The long-term effectiveness of generic adult fixed-dose combination antiretroviral therapy for HIV-infected Ugandan children

Background

Access to pediatric antiretroviral formulations is increasing in resource-limited countries, however adult FDCs are still commonly used by antiretroviral therapy (ART) programs.

Objective

To describe long-term effectiveness of using adult FDC of d4T+3TC+NVP (Triomune) in children for HIV treatment.

Methods

Clinical, immunologic, and virologic outcomes of HIV-infected ART-naïve children aged six months to 12 years, were evaluated up to 96 weeks post-ART initiation.

Results

From March 2004 to June 2006, 104 children were followed with a median age of 5.4 years, median CD4 cell percent and HIV-1 RNA were 11.0% (IQR 6.7–13.9) and 348,846copies/mL (IQR 160,941–681,313) respectively at baseline. Using Kaplan-Meir estimates, 75% of children had undetectable viral loads (<400copies/mL) at 96weeks of ART. Children with a baseline CD4 cell percent >15% were 3 times more likely to achieve viral load <400copies/mL than those with baseline CD4 cell percent <5% after adjusting for baseline age {aHR = 3.03 (1.10–8.32), p=0.03}; no difference was found among those with CD4 cell percent >5–14.9% and <5%.

Conclusion

Treatment with generic adult FDC for HIV-infected Ugandan children led to sustained clinical, immunologic and virologic response during 96 weeks of ART. Early initiation of ART is key to achieving virological success.     

Effect of BH4 on blood phenylalanine and tyrosine variations in patients with phenylketonuria

BackgroundIn patients with phenylketonuria, stability of blood phenylalanine and tyrosine concentrations might influence brain chemistry and therefore patient outcome. This study prospectively investigated the effects of tetrahydrobiopterin (BH4), as a chaperone of phenylalanine hydroxylase on diurnal and day-to-day variations of blood phenylalanine and tyrosine concentrations.MethodsBlood phenylalanine and tyrosine were measured in dried blood spots (DBS) four times daily for 2 days (fasting, before lunch, before dinner, evening) and once daily (fasting) for 6 days in a randomized cross-over design with a period with BH4 and a period without BH4. The sequence was randomized. Eleven proven BH4 responsive PKU patients participated, 5 of them used protein substitutes during BH4 treatment. Natural protein intake and protein substitute dosing was adjusted during the period without BH4 in order to keep DBS phenylalanine levels within target range. Patients filled out a 3-day food diary during both study periods. Variations of DBS phenylalanine and Tyr were expressed in standard deviations (SD) and coefficient of variation (CV).ResultsBH4 treatment did not significantly influence day-to-day phenylalanine and tyrosine variations nor diurnal phenylalanine variations, but decreased diurnal tyrosine variations (median SD 17.6 μmol/l, median CV 21.3%, p = 0.01) compared to diet only (median SD 34.2 μmol/l, median CV 43.2%). Consequently, during BH4 treatment diurnal phenylalanine/tyrosine ratio variation was smaller, while fasting tyrosine levels tended to be higher.ConclusionBH4 did not impact phenylalanine variation but decreased diurnal tyrosine and phenylalanine/tyrosine ratio variations, possibly explained by less use of protein substitute and increased tyrosine synthesis.     

Type D personality is associated with increased metabolic syndrome prevalence and an unhealthy lifestyle in a cross-sectional Dutch community sample

Background  

People with Type D-Distressed-personality have a general tendency towards increased negative affectivity (NA), while at the same time inhibiting these emotions in social situations (SI). Type D personality is associated with an increased risk of adverse outcomes in patients with cardiovascular disease. Whether Type D personality is a cardiovascular risk factor in healthy populations remains to be investigated. In the present study, the relations between Type D personality and classical cardiovascular risk factors, i.e. metabolic syndrome and lifestyle were investigated in a Dutch community sample.     

EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state

Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%–6% of WS2.     

High-throughput methylation profiling by MCA coupled to CpG island microarray

An abnormal pattern of DNA methylation occurs at specific genes in almost all neoplasms. The lack of high-throughput methods with high specificity and sensitivity to detect changes in DNA methylation has limited its application for clinical profiling. Here we overcome this limitation and present an improved method to identify methylated genes genome-wide by hybridizing a CpG island microarray with amplicons obtained by the methylated CpG island amplification technique (MCAM). We validated this method in three cancer cell lines and 15 primary colorectal tumors, resulting in the discovery of hundreds of new methylated genes in cancer. The sensitivity and specificity of the method to detect hypermethylated loci were 88% and 96%, respectively, according to validation by bisulfite-PCR. Unsupervised hierarchical clustering segregated the tumors into the expected subgroups based on CpG island methylator phenotype classification. In summary, MCAM is a suitable technique to discover methylated genes and to profile methylation changes in clinical samples in a high-throughput fashion.     

Effects of latex membrane on guided regeneration of long bones

Abstract

Natural latex extracted from Hevea brasiliensis is one of the materials pointed out as potential tissue regenerators. The use of latex-based membranes in bone regeneration might be an alternative to stimulate bone formation. The aim of this study was to evaluate the effects of latex membranes in guided bone regeneration of defects produced in long bones of rats. Sixty rats were equally divided into latex and control groups, and each group was subdivided into two subgroups according to treatment duration of 1 and 4 weeks. Bone defects with 2.5?mm in diameter were surgically made in the left tibia. In the animals of the latex group, a latex membrane was placed over the bone defect. The samples underwent quantitative histological analysis of bone formation and collagen matrix, immunohistochemical analysis of osteogenic protein markers, assessment of bone mechanical properties and bone densitometry, and radiological assessment. The osteocalcin immunostaining data were submitted to the generalized linear model test with two independent factors. For the other data, the multivariate ANOVA with two independent factors was performed. The use of the latex membrane significantly improved (p?<?0.005) the volume of newly formed bone, collagen type I matrix, expression of osteopontin, and bone stiffness, both in the early and late stages of regeneration. In conclusion, the latex membrane was able to promote bone regeneration in long bones.     

Life Change Events,Ballistocardiography and Coronary Death

Abstract

Thirty-six men and women who experienced a documented myocardial infarction, half of whom ultimately died from their disease and half of whom survived over a six-year period, provided longitudinal recent life changes and ballistocardiographic data. The 18 patients who died from their coronary disease indicated a significant buildup in life changes which peaked approximately one year prior to death; their serial ballistocardiograms indicated a significant buildup in average force of contraction which was seen to peak approximately six months prior to death. The 18 post-infarction patients who survived the six-year follow-up showed neither a buildup in life change nor a buildup in the ballistocardiographic index of cardiac contraction force. These findings of a life change peak preceding ballistocardiographic evidence of an “overworked” heart are discussed in terms of their possible medical and psychophysiological significances.     

From the outside-in: Epidermal targeting as a paradigm for atopic disease therapy

Atopic dermatitis(AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.