impairs their activation in response to a physiologically relevant sodium stimulus in vitro and in vivo These data reveal that NaX operates as a sodium sensor in these cells and that the endogenous sensory properties of osmoregulatory effector neurons contribute to their homeostatic activation in vivo.

Febrile Children with Pneumonia Have Higher Nasopharyngeal Bacterial Load Than Other Children with Fever.

Febrile episodes are common in children and the most frequent reason for attending emergency services. Although most infections have a benign and self-limiting course, severe and sometimes life-threatening infections occur. This prospective study describes a cohort of children presenting to a single-centre pediatric emergency department (ED) with suspected invasive bacterial infection, and explores the relationships between nasopharyngeal microbes and outcomes. All children attending the ED who had a blood culture taken were offered to participate over a two-year period. In addition to conventional medical care, a nasopharyngeal swab was obtained., which was analysed for respiratory viruses and three bacterial species using a quantitative PCR. Fisher's exact test, Wilcoxon rank sum, and multivariable models were used for statistical analyses of the 196 children (75% younger than four years) who were enrolled and had sufficient data for analysis; 92 had severe infections according to the study protocol, while five had bloodstream infections. Radiologically confirmed pneumonia was the most common severe infection found in 44/92 patients. The presence of respiratory viruses and the carriage of Streptococcus pneumoniae and Haemophilus influenzae were associated with a higher risk of pneumonia. Higher density colonisation with these bacteria were independent risk factors for pneumonia, whereas Moraxella catarrhalis carriage was associated with lower risk. Our data support the hypothesis that higher nasopharyngeal density of pneumococci and H. influenzae could play a role in the development of bacterial pneumonia in children. A preceding viral infection of the respiratory tract may be a trigger and play a role in the progression to severe lower respiratory tract infection.

Analysis of the genomic diversity of human papillomavirus type 31 in cervical samples reveals the presence of novel sublineages in clade C.

Human papillomavirus 31 (HPV31) is the fourth most frequent high-risk HPV (HR-HPV) genotype identified in cervical cancer (CC) worldwide and in Mexico. It has been recently classified into three lineages (A, B, and C) and eight sublineages (A1, A2, B1, B2, and C1 - C4). Here, we report the complete genomic sequences of 14 HPV31 isolates from cervical samples, and these were compared with viral genome sequences from the GenBank database for phylogenetic and genetic distance analysis. The formation of two novel clades within the C lineage (proposed as C5 and C6) was observed, with a well-defined variant-specific mutational pattern. The smallest average pairwise distance was 0.71% for lineages A and B, 0.94% for lineages A and C, and 1.01% for lineages B and C, and between sublineages, these values were 0.21% for clade A, 0.29% for clade B, and 0.24% for clade C. The isolates were grouped into the sublineages A1, B2, C1-C3, and C6. This is the first report on the whole-genome diversity of HPV31 in Mexico.

Procedural outcomes of the 34 mm EvolutR Transcatheter valve in a real-world population insights from the HORSE multicenter collaborative registry.

OBJECTIVES: The aim of this study was to evaluate outcomes of real-world patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with the 34 mm Evolut R (Medtronic, Minneapolis, Minnesota). BACKGROUND: Larger aortic annulus has been associated with increased incidence of paravalvular leaks (PVLs) after TAVR. However, little is known, so far, about the performance of the 34 mm Evolut R in this setting. METHODS: From the multicenter, international, retrospective Horizontal Aorta in Transcatheter Self-expanding Valves (HORSE) registry, including patients who underwent TAVR for native severe AS, we selected patients treated with the 34 mm Evolut R evaluating procedural characteristics and VARC-2 defined device success. We also compared 34 mm Evolut R with other Evolut R sizes. RESULTS: Among the 4434 patients included in the registry, 572 (13%) received the 34 mm Evolut R valve. Mean age was 80.8 ± 6.5 years and the median STS PROM score was 4 [interquartile range 2-6]. Device success was achieved in 87.4% with 7.7% of PVLs; moreover, the rate of permanent pacemaker implantation (PPMI) was 22.4%. Patients who underwent 34 mm Evolut R implantation experienced more in-hospital permanent pacemaker implantation (22.4% vs. 15%; p < 0.001). At multivariate analysis, 34 mm Evolut R did not affect device success (OR: 0.81 [0.60-1.09]; p = 0.151). Device success was consistent with other THVs sizes (87.4% vs. 89.6%; p = 0.157). CONCLUSIONS: THV replacement in patients requiring 34 mm Evolut R has an acceptable performance. Compared to other Medtronic sizes it demonstrated to be comparable in terms of device success, despite an increased rate of pacemaker implantation.

High Rate of Hepatitis C Virus Reinfection Among Recently Injecting Drug Users: Results From the TraP Hep C Program-A Prospective Nationwide, Population-Based Study.

BACKGROUND: The Treatment as Prevention for Hepatitis C program started in 2016 in Iceland, offering treatment with direct-acting antivirals to hepatitis C virus (HCV)-infected individuals. Reinfections through injection drug use (IDU) can hamper elimination efforts. We determined reinfection rates of HCV among patients in the program. METHODS: Clinical data were gathered prospectively. The study cohort consisted of HCV-cured patients with an estimated sustained virologic response between 1 February 2016 and 20 November 2018, with follow-up until 20 November 2019. The observation period and time until reinfection was estimated using a single random point imputation method coupled with Monte Carlo simulation. The reinfection rates were expressed as reinfections per 100 person-years (PY). RESULTS: In total, 640 treatments of 614 patients (417 male; mean age, 44.3 years) resulted in cure, with 52 reinfections subsequently confirmed in 50 patients (37 male). Follow-up was 672.1 PY, with a median time to reinfection of 232 days. History of IDU was reported by 523 patients (84.8%) and recent IDU with 220 treatments (34.4%). Stimulants were the preferred injected drug in 85.5% of patients with a history of IDU. The reinfection rate was 7.7/100 PY. Using multivariate Cox proportional hazards models for interval-censored data, age (hazard ratio, 0.96 [95% confidence interval, .94-.99]) and recent IDU (2.91 [1.48-5.76]) were significantly associated with reinfection risk. CONCLUSIONS: The reinfection rate is high in a setting of widespread stimulant use, particularly in young people with recent IDU. Regular follow-up is important among high-risk populations to diagnose reinfections early and reduce transmission. CLINICAL TRIALS REGISTRATION: NCT02647879.

A case report of cocaine abuse, acute coronary syndrome, and eroded plaque: stent or not stent?

BACKGROUND: Intracoronary imaging techniques have allowed characterizing atherosclerotic plaques morphologically in patients with the acute coronary syndrome (ACS). Although the main feature described is plaque rupture, the use of optical coherence tomography has made it possible to objectify that the eroded plaque is not uncommon in this setting. CASE SUMMARY: We presented a case of a 45-year-old man with active smoking and cocaine user, admitted to the emergency department for chest pain. The electrocardiogram showed ST-segment elevation myocardial infarction (STEMI) in the inferior leads. Emergent coronary angiography was performed, showing thrombotic occlusion of mid-distal right coronary artery. After successful thromboaspiration, no areas of significant angiographic stenosis were observed. Optical coherence tomography imaging at the occlusion site revealed an eroded plaque and a remaining small thrombusburden. Conservative management without stent implantation was decided. Treatments consisted of an acute phase glycoprotein IIb/IIIa inhibitor and subsequently dual antiplatelet therapy with Aspirin (ASA) and Ticagrelor 90 mg b.i.d. for 12 months. The patient remains asymptomatic and uneventful at 9-month follow-up. DISCUSSION: Young age, history of active smoking, and cocaine use are common clinical features in patients with ACS due to an eroded plaque. These patients frequently display a STEMI with the involvement of a single coronary vessel. Optical coherence tomography imaging aids to a precise diagnosis and to define a proper treatment.

Cascade of care during the first 36 months of the treatment as prevention for hepatitis C (TraP HepC) programme in Iceland: a population-based study.

BACKGROUND: WHO has set targets to eliminate hepatitis C virus (HCV) infection as a global health threat by 2030 through a 65% reduction in HCV-related deaths and 80% reduction in HCV incidence. To achieve these goals, WHO set service coverage targets of 90% of the infected population being diagnosed and 80% of eligible patients being treated. In February, 2016, Iceland initiated a nationwide HCV elimination programme known as treatment as prevention for hepatitis C (TraP HepC), which aimed to maximise diagnosis and treatment access. This analysis reports on the HCV cascade of care in the first 3 years of the programme. METHODS: This population-based study was done between Feb 10, 2016, and Feb 10, 2019. Participants aged 18 years or older with permanent residence in Iceland and PCR-confirmed HCV were offered direct-acting antiviral (DAA) therapy. The programme used a multidisciplinary team approach in which people who inject drugs were prioritised. Nationwide awareness campaigns, improved access to testing, and harm reduction services were scaled up simultaneously. The number of infected people in the national HCV registry was used in combination with multiple other data sources, including screening of low-risk groups and high-risk groups, to estimate the total number of HCV infections. The number of people diagnosed, linked to care, initiated on treatment, and cured were recorded during the study. This study is registered with ClinicalTrials.gov, NCT02647879. FINDINGS: In February, 2016, at the onset of the programme, 760 (95% CI 690-851) individuals were estimated to have HCV infection, with 75 (95% CI 6-166) individuals undiagnosed. 682 individuals were confirmed to be HCV PCR positive. Over the next 3 years, 183 new infections (including 42 reinfections) were diagnosed, for a total of 865 infections in 823 individuals. It was estimated that more than 90% of all domestic HCV infections had been diagnosed as early as January, 2017. During the 3 years, 824 (95·3%) of diagnosed infections were linked to care, and treatment was initiated for 795 (96·5%) of infections linked to care. Cure was achieved for 717 (90·2%) of 795 infections. INTERPRETATION: By using a multidisciplinary public health approach, involving tight integration with addiction treatment services, the core service coverage targets for 2030 set by WHO have been reached. These achievements position Iceland to be among the first nations to subsequently achieve the WHO goal of eliminating HCV as a public health threat. FUNDING: The Icelandic Government and Gilead Sciences.

A nationwide population-based prospective study of cirrhosis in Iceland.

BACKGROUND & AIMS: The incidence of cirrhosis in Iceland has been the lowest in the world with only 3 cases per 100,000 inhabitants. Alcohol consumption has almost doubled in Iceland from 1980 to 2016. Obesity has also risen and hepatitis C virus has spread among people who inject drugs in Iceland. The aim of this study was to evaluate the effects of these risk factors on the incidence and aetiology of cirrhosis in Iceland. METHODS: The study included all patients diagnosed with cirrhosis for the first time during 2010-2015. Diagnosis was based on liver histology or 2 of 4 criteria: cirrhosis on imaging, ascites, varices, and/or elevated INR. RESULTS: Overall, 157 patients were diagnosed, 105 (67%) males, mean age 61 years. The overall incidence was 9.7 cases per 100,000 inhabitants annually. Alcohol was the only underlying cause in 48/157 (31%), non-alcoholic fatty liver disease (NAFLD) in 34/157(22%), and alcohol and hepatitis C together in 23/157(15%) were the most common causes. Only 6% of patients had an unknown cause of cirrhosis. Upon diagnosis, the median model for end-stage liver disease score was 11 (IQR 8-15), 53% were of Child-Pugh class A whereas 61 (39%) had ascites, 11% encephalopathy, and 8% variceal bleeding. In all, 25% of deaths were from HCC and 25% from liver failure. CONCLUSION: A major increase in incidence of cirrhosis has occurred in Iceland associated with increases in alcohol consumption, obesity, and hepatitis C. In a high proportion NAFLD was the aetiology and very few had unknown cause of cirrhosis. The highest death rate was from HCC. LAY SUMMARY: In a nationwide population-based study from Iceland, including all patients diagnosed with cirrhosis of the liver over a period of 5 years, we found the incidence of new cases had increased 3-fold compared with a previous study 20 years ago. The increase is attributable to increased alcohol consumption, an epidemic of diabetes and obesity, and infection with the hepatitis C virus. Furthermore, we found that with thorough investigations, a specific cause for cirrhosis could be found in 94% of patients. Patients with cirrhosis frequently die of liver cancer and other complications related to their liver disease.

Transcatheter aortic valve implantation for degenerated aortic valves: Experience with a new supra-annular device. The Spanish Allegra valve-in-valve (SAVIV) registry.

OBJECTIVES: The objective was to evaluate the results of valve-in-valve procedures performed with the Allegra device. BACKGROUND: Transcatheter aortic valve implantation to treat degenerated biological aortic valves (valve-in-valve) is an established procedure in most catheterization laboratories, but the results are poorer than procedures done in native aortic stenosis. The Allegra device (Biosensors, Morges, Switzerland) has an excellent design to treat these patients. METHODS: All patients with severely degenerated biological aortic valve treated with the Allegra device in centers from Spain until December 2020 were included (n = 29). Hemodynamic results and 30-day clinical outcomes were evaluated. The predominant hemodynamic failure was stenosis in 15, regurgitation in 11, and a combination of both in 3 cases. Time from aortic valve replacement to valve-in-valve procedure was 8.4 ± 3.9 years (range 3.3-22.1). RESULTS: After the procedure, maximum and mean trans-valvular gradients were 17.4 ± 12.3 and 8.4 ± 6.1 mmHg, respectively. Device success was obtained in 28 patients (96.6%). In one patient with a degenerated 19 mm prosthetic valve, mean gradient after the procedure was 22 mmHg. No patients had a para-valvular leak grade >1. There were no deaths during the hospitalization or at 30 days and one patient suffered a stroke. CONCLUSIONS: The Allegra trans-catheter aortic valve offers optimal hemodynamic results in patients with severely degenerated biological aortic valve.

Analysis of CRISPR-Cas systems in Gardnerella suggests its potential role in the mechanisms of bacterial vaginosis.

Bacterial vaginosis (BV) is the principal cause of vaginal discharge among women, and it can lead to many comorbidities with a negative impact in women's daily activities. Despite the fact that the pathophysiological process of BV remains unclear, great advances had been achieved in determining consequences of the shift in the vaginal community, and it was defined that Gardnerella spp., plays a key role in the pathogenesis of BV. Interactions of vaginal phage communities and bacterial hosts may be relevant in eubiosis/dysbiosis states, so defense mechanisms in Gardnerella spp., against phage infections could be relevant in BV development. In this study, we analyzed CRISPR-Cas systems among the 13 Gardnerella species recently classified, considering that these systems act as prokaryotic immune systems against phages, plasmids, and other mobile genetic elements. In silico analyses for CRISPR-Cas systems mining over the 81 Gardnerella spp., strains genomes analyzed led to the identification of subtypes I-E and II-C. Spacers analyses showed a hypervariable region across species, providing a high resolution level in order to distinguish clonality in strains, which was supported with phylogenomic analyses based on Virtual Genomic Fingerprinting. Moreover, most of the spacers revealed interactions between Gardnerella spp., strains and prophages over the genus. Furthermore, virulence traits of the 13 species showed insights of potential niche specificity in the vaginal microbiome. Overall, our results suggest that the CRISPR-Cas systems in the genus Gardnerella may play an important role in the mechanisms of the development and maintenance of BV, considering that the Gardnerella species occupies different niches in the vaginal community; in addition, spacer sequences can be used for genotyping studies.

Histamine H1 and H3 receptor activation increases the expression of Glucose Transporter 1 (GLUT-1) in rat cerebro-cortical astrocytes in primary culture.

Astrocytes take up glucose via the 45 kDa isoform of the Glucose Transporter 1 (GLUT-1), and in this work we have investigated whether histamine regulates GLUT-1 expression in rat cerebro-cortical astrocytes in primary culture. Cultured astrocytes expressed histamine H1 and H3 receptors (H1Rs and H3Rs) as evaluated by radioligand binding. Receptor functionality was confirmed by the increase in the intracellular concentration of Ca2+ (H1R) and the inhibition of forskolin-induced cAMP accumulation (H3R). Quantitative RT-PCR showed that histamine and selective H1R and H3R agonists (1 h incubation) significantly increased GLUT-1 mRNA to 153 ±â€¯7, 163 ±â€¯2 and 168 ±â€¯13% of control values, respectively. In immunoblot assays, incubation (3 h) with histamine or H1R and H3R agonists increased GLUT-1 protein levels to 224 ±â€¯12, 305 ±â€¯11 and 193 ±â€¯13% of control values, respectively, an action confirmed by inmunocytochemistry. The effects of H1R and H3R agonists were blocked by the selective antagonists mepyramine (H1R) and clobenpropit (H3R). The pharmacological inhibition of protein kinase C (PKC) prevented the increase in GLUT-1 protein induced by either H1R or H3R activation. Furthermore, histamine increased ERK-1/2 phosphorylation, and the effect of H1R and H3R activation on GLUT-1 protein levels was reduced or prevented, respectively, by MEK-1/2 inhibition. These results indicate that by activating H1Rs and H3Rs histamine regulates the expression of GLUT-1 by astrocytes. The effect appears to involve the phospholipase C (PLC) → diacylglycerol (DAG)/Ca2+→ PKC and PLC → DAG/Ca2+ → PKC → MAPK pathways.

Adenosine A2A and histamine H3 receptors interact at the cAMP/PKA pathway to modulate depolarization-evoked [3H]-GABA release from rat striato-pallidal terminals.

We previously reported that the activation of histamine H3 receptors (H3Rs) selectively counteracts the facilitatory action of adenosine A2A receptors (A2ARs) on GABA release from rat globus pallidus (GP) isolated nerve terminals (synaptosomes). In this work, we examined the mechanisms likely to underlie this functional interaction. Three possibilities were explored: (a) changes in receptor affinity for agonists induced by physical A2AR/H3R interaction, (b) opposite actions of A2ARs and H3Rs on depolarization-induced Ca2+ entry, and (c) an A2AR/H3R interaction at the level of adenosine 3',5'-cyclic monophosphate (cAMP) formation. In GP synaptosomal membranes, H3R activation with immepip reduced A2AR affinity for the agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride hydrate (CGS-21680) (Ki control 4.53 nM; + immepip 9.32 nM), whereas A2AR activation increased H3R affinity for immepip (Ki control 0.63 nM; + CGS-21680 0.26 nM). Neither A2AR activation nor H3R stimulation modified calcium entry through voltage-gated calcium channels in GP synaptosomes, as evaluated by microfluorometry. A2AR-mediated facilitation of depolarization-evoked [2,3-3H]-γ-aminobutyric acid ([3H]-GABA) release from GP synaptosomes (130.4 ± 3.6% of control values) was prevented by the PKA inhibitor H-89 and mimicked by the adenylyl cyclase activator forskolin or by 8-Bromo-cAMP, a membrane permeant cAMP analogue (169.5 ± 17.3 and 149.5 ± 14.5% of controls). H3R activation failed to reduce the facilitation of [3H]-GABA release induced by 8-Bromo-cAMP. In GP slices, A2AR activation stimulated cAMP accumulation (290% of basal) and this effect was reduced (- 75%) by H3R activation. These results indicate that in striato-pallidal nerve terminals, A2ARs and H3Rs interact at the level of cAMP formation to modulate PKA activity and thus GABA release.

Modelling the elimination of hepatitis C as a public health threat in Iceland: A goal attainable by 2020.

BACKGROUND & AIMS: In Iceland a nationwide program has been launched offering direct-acting antiviral (DAA) treatment for everyone living with hepatitis C virus (HCV). We estimate (i) the time and treatment scale-up required to achieve the World Health Organization's HCV elimination target of an 80% reduction in incidence; and (ii) the ongoing frequency of HCV testing and harm reduction coverage among people who inject drugs (PWID) required to minimize the likelihood of future HCV outbreaks occurring. METHODS: We used a dynamic compartmental model of HCV transmission, liver disease progression and the HCV cascade of care, calibrated to reproduce the epidemic of HCV in Iceland. The model was stratified according to injecting drug use status, age and stage of engagement. Four scenarios were considered for the projections. RESULTS: The model estimated that an 80% reduction in domestic HCV incidence was achievable by 2030, 2025 or 2020 if a minimum of 55/1,000, 75/1,000 and 188/1,000 PWID were treated per year, respectively (a total of 22, 30 and 75 of the estimated 400 PWID in Iceland per year, respectively). Regardless of time frame, this required an increased number of PWID to be diagnosed to generate enough treatment demand, or a 20% scale-up of harm reduction services to complement treatment-as-prevention incidence reductions. When DAA scale-up was combined with annual antibody testing of PWID, the incidence reduction target was reached by 2024. Treatment scale-up with no other changes to current testing and harm reduction services reduced the basic reproduction number of HCV from 1.08 to 0.59, indicating that future outbreaks would be unlikely. CONCLUSION: HCV elimination in Iceland is achievable by 2020 with some additional screening of PWID. Maintaining current monitoring and harm reduction services while providing ongoing access to DAA therapy for people diagnosed with HCV would ensure that outbreaks are unlikely to occur once elimination targets have been reached. LAY SUMMARY: In Iceland, a nationwide program has been launched offering treatment for the entire population living with hepatitis C virus (HCV). A mathematical model was used to estimate the additional health system requirements to achieve the HCV elimination targets of the World Health Organization (WHO), as well as the year that this could occur. With some additional screening of people who inject drugs, Iceland could reach the WHO targets by 2020, becoming one of the first countries to achieve HCV elimination. The model estimated that once elimination targets were reached, maintaining current monitoring and harm reduction services while providing ongoing access to DAA therapy for people diagnosed with HCV would ensure that future HCV outbreaks are unlikely to occur.

Histamine H3 receptor activation stimulates calcium mobilization in a subpopulation of rat striatal neurons in primary culture, but not in synaptosomes.

The histamine H3 receptor (H3R) is abundantly expressed in the Central Nervous System where it regulates several functions pre and postsynaptically. H3Rs couple to Gαi/o proteins and trigger or modulate several intracellular signaling pathways, including the cAMP/PKA pathway and the opening of N- and P/Q-type voltage-gated Ca2+ channels. In transfected cells, activation of the human H3R of 445 amino acids (hH3R445) results in phospholipase C (PLC) stimulation and release of Ca2+ from intracellular stores. In this work we have studied whether H3R activation induces Ca2+ mobilization from intracellular stores in native systems, either isolated nerve terminals (synaptosomes) or neurons in primary culture. In rat striatal synaptosomes H3R activation induced inositol 1,4,5-trisphosphate (IP3) formation but failed to increase the intracellular calcium concentration ([Ca2+]i). In striatal primary cultures H3R activation resulted in IP3 formation and increased the [Ca2+]i in 18 out of 70 cells that responded with an elevation in the [Ca2+]i to membrane depolarization with KCl (100 mM) as evaluated by microfluorometry. Confocal microscopy studies corroborated the increase in [Ca2+]i induced by H3R activation in a fraction of those cells that were responsive to membrane depolarization. These results indicate that H3R activation stimulates the PLC/IP3/Ca2+ pathway but only in a subpopulation of striatal neurons.

Heterologous, PKC-Mediated Desensitization of Human Histamine H3 Receptors Expressed in CHO-K1 Cells.

Desensitization is a major mechanism to regulate the functional response of G protein-coupled receptors. In this work we studied whether the human histamine H3 receptor of 445 amino acids (hH3R445) experiences heterologous desensitization mediated by PKC activation. Bioinformatic analysis indicated the presence of Serine and Threonine residues susceptible of PKC-mediated phosphorylation on the third intracellular loop and the carboxyl terminus of the hH3R445. In CHO-K1 cells stably transfected with the hH3R445 direct PKC activation by phorbol 12-myristate 13-acetate (TPA, 200 nM) abolished H3R-mediated inhibition of forskolin-stimulated cAMP accumulation. Activation of endogenous purinergic receptors by ATP (adenosine 5'-triphosphate, 10 µM) increased the free calcium intracellular concentration ([Ca(2+)]i) confirming their coupling to phospholipase C stimulation. Incubation with ATP also abolished H3R-mediated inhibition of forskolin-induced cAMP accumulation, and this effect was prevented by the PKC inhibitors Ro-31-8220 and Gö-6976. Pre-incubation with TPA or ATP reduced H3R-mediated stimulation of [(35)S]-GTPγS binding to membranes from CHO-K1-hH3R445 cells by 39.7 and 54.2 %, respectively, with no change in the agonist potency, and the effect was prevented by either Ro-31-8220 or Gö-6976. Exposure to ATP or TPA also resulted in the loss of cell surface H3Rs (-30.4 and -45.1 %) as evaluated by [(3)H]-NMHA binding to intact cells. These results indicate that the hH3R445 undergoes heterologous desensitization upon activation of receptors coupled to PKC stimulation.

Intense habitat-specific fisheries-induced selection at the molecular Pan I locus predicts imminent collapse of a major cod fishery.

Predation is a powerful agent in the ecology and evolution of predator and prey. Prey may select multiple habitats whereby different genotypes prefer different habitats. If the predator is also habitat-specific the prey may evolve different habitat occupancy. Drastic changes can occur in the relation of the predator to the evolved prey. Fisheries exert powerful predation and can be a potent evolutionary force. Fisheries-induced selection can lead to phenotypic changes that influence the collapse and recovery of the fishery. However, heritability of the phenotypic traits involved and selection intensities are low suggesting that fisheries-induced evolution occurs at moderate rates at decadal time scales. The Pantophysin I (Pan I) locus in Atlantic cod (Gadus morhua), representing an ancient balanced polymorphism predating the split of cod and its sister species, is under an unusual mix of balancing and directional selection including current selective sweeps. Here we show that Pan I alleles are highly correlated with depth with a gradient of 0.44% allele frequency change per meter. AA fish are shallow-water and BB deep-water adapted in accordance with behavioral studies using data storage tags showing habitat selection by Pan I genotype. AB fish are somewhat intermediate although closer to AA. Furthermore, using a sampling design covering space and time we detect intense habitat-specific fisheries-induced selection against the shallow-water adapted fish with an average 8% allele frequency change per year within year class. Genotypic fitness estimates (0.08, 0.27, 1.00 of AA, AB, and BB respectively) predict rapid disappearance of shallow-water adapted fish. Ecological and evolutionary time scales, therefore, are congruent. We hypothesize a potential collapse of the fishery. We find that probabilistic maturation reaction norms for Atlantic cod at Iceland show declining length and age at maturing comparable to changes that preceded the collapse of northern cod at Newfoundland, further supporting the hypothesis. We speculate that immediate establishment of large no-take reserves may help avert collapse.