Cystic fibrosis and the phenotypic expression of autosomal dominant polycystic kidney disease

Recent experiments in cultured cyst epithelial cells from kidneys of patients with autosomal dominant polycystic kidney disease (ADPKD) have shown that the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is present in the apical surface of these cells and mediates chloride (Cl-) and fluid secretion in vitro. To determine whether the presence of CF with the expression of mutated CFTR proteins modifies cyst formation in ADPKD, we studied a large family with both inherited diseases. ADPKD in this family is linked to PKD1. The family is composed of 26 members; 11 members with ADPKD, 4 members with CF, and 2 members with both diseases. Renal volumes measured by computerized tomography (CT), calculated creatinine clearances, and other clinical parameters in the family members with ADPKD and CF were compared with those in the family members with ADPKD alone, as well as to a large population of patients with ADPKD. The patients with CF and ADPKD, but not the CF heterozygote carriers with ADPKD, had less severe polycystic kidney and liver disease, as indicated by normal renal function; smaller renal volume, even when corrected for height and body surface area; and the absence of hypertension and liver cysts. These observations suggest that the coexistence of CF may reduce the severity of ADPKD.     

Patterns of cell proliferation and cell migration in the Sezary syndrome

The patterns of cell proliferation and cell migration were studied in three patients with the Sezary syndrome using autoradiographic techniques. Cell labeling patterns following pulse labeling with tritiated thymidine in vivo indicated that Sezary cells proliferate actively in skin and in lymph nodes but that few if any Sezary cells proliferate in the peripheral blood. In two of the patients serial samples were obtained. Label dilution patterns in skin and blood over time suggested that circulating Sezary cells originated in extracutaneous sites where cells were proliferating more rapidly than in the skin. Cells labeled in extracutaneous sites of proliferation appear rapidly in the blood, and their transit time through the peripheral blood compartment is short. Circulating Sezary cells may then be deposited in the skin where they resume proliferation at a low rate. Thus, while Sezary cells proliferate in both cutaneous and extracutaneous sites, proliferation appears to be more rapid in extracutaneous sites such as lymph nodes. This suggests that trials of systemic therapeutic approaches should be undertaken.     

Impact of a modified directly administered antiretroviral treatment intervention on virological outcome in HIV-infected patients treated in Burkina Faso and Mali

Objective

This study explores whether viral load measurements can be used in resource‐limited settings to target those in need of adherence assistance. It was hypothesized that high plasma viral loads (pVLs) (≥500 HIV‐1 RNA copies/mL) were the result of poor antiretroviral therapy adherence and amenable to improvement with adherence assistance.

Design

A single‐arm, multicentre pilot study was conducted from November 2003 to March 2004 on 606 treatment‐experienced patients who had initiated an antiretroviral regimen in Mali and Burkina Faso ≥6 months before study enrolment. In these patients, those whose pVL was ≥500 copies/mL were offered 1 month of modified directly administered antiretroviral treatment (mDAART) with weekly follow‐up visits from pharmacists or adherence counsellors.

Methods

An adherence questionnaire was given to all cohort patients and viral load was used to screen for patients with ≥500 copies/mL. mDAART participants included cohort patients with ≥500 copies/mL, who completed the adherence questionnaire. Genotypic analyses were conducted on samples taken prior to and after the intervention. The intervention was considered effective when there was a decrease of ≥1 log₁₀ in pVL.

Results

mDAART was effective in over one‐third of the intervention participants, while in two‐thirds no decrease in pVL was observed. The majority of mDAART participants had major resistance mutations.

Conclusions

pVL measurement was useful to identify patients who needed adherence assistance. However, because it was performed ≥6 months after starting treatment, mDAART came too late for most participants, as they had already developed important resistance mutations that might have been avoided with better laboratory monitoring.     

Correspondence between altered functional and structural connectivity in the contralesional sensorimotor cortex after unilateral stroke in rats: a combined resting-state functional MRI and manganese-enhanced MRI study

This study shows a significant correlation between functional connectivity, as measured with resting-state functional magnetic resonance imaging (MRI), and neuroanatomical connectivity, as measured with manganese-enhanced MRI, in rats at 10 weeks after unilateral stroke and in age-matched controls. Reduced interhemispheric functional connectivity between the contralesional primary motor cortex (M1) and ipsilesional sensorimotor cortical regions was accompanied by a decrease in transcallosal manganese transfer from contralesional M1 to the ipsilesional sensorimotor cortex after a large unilateral stroke. Increased intrahemispheric functional connectivity in the contralesional sensorimotor cortex was associated with locally enhanced neuroanatomical tracer uptake, which underlines the strong link between functional and structural reorganization of neuronal networks after stroke.     

An adenovirus type 5 (AdV5) vector encoding an envelope domain III-based tetravalent antigen elicits immune responses against all four dengue viruses in the presence of prior AdV5 immunity

Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of dengue viruses (DENVs). This disease, which is prevalent in over a hundred tropical and sub-tropical countries of the world, represents a significant global public health problem. A tetravalent dengue vaccine capable of protecting against all four DENV serotypes has been elusive so far. Current efforts are focused on producing a tetravalent vaccine by mixing four monovalent vaccine components. In this work, we have utilized a discrete carboxy-terminal region of the major DENV envelope (E) protein, known as domain III (EDIII), which mediates virus entry into target cells and contains multiple serotype-specific neutralizing epitopes, to create a chimeric tetravalent antigen. This antigen derived by in-frame fusion of the EDIII-encoding sequences of the four DENV serotypes was expressed using a replication-defective recombinant human adenovirus type 5 (rAdV5) vaccine vector. This rAdV5 vector induced cell-mediated immune responses and virus-neutralizing antibodies specific to each of the four DENVs in mice. Interestingly, anti-AdV5 antibodies did not suppress the induction of DENV-specific neutralizing antibodies. We observed that anti-AdV5 antibodies in the sera of immunized mice could promote uptake of a rAdV5-derived reporter vector into U937 cells, suggesting that pre-existing immunity to AdV5 may in fact facilitate the uptake of rAdV5 vectored vaccines into antigen presenting cells. This work presents an alternative approach to developing a single component tetravalent vaccine that bypasses the complexities inherent in the currently adopted four-in-one physical mixture approach.