Coordinated multidisciplinary care for ambulatory Huntington's disease patients. Evaluation of 18 months of implementation

Background

terminal deletions of the distal portion of the short arm of chromosome 3 cause a rare contiguous gene disorder characterized by growth retardation, developmental delay, mental retardation, dysmorphisms, microcephaly and ptosis. The phenotype of individuals with deletions varies from normal to severe. It was suggested that a 1,5 Mb minimal terminal deletion including the two genes CRBN and CNTN4 is sufficient to cause the syndrome. In addition the CHL1 gene, mapping at 3p26.3 distally to CRBN and CNTN4, was proposed as candidate gene for a non specific mental retardation because of its high level of expression in the brain.

Methods and Results

we describe two affected siblings in which array-CGH analysis disclosed an identical discontinuous terminal 3p26.3 deletion spanning less than 1 Mb. The deletion was transmitted from their normal father and included only the CHL1 gene. The two brothers present microcephaly, light mental retardation, learning and language difficulties but not the typical phenotype manifestations described in 3p- syndrome.

Conclusion

a terminal 3p26.3 deletion including only the CHL1 gene is a very rare finding previously reported only in one family. The phenotype of the affected individuals in the two families is very similar and the deletion has been inherited from an apparently normal parent. As already described for others recurrent syndromes with variable phenotype, these findings are challenging in genetic counselling because of an evident variable penetrance.     

Effect of heating and glycation on the allergenicity of 2S albumins (Ara h 2/6) from peanut

Background

Peanut allergy is one of the most common and severe food allergies, and processing is known to influence the allergenicity of peanut proteins. We aimed to establish the effect of heating and glycation on the IgE-binding properties and biological activity of 2S albumins (Ara h 2/6) from peanut.

Methodology/Principal Findings

Native Ara h 2/6 was purified from raw peanuts and heated in solution (15 min, 110°C) in the presence or absence of glucose. Ara h 2 and 6 were also purified from roasted peanut. Using PBMC and sera from peanut-allergic patients, the cellular proliferative potency and IgE reactivity (reverse EAST inhibition) and functionality (basophil degranulation capacity) of allergens were assessed. Heating Ara h 2/6 at 110°C resulted in extensive denaturation, hydrolysis and aggregation of the protein, whilst Ara h 2 and 6 isolated from roasted peanut retained its native conformation. Allergen stimulation of PBMC induced proliferation and Th2 cytokine secretion which was unaffected by thermal processing. Conversely, IgE reactivity and functionality of Ara h 2/6 was decreased by heating. Whilst heating-glycation further reduced the IgE binding capacity of the proteins, it moderated their loss of histamine releasing capacity. Ara h 2 and 6 purified from roasted peanut demonstrated the same IgE reactivity as unheated, native Ara h 2/6.

Conclusions/Significance

Although no effect of processing on T-cell reactivity was observed, heat induced denaturation reduced the IgE reactivity and subsequent functionality of Ara h 2/6. Conversely, Ara h 2 and 6 purified from roasted peanut retained the structure and IgE reactivity/functionality of the native protein which may explain the allergenic potency of this protein. Through detailed molecular study and allergenicity assessment approaches, this work then gives new insights into the effect of thermal processing on structure/allergenicity of peanut proteins.     

High burden of prevalent and recently acquired HIV among female sex workers and female HIV voluntary testing center clients in Kigali, Rwanda

Objectives

To estimate HIV prevalence and risk factors in population-based samples of female sex workers (FSW) and female voluntary counseling and testing (VCT) clients in Rwanda.

Methods

We conducted a cross-sectional survey of 800 FSW and 1,250 female VCT clients in Rwanda, which included interviewing and testing for HIV-1/2, HSV-2 and pregnancy, and BED-CEIA and Avidity Index (AI) to identify recent infections among HIV-infected women.

Results

Prevalence of HIV-1, HSV-2, and pregnancy were 24% (95% CI: 21.0–27.0), 59.8% (56.4–63.2), and 7.6% (5.8–9.5) among FSW, and 12.8% (10.9–14.6), 43.2% (40.4–46.0), and 11.4% (9.7–13.3) among VCT clients, respectively. Thirty-five percent of FSW and 25% of VCT clients had never been HIV tested. Per national guidelines, 33% of newly HIV-diagnosed FSW and 36% of VCT clients were already eligible for ART based on CD4<350 cells/µl. Condom use at last sex was higher among FSW (74%) than VCT clients (12%). In age and district of residence-adjusted models, HIV-1 seropositivity was associated with HSV-2 co-infection; recent treatment for sexually transmitted infection (STI); genital symptoms; forced sex; imprisonment; widowhood; and alcohol consumption. Eleven percent of FSW and 12% of VCT clients had recently acquired HIV-1 per BED-CEIA and AI. HSV-2 infection and recent STI treatment were associated with recent HIV infection in both groups, and being married and vaginal cleansing were associated with recent infection before last sex among VCT clients.

Conclusions

This population-based survey reveals a high HIV prevalence and incidence among FSW and female VCT clients in Kigali, the scale of which is masked by the low general-population HIV prevalence in Rwanda. HIV/STI and family planning services should be strengthened.     

Acceptability of Carraguard vaginal microbicide gel among HIV-infected women in Chiang Rai, Thailand

Background

Few studies of microbicide acceptability among HIV-infected women have been done. We assessed Carraguard® vaginal gel acceptability among participants in a randomized, controlled, crossover safety trial in HIV-infected women in Thailand.

Methodology/Principal Findings

Participants used each of 3 treatments (Carraguard gel, methylcellulose placebo gel, and no product) for 7 days, were randomized to one of six treatment sequences, and were blinded to the type of gel they received in the two gel-use periods. After both gel-use periods, acceptability was assessed by face-to-face interview. Responses were compared to those of women participating in two previous Carraguard safety studies at the same study site. Sixty women enrolled with a median age of 34 years; 25% were sexually active. Self-reported adherence (98%) and overall satisfaction rating of the gels (87% liked “somewhat” or “very much”) were high, and most (77%) considered the volume of gel “just right.” For most characteristics, crossover trial participants evaluated the gels more favorably than women in the other two trials, but there were few differences in the desired characteristics of a hypothetical microbicide. Almost half (48%) of crossover trial participants noticed a difference between Carraguard and placebo gels; 33% preferred Carraguard while 12% preferred placebo (p = 0.01).

Conclusions/Significance

Daily Carraguard vaginal gel use was highly acceptable in this population of HIV-infected women, who assessed the gels more positively than women in two other trials at the site. This may be attributable to higher perceived need for protection among HIV-infected women, as well as to study design differences. This trial was registered in the U.S. National Institutes of Health clinical trials registry under registration number {"type":"clinical-trial","attrs":{"text":"NCT00213044","term_id":"NCT00213044"}}NCT00213044.     

Cost-Effectiveness of Pre-Exposure Prophylaxis (PrEP) in Preventing HIV-1 Infections in Rural Zambia: A Modeling Study

Background

Pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine effectively prevents new HIV infections. The optimal scenario for implementing PrEP where most infections are averted at the lowest cost is unknown. We determined the impact of different PrEP strategies on averting new infections, prevalence, drug resistance and cost-effectiveness in Macha, a rural setting in Zambia.

Methods

A deterministic mathematical model of HIV transmission was constructed using data from the Macha epidemic (antenatal prevalence 7.7%). Antiretroviral therapy is started at CD4<350 cells/mm³. We compared the number of infections averted, cost-effectiveness, and potential emergence of drug resistance of two ends of the prioritization spectrum: prioritizing PrEP to half of the most sexually active individuals (5–15% of the total population), versus randomly putting 40–60% of the total population on PrEP.

Results

Prioritizing PrEP to individuals with the highest sexual activity resulted in more infections averted than a non-prioritized strategy over ten years (31% and 23% reduction in new infections respectively), and also a lower HIV prevalence after ten years (5.7%, 6.4% respectively). The strategy was very cost-effective at $323 per quality adjusted life year gained and appeared to be both less costly and more effective than the non-prioritized strategy. The prevalence of drug resistance due to PrEP was as high as 11.6% when all assumed breakthrough infections resulted in resistance, and as low as 1.3% when 10% of breakthrough infections resulted in resistance in both our prioritized and non-prioritized scenarios.

Conclusions

Even in settings with low test rates and treatment retention, the use of PrEP can still be a useful strategy in averting infections. Our model has shown that PrEP is a cost-effective strategy for reducing HIV incidence, even when adherence is suboptimal and prioritization is imperfect.     

Moving forward in global‐change ecology: capitalizing on natural variability

Natural resources managers are being asked to follow practices that accommodate for the impact of climate change on the ecosystems they manage, while global‐ecosystems modelers aim to forecast future responses under different climate scenarios. However, the lack of scientific knowledge about short‐term ecosystem responses to climate change has made it difficult to define set conservation practices or to realistically inform ecosystem models. Until recently, the main goal for ecologists was to study the composition and structure of communities and their implications for ecosystem function, but due to the probable magnitude and irreversibility of climate‐change effects (species extinctions and loss of ecosystem function), a shorter term focus on responses of ecosystems to climate change is needed. We highlight several underutilized approaches for studying the ecological consequences of climate change that capitalize on the natural variability of the climate system at different temporal and spatial scales. For example, studying organismal responses to extreme climatic events can inform about the resilience of populations to global warming and contribute to the assessment of local extinctions. Translocation experiments and gene expression are particular useful to quantitate a species' acclimation potential to global warming. And studies along environmental gradients can guide habitat restoration and protection programs by identifying vulnerable species and sites. These approaches identify the processes and mechanisms underlying species acclimation to changing conditions, combine different analytical approaches, and can be used to improve forecasts of the short‐term impacts of climate change and thus inform conservation practices and ecosystem models in a meaningful way.     

Living Situation Affects Adherence to Combination Antiretroviral Therapy in HIV-Infected Adolescents in Rwanda: A Qualitative Study

Introduction

Adherence to combination antiretroviral therapy (cART) is vital for HIV-infected adolescents for survival and quality of life. However, this age group faces many challenges to remain adherent. We used multiple data sources (role-play, focus group discussions (FGD), and in-depth interviews (IDI)) to better understand adherence barriers for Rwandan adolescents. Forty-two HIV positive adolescents (ages 12–21) and a selection of their primary caregivers were interviewed. All were perinatally-infected and received (cART) for ≥12 months. Topics discussed during FGDs and IDIs included learning HIV status, disclosure and stigma, care and treatment issues, cART adherence barriers.

Results

Median age was 17 years, 45% female, 45% orphaned, and 48% in boarding schools. We identified three overarching but inter-related themes that appeared to influence adherence. Stigma, perceived and experienced, and inadvertent disclosure of HIV status hampered adolescents from obtaining and taking their drugs, attending clinic visits, carrying their cARTs with them in public. The second major theme was the need for better support, in particular for adolescents with different living situations, (orphanages, foster-care, and boarding schools). Lack of privacy to keep and take medication came out as major barrier for adolescents living in congested households, as well the institutionalization of boarding schools where privacy is almost non-existent. The third important theme was the desire to be ‘normal’ and not be recognized as an HIV-infected individual, and to have a normal life not perturbed by taking a regimen of medications or being forced to disclose where others would treat them differently.

Conclusions

We propose better management of HIV-infected adolescents integrated into boarding school, orphanages, and foster care; training of school-faculty on how to support students and allow them privacy for taking their medications. To provide better care and support, HIV programs should stimulate caregivers of HIV-infected adolescents to join them for their clinic visits.     

Intrauterine, postpartum and adult relationships between arachidonic acid (AA) and docosahexaenoic acid (DHA)

Erythrocyte (RBC) fatty acid compositions from populations with stable dietary habits but large variations in RBC-arachidonic (AA) and RBC-docosahexaenoic acid (DHA) provided us with insight into relationships between DHA and AA. It also enabled us to estimate the maternal RBC-DHA (mRBC-DHA) status that corresponded with no decrease in mRBC-DHA during pregnancy, or in infant (i) RBC-DHA or mRBC-DHA during the first 3 months postpartum (DHA-equilibrium) while exclusively breastfeeding. At delivery, iRBC-AA is uniformly high and independent of mRBC-AA. Infants born to mothers with low RBC-DHA exhibit higher, but infants born to mothers with high RBC-DHA exhibit lower RBC-DHA than their mothers. This switch from ‘biomagnification’ into ‘bioattenuation’ occurs at 6 g% mRBC-DHA. At 6 g%, mRBC-DHA is stable throughout pregnancy, corresponds with postpartum infant DHA-equilibrium of 6 and 0.4 g% DHA in mature milk, but results in postpartum depletion of mRBC-DHA to 5 g%. Postpartum maternal DHA-equilibrium is reached at 8 g% mRBC-DHA, corresponding with 1 g% DHA in mature milk and 7 g% iRBC-DHA at delivery that increases to 8 g% during lactation. This 8 g% RBC-DHA concurs with the lowest risks of cardiovascular and psychiatric diseases in adults. RBC-data from 1866 infants, males and (non-)pregnant females indicated AA vs. DHA synergism at low RBC-DHA, but antagonism at high RBC-DHA. These data, together with high intakes of AA and DHA from our Paleolithic diet, suggest that bioattenuation of DHA during pregnancy and postnatal antagonism between AA and DHA are the physiological standard for humans across the life cycle.     

Blockade of IDO inhibits nasal tolerance induction

The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.