Testing Milk and Cream

The Babcock test and the scales are in reality the foundation of profitable dairy farming. By the proper use of these utensils it is possible, not only to find the average production of the cows in general, but also to single out those which are not paying for their keep. By disposing of those animals and replacing them with better ones, it is possible to put dairy farming on a business-like and profitable basis

Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.

The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination

Time trends in incidence and prevalence of chronic pancreatitis:A 25-year population-based nationwide study

BACKGROUND: Updated population‐based estimates on incidence and prevalence of chronic pancreatitis are scarce. METHODS: We used nationwide healthcare registries to identify all Danish patients diagnosed with chronic pancreatitis and computed crude and standardised incidence rates and prevalence estimates in 1994–2018. Incidence and prevalence were evaluated in relation to patients age and gender, aetiology (alcoholic vs. non‐alcoholic) and smoking and alcohol consumption in the general Danish population. RESULTS: The mean incidence rate of chronic pancreatitis during the study period was 12.6 per 100,000 person years for the total population, for women it was 8.6 per 100,000 person years and for men it was 16.7 per 100,000 person years. The standardised incidence rate was stable from 1994 to 2018, remaining at 12.5 per 100,000 person years in the last observation period (2014–2018). The point prevalence of chronic pancreatitis in 2016 was 153.9 per 100,000 persons. A gradual increase in standardised prevalence estimates was observed during the study period from 126.6 in 1996 to 153.9 in 2016. The mean age at chronic pancreatitis diagnosis increased from 52.1 to 60.0 years during the study period. CONCLUSION: The prevalence of chronic pancreatitis is increasing in the Danish population despite a stable incidence level. Improved management strategies and changes in the underlying patient population may explain these observations

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

OBJECTIVE: First, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk. METHODS: We conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011. RESULTS: Compared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10-0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33-0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12-0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98-1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90-1.27; p for heterogeneity: 0.098)]. CONCLUSION: The well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation

The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo.

UNLABELLED: Pharmacologically-induced activation of replication competent proviruses from latency in the presence of antiretroviral treatment (ART) has been proposed as a step towards curing HIV-1 infection. However, until now, approaches to reverse HIV-1 latency in humans have yielded mixed results. Here, we report a proof-of-concept phase Ib/IIa trial where 6 aviremic HIV-1 infected adults received intravenous 5 mg/m2 romidepsin (Celgene) once weekly for 3 weeks while maintaining ART. Lymphocyte histone H3 acetylation, a cellular measure of the pharmacodynamic response to romidepsin, increased rapidly (maximum fold range: 3.7-7.7 relative to baseline) within the first hours following each romidepsin administration. Concurrently, HIV-1 transcription quantified as copies of cell-associated un-spliced HIV-1 RNA increased significantly from baseline during treatment (range of fold-increase: 2.4-5.0; p = 0.03). Plasma HIV-1 RNA increased from <20 copies/mL at baseline to readily quantifiable levels at multiple post-infusion time-points in 5 of 6 patients (range 46-103 copies/mL following the second infusion, p = 0.04). Importantly, romidepsin did not decrease the number of HIV-specific T cells or inhibit T cell cytokine production. Adverse events (all grade 1-2) were consistent with the known side effects of romidepsin. In conclusion, romidepsin safely induced HIV-1 transcription resulting in plasma HIV-1 RNA that was readily detected with standard commercial assays demonstrating that significant reversal of HIV-1 latency in vivo is possible without blunting T cell-mediated immune responses. These finding have major implications for future trials aiming to eradicate the HIV-1 reservoir. TRIAL REGISTRATION: clinicaltrials.gov NTC02092116

In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals

Histone deacetylase inhibitors (HDACi) have proven to induce HIV-RNA and antigen expression in resting CD4 T cells of antiretroviral therapy (ART)-treated HIV-infected individuals. However, to achieve viral eradication, immune clearance must follow latency reversal, and thus it is essential to understand the impact of latency reversal agents on immune function.Design:Here we evaluate the impact of in-vivo administration of vorinostat (VOR) and panobinostat (PNB) during clinical trials on natural killer (NK) cell function and phenotype.Methods:Cryopreserved peripheral blood mononuclear cells from HIV-positive participants receiving VOR (NCT01319383) or PNB (NCT01680094) were selected to assess the impact of the drugs on cell composition, activation, NK cell phenotype (CD16, NKG2D, NKp30, NKp46 and DNAM-1), cytotoxic activity (CD107a), and interferon (IFN)-γ production.Results:No impairment of NK cell function was observed during treatment with either VOR or PNB. An increase in the frequency of CD3-CD56 NK cells was consistently observed. Interestingly, after VOR administration, NK cells increased expression of NKp46 and CD16, and showed improved degranulation and IFN-γ production capacity. Moreover, taking together VOR and PNB samples, HIV DNA levels in CD4 cells were negatively correlated with NK cell frequency and NK cell expression of CD16.Conclusions:In-vivo treatment with HDACi does not have measurable negative effects on NK cell function, with some evidence of improved function in vitro. These results have important implications for potential combinatorial approaches to target HIV reservoirs, suggesting that the use of HDACis as a latency reversal agent could be paired with interventions to enhance NK cell activity or recruitment

Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology.

Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates. The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant CHMP2B. Ultrastructural analysis and immuno- gold labelling confirmed that they are derived from the endolysosomal system. Consistent with these findings, CHMP2B mutation patient brains contain morphologically similar autofluorescent aggregates. These aggregates occur significantly more frequently in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B are important for lysosomal function. Our identification of lysosomal storage pathology in FTD caused by CHMP2B mutation now provides evidence that endolysosomal dysfunction is a major degenerative pathway in FTD