Predicting urinary creatinine excretion and its usefulness to identify incomplete 24h urine collections

Studies using 24 h urine collections need to incorporate ways to validate the completeness of the urine samples. Models to predict urinary creatinine excretion (UCE) have been developed for this purpose; however, information on their usefulness to identify incomplete urine collections is limited. We aimed to develop a model for predicting UCE and to assess the performance of a creatinine index using para-aminobenzoic acid (PABA) as a reference. Data were taken from the European Food Consumption Validation study comprising two non-consecutive 24 h urine collections from 600 subjects in five European countries. Data from one collection were used to build a multiple linear regression model to predict UCE, and data from the other collection were used for performance testing of a creatinine index-based strategy to identify incomplete collections. Multiple linear regression (n 458) of UCE showed a significant positive association for body weight (ß = 0·07), the interaction term sex × weight (ß = 0·09, reference women) and protein intake (ß = 0·02). A significant negative association was found for age (ß = - 0·09) and sex (ß = - 3·14, reference women). An index of observed-to-predicted creatinine resulted in a sensitivity to identify incomplete collections of 0·06 (95 % CI 0·01, 0·20) and 0·11 (95 % CI 0·03, 0·22) in men and women, respectively. Specificity was 0·97 (95 % CI 0·97, 0·98) in men and 0·98 (95 % CI 0·98, 0·99) in women. The present study shows that UCE can be predicted from weight, age and sex. However, the results revealed that a creatinine index based on these predictions is not sufficiently sensitive to exclude incomplete 24 h urine collections

Pesticide exposure and lymphohaematopoietic cancers: a case-control study in an agricultural region (Larissa, Thessaly, Greece)

<p>Abstract</p> <p>Background</p> <p>The causality of lymphohaematopoietic cancers (LHC) is multifactorial and studies investigating the association between chemical exposure and LHC have produced variable results. The aim of this study was to investigate the relationships between exposure to pesticides and LHC in an agricultural region of Greece.</p> <p>Methods</p> <p>A structured questionnaire was employed in a hospital-based case control study to gather information on demographics, occupation, exposure to pesticides, agricultural practices, family and medical history and smoking. To control for confounders, backward conditional and multinomial logistic regression analyses were used. To assess the dose-response relationship between exposure and disease, the chi-square test for trend was used.</p> <p>Results</p> <p>Three hundred and fifty-four (354) histologically confirmed LHC cases diagnosed from 2004 to 2006 and 455 sex- and age-matched controls were included in the study. Pesticide exposure was associated with total LHC cases (OR 1.46, 95% CI 1.05-2.04), myelodysplastic syndrome (MDS) (OR 1.87, 95% CI 1.00-3.51) and leukaemia (OR 2.14, 95% CI 1.09-4.20). A dose-response pattern was observed for total LHC cases (P = 0.004), MDS (P = 0.024) and leukaemia (P = 0.002). Pesticide exposure was independently associated with total LHC cases (OR 1.41, 95% CI 1.00 - 2.00) and leukaemia (OR 2.05, 95% CI 1.02-4.12) after controlling for age, smoking and family history (cancers, LHC and immunological disorders). Smoking during application of pesticides was strongly associated with total LHC cases (OR 3.29, 95% CI 1.81-5.98), MDS (OR 3.67, 95% CI 1.18-12.11), leukaemia (OR 10.15, 95% CI 2.15-65.69) and lymphoma (OR 2.72, 95% CI 1.02-8.00). This association was even stronger for total LHC cases (OR 18.18, 95% CI 2.38-381.17) when eating simultaneously with pesticide application.</p> <p>Conclusions</p> <p>Lymphohaematopoietic cancers were associated with pesticide exposure after controlling for confounders. Smoking and eating during pesticide application were identified as modifying factors increasing the risk for LHC. The poor pesticide work practices identified during this study underline the need for educational campaigns for farmers.</p

Novel therapeutic strategies targeting HIV integrase

Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds

LEDGF/p75-Independent HIV-1 Replication Demonstrates a Role for HRP-2 and Remains Sensitive to Inhibition by LEDGINs

Lens epithelium–derived growth factor (LEDGF/p75) is a cellular cofactor of HIV-1 integrase (IN) that interacts with IN through its IN binding domain (IBD) and tethers the viral pre-integration complex to the host cell chromatin. Here we report the generation of a human somatic LEDGF/p75 knockout cell line that allows the study of spreading HIV-1 infection in the absence of LEDGF/p75. By homologous recombination the exons encoding the LEDGF/p75 IBD (exons 11 to 14) were knocked out. In the absence of LEDGF/p75 replication of laboratory HIV-1 strains was severely delayed while clinical HIV-1 isolates were replication-defective. The residual replication was predominantly mediated by the Hepatoma-derived growth factor related protein 2 (HRP-2), the only cellular protein besides LEDGF/p75 that contains an IBD. Importantly, the recently described IN-LEDGF/p75 inhibitors (LEDGINs) remained active even in the absence of LEDGF/p75 by blocking the interaction with the IBD of HRP-2. These results further support the potential of LEDGINs as allosteric integrase inhibitors

Diverse Roles and Interactions of the SWI/SNF Chromatin Remodeling Complex Revealed Using Global Approaches

A systems understanding of nuclear organization and events is critical for determining how cells divide, differentiate, and respond to stimuli and for identifying the causes of diseases. Chromatin remodeling complexes such as SWI/SNF have been implicated in a wide variety of cellular processes including gene expression, nuclear organization, centromere function, and chromosomal stability, and mutations in SWI/SNF components have been linked to several types of cancer. To better understand the biological processes in which chromatin remodeling proteins participate, we globally mapped binding regions for several components of the SWI/SNF complex throughout the human genome using ChIP-Seq. SWI/SNF components were found to lie near regulatory elements integral to transcription (e.g. 5′ ends, RNA Polymerases II and III, and enhancers) as well as regions critical for chromosome organization (e.g. CTCF, lamins, and DNA replication origins). Interestingly we also find that certain configurations of SWI/SNF subunits are associated with transcripts that have higher levels of expression, whereas other configurations of SWI/SNF factors are associated with transcripts that have lower levels of expression. To further elucidate the association of SWI/SNF subunits with each other as well as with other nuclear proteins, we also analyzed SWI/SNF immunoprecipitated complexes by mass spectrometry. Individual SWI/SNF factors are associated with their own family members, as well as with cellular constituents such as nuclear matrix proteins, key transcription factors, and centromere components, implying a ubiquitous role in gene regulation and nuclear function. We find an overrepresentation of both SWI/SNF-associated regions and proteins in cell cycle and chromosome organization. Taken together the results from our ChIP and immunoprecipitation experiments suggest that SWI/SNF facilitates gene regulation and genome function more broadly and through a greater diversity of interactions than previously appreciated

HIV infection of non-dividing cells: a divisive problem

Understanding how lentiviruses can infect terminally differentiated, non-dividing cells has proven a very complex and controversial problem. It is, however, a problem worth investigating, for it is central to HIV-1 transmission and AIDS pathogenesis. Here I shall attempt to summarise what is our current understanding for HIV-1 infection of non-dividing cells. In some cases I shall also attempt to make sense of controversies in the field and advance one or two modest proposals

Retrospective study of owners’ perception on home monitoring of blood glucose in diabetic dogs and cats

Home monitoring of blood glucose (HMBG) concentrations has been recommended in the monitoring of human diabetics for 3 decades. During the last number of years, it also gained popularity in long-term follow-up of diabetic cats and dogs. The aim of this retrospective study was to evaluate the practical feasibility of and identify the major problems encountered with HMBG in diabetic pets. A standard questionnaire was filled in by owners of 9 diabetic pets monitored with HMBG. The need for more than 1 puncture to obtain a blood drop, the creation of a sufficient blood drop, the need for assistance in restraining the pet, and the resistance of the pet were the most frequently encountered problems during HMBG. The major obstacles for the owners to start with HMBG were also identified. In conclusion, HMBG is a practical and simple technique for most owners and, overall, owners were satisfied