Alteration of cytokine levels in murine retrovirus infection: modulation by combination therapy

Immunoregulatory cytokines may regulate the resistance or susceptibility of a host to retroviral infection. These cytokines may be therapeutically modulated to prevent or limit the progression of infection. The non-progression to AIDS of some HIV+ patients has been related to a strong type 1 cytokine response (IL-2, IL-12, and IFNgamma). For this reason, we investigated the ability of combination therapeutics to modulate cytokines in vivo towards a type 1 cytokine response in a murine retroviral infection using Friend leukemia virus (FLV). BALB/c mice were infected with FLV and treated with either 3'-azido-3'-deoxythymidine (AZT), the immunomodulator methionine enkephalin (MENK), or a combination of both AZT and MENK starting 3 d post infection. Splenocytes were harvested on days 1, 3, 7, 14, 21 and 28 post treatment initiation and cultured with 1 microg/ml concanavalin A (ConA) for 24 h. Supernatants were examined for IL-2, IL-4, IL-10, IL-12, and IFNgamma cytokine production using cytokine specific ELISAs. The levels of type 2 cytokines were not significantly changed by any treatment group over the course of the disease. However, although decreased in all infected animals, type 1 cytokines were partially maintained by the combination treatment through day 21. RT-PCR for cytokine specific mRNA confirmed these results, with expression of the type 1 cytokines, especially IFNgamma, being maintained through day 21. Establishment of a treatment regime that can maintain protective cytokine activities against disease progression may prove applicable to other retroviral infections.     

Associations between electrocardiographic interval durations and coronary artery calcium scores: the Diabetes Heart Study

Background: The mechanisms underlying the associations between QT interval duration and risk of cardiovascular disease (CVD) remain unclear. It has been assumed that these associations are driven by abnormal myocardial repolarization. We examined the relationship between coronary artery disease, measured by coronary artery calcified plaque (CAC), and the duration of QRS, JT, and QT intervals, among predominantly type two diabetic participants.
Methods: The study sample included 1,123 subjects from the Diabetes Heart Study, of whom 85% had type 2 diabetes. Correlations between electrocardiogram interval durations and log-transformed coronary artery calcified (CAC) were assessed in univariate and sequential multivariable generalized estimating equation models adjusted for familial correlations, heart rate, age, race, gender, diabetes status, hypertension status, Body Mass Index (BMI), smoking status, systolic blood pressure, Low Density Lipoprotein (LDL) cholesterol, QT-prolonging medications, and use of exogenous estrogen.
Results: QT interval duration significantly correlated with the extent of CAC in univariate (r = 0.09, P = 0.01) and multivariable models (r = 0.08, P = 0.01). We observed strong correlations between the QRS duration and CAC in univariate (r = 0.23, P < 0.0001) and adjusted models (r = 0.10, P = 0.01). In contrast, the JT interval was not associated with CAC. A strong correlation existed between the QRS interval and CAC in men (QRS: r = 0.24, P ≤ 0.0001) and diabetics (QRS: r = 0.25, P ≤ 0.0001) but was absent in women and nondiabetics. These relationships were not modified by CVD, race, or presence of bundle branch block.
Conclusion: QT duration correlates with the amount of CAC in a predominantly diabetic population. The association between QT duration and CAC is driven by QRS and not JT interval duration.     

Depressive relapse during lithium treatment associated with increased serum thyroid‐stimulating hormone: results from two placebo‐controlled bipolar I maintenance studies

Objective: To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder. Method: Mean thyroid‐stimulating hormone (TSH) and outcome data were pooled from two 18‐month, double‐blind, placebo‐controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (±14 days) or study drop‐out was conducted. Results: Lithium‐treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 μIU/ml) compared with lithium‐treated subjects who did not require intervention for a depressive episode (2.4 μIU/ml). Conclusion: Lithium‐related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.     

Investigation of the estrogen receptor-alpha gene with type 2 diabetes and/or nephropathy in African-American and European-American populations

The estrogen receptor-alpha gene (ESR1) was selected as a positional candidate under a type 2 diabetes linkage peak at 6q24-27. A total of 42 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 380 African-American type 2 diabetic case subjects with end-stage renal disease (ESRD) and 276 African-American control subjects. A total of 22 ancestry informative markers were also genotyped, and the program Admixmap was used to adjust allelic and haplotypic association tests for individual estimates of admixture. The most significant association with type 2 diabetes-ESRD was with rs1033182 in intron 2 (P = 0.013, admixture-adjusted P(a) = 0.021). Genotyping 17 SNPs across a region of ESR1 intron 1-intron 2 in an expanded population of 851 case and 635 control subjects supported association with rs1033182 (P = 0.004, P(a) = 0.027) and with an independent six-SNP haplotype of high linkage disequilibrium spanning 6.4 kb (P < 0.0001, P(a) < 0.0001). The same 17 ESR1 SNPs were genotyped in 300 European-American type 2 diabetes-ESRD case subjects and 310 European-American control subjects. Two intron 2 SNPs, rs2431260 (P = 0.015) and rs1709183 (P = 0.019), and a four-SNP haplotype containing these SNPs (P = 0.033) were associated with type 2 diabetes and/or ESRD. Results suggest that intron 1 and intron 2 of the ESR1 gene may contain functionally important regions related to type 2 diabetes or ESRD risk.     

Telling partners about chlamydia: how acceptable are the new technologies?

Background  

Partner notification is accepted as a vital component in the control of chlamydia. However, in reality, many sexual partners of individuals diagnosed with chlamydia are never informed of their risk. The newer technologies of email and SMS have been used as a means of improving partner notification rates. This study explored the use and acceptability of different partner notification methods to help inform the development of strategies and resources to increase the number of partners notified.     

Failure of lamivudine to reverse hepatitis B virus-associated changes in ERK, Akt and cell cycle regulatory proteins

BACKGROUND: Chronic infection with hepatitis B virus (HBV) is a major factor associated with the development of hepatocellular carcinoma, but the mechanism by which this occurs is unknown. Treatment of chronic hepatitis B with lamivudine results in virological suppression and histological improvement; however, the role of lamivudine in preventing the development of hepatocellular carcinoma is less well defined. We recently reported that replication of HBV in a cell-culture system was associated with the upregulation of pERK, pAkt, pc-Myc, nuclear cyclin B1, p21(cip1) and p53 together with G2 cell cycle arrest. METHODS: In order to determine whether lamivudine is able to reverse the HBV-induced changes on signal transduction and cell cycle, we infected Huh7 cells with a recombinant adeno-HBV virus in the presence of 0-50 microM of lamivudine. Signal transduction and cell cycle regulatory proteins were analysed by western immunoblot. RESULTS: Although lamivudine was able to inhibit HBV replication, it failed to reverse the changes on ERK and Akt phosphorylation. Correspondingly, levels of phospho-GSK3beta and p21(cp1/waf1) were increased, as were cyclin D1, cyclin B1, p53 and pc-Myc. CONCLUSIONS: Lamivudine was ineffective in reversing the HBV-induced changes in signal transduction pathways and cell cycle regulatory proteins, indicating that the HBV-infected cells remained primed for oncogenic transformation despite viral suppression.     

Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure

Introduction  

The dural sheath surrounding the optic nerve communicates with the subarachnoid space, and distends when intracranial pressure is elevated. Magnetic resonance imaging (MRI) is often performed in patients at risk for raised intracranial pressure (ICP) and can be used to measure precisely the diameter of optic nerve and its sheath. The objective of this study was to assess the relationship between optic nerve sheath diameter (ONSD), as measured using MRI, and ICP.     

People of the British Isles: preliminary analysis of genotypes and surnames in a UK-control population

There is a great deal of interest in a fine-scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to have a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. In this study, we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK-control population that can be used as a resource by the research community, as well as providing a fine-scale genetic information on the British population. So far, some 4000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3 km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1057 samples demonstrates the value of these samples for investigating a fine-scale population structure within the UK, and shows how this can be enhanced by the use of surnames.     

Using Tendon Inherent Electric Properties to Consistently Track Induced Mechanical Strain

The present work explores the possibility that the inherent electrical properties of a tendon might allow it to act as its own strain gauge. Tendon has been shown to exhibit piezoelectric effects as well as streaming potentials when subjected to a mechanical stress. To assess the feasibility of using these properties to repeatably measure in situ strain,bovine Achilles tendon test specimens were connected in series with a control resistor in a direct current circuit. Longitudinal(along the collagen fiber direction) and transverse test specimens were subjected to sinusoidal tension while electrical resistance data for the specimens was collected. Change in resistance per unit strain and gauge factors (GFs) revealed a repeatable and significantly different correlation between resistance and strain for the longitudinal and transverse specimens (p<0.001). Change in resistance per unit strain values for longitudinal and transverse specimens were 0.85 and 1.76 MX/e, respectively while corresponding GFs were 0.52 and 0.74, respectively. Others have reported piezoelectric mechanisms and streaming potential mechanisms in hydrated collagen, however the present work is unique in presenting an accurate and repeatable model of anisotropic tendon behavior that could be used to develop an in situ strain sensor.