Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~ 50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~ 10 mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~ 20 mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~ 40–60 mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~ 50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone

Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice

Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS

HIV-1 protease inhibitors and clinical malaria: A secondary analysis of the AIDS Clinical Trials Group A5208 study

HIV-1 protease inhibitors (PIs) have antimalarial activity in vitro and in murine models. The potential beneficial effect of HIV-1 PIs on malaria has not been studied in clinical settings. We used data from Adult AIDS Clinical Trials Group A5208 sites where malaria is endemic to compare the incidence of clinically diagnosed malaria among HIV-infected adult women randomized to either lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) or to nevirapine (NVP)-based ART. We calculated hazard ratios and 95% confidence intervals. We conducted a recurrent events analysis that included both first and second clinical malarial episodes and also conducted analyses to assess the sensitivity of results to outcome misclassification. Among the 445 women in this analysis, 137 (31%) received a clinical diagnosis of malaria at least once during follow-up. Of these 137, 72 (53%) were randomized to LPV/r-based ART. Assignment to the LPV/r treatment group (n = 226) was not consistent with a large decrease in the hazard of first clinical malarial episode (hazard ratio = 1.11 [0.79 to 1.56]). The results were similar in the recurrent events analysis. Sensitivity analyses indicated the results were robust to reasonable levels of outcome misclassification. In this study, the treatment with LPV/r compared to NVP had no apparent beneficial effect on the incidence of clinical malaria among HIV-infected adult women. Additional research concerning the effects of PI-based therapy on the incidence of malaria diagnosed by more specific criteria and among groups at a higher risk for severe disease is warranted. Copyrigh

Strain Typing Methods and Molecular Epidemiology of Pneumocystis Pneumonia

Several typing methods, with different strengths and weaknesses, are available for studies of Pneumocystis pneumonia

HSPG-Binding Peptide Corresponding to the Exon 6a-Encoded Domain of VEGF Inhibits Tumor Growth by Blocking Angiogenesis in Murine Model

Vascular endothelial growth factor VEGF165 is a critical element for development of the vascular system in physiological and pathological angiogenesis. VEGF isoforms have different affinities for heparan sulphate proteoglycan (HSPG) as well as for VEGF receptors; HSPGs are important regulators in vascular development. Therefore, inhibition of interactions between VEGF and HSPGs may prevent angiogenesis. Here, we demonstrate that an HSPG-binding synthetic peptide, corresponding to exon 6a-encoded domain of VEGF gene, has anti-angiogenic property. This 20 amino acids synthetic peptide prevents VEGF165 binding to several different cell types, mouse embryonic sections and inhibits endothelial cell migration, despite its absence in VEGF165 sequence. Our in vivo anti-tumor studies show that the peptide inhibits tumor growth in both mouse Lewis-Lung Carcinoma and human Liposarcoma tumor-bearing animal models. This is the first evidence that a synthetic VEGF fragment corresponding to exon 6a has functional antagonism both in vitro and in vivo. We conclude that the above HPSG binding peptide (6a-P) is a potent inhibitor of angiogenesis-dependent diseases

The Frequency of Malaria Is Similar among Women Receiving either Lopinavir/Ritonavir or Nevirapine-based Antiretroviral Treatment

HIV protease inhibitors (PIs) show antimalarial activity in vitro and in animals. Whether this translates into a clinical benefit in HIV-infected patients residing in malaria-endemic regions is unknown. We studied the incidence of malaria, as defined by blood smear positivity or a positive Plasmodium falciparum histidine-rich protein 2 antigen test, among 444 HIV-infected women initiating antiretroviral treatment (ART) in the OCTANE trial (A5208; ClinicalTrials.gov: NCT00089505). Participants were randomized to treatment with PI-containing vs. PI-sparing ART, and were followed prospectively for ≥48 weeks; 73% also received cotrimoxazole prophylaxis. PI-containing treatment was not associated with protection against malaria in this study population

How HIV/AIDS scale-up has impacted on non- HIV priority services in Zambia

Background: Much of the debate as to whether or not the scaling up of HIV service delivery in Africa benefits non-HIV priority services has focused on the use of nationally aggregated data. This paper analyses and presents routine health facility record data to show trend correlations across priority services. Methods: Review of district office and health facility client records for 39 health facilities in three districts of Zambia, covering four consecutive years (2004-07). Intra-facility analyses were conducted, service and coverage trends assessed and rank correlations between services measured to compare service trends within facilities. Results: VCT, ART and PMTCT client numbers and coverage levels increased rapidly. There were some strong positive correlations in trends within facilities between reproductive health services (family planning and antenatal care) and ART and PMTCT, with Spearman rank correlations ranging from 0.33 to 0.83. Childhood immunisation coverage also increased. Stock-outs of important drugs for non-HIV priority services were significantly more frequent than were stock-outs of antiretroviral drugs. Conclusions: The analysis shows scale-up in reproductive health service numbers in the same facilities where HIV services were scaling up. While district childhood immunisations increased overall, this did not necessarily occur in facility catchment areas where HIV service scale-up occurred. The paper demonstrates an approach for comparing correlation trends across different services, using routine health facility information. Larger samples and explanatory studies are needed to understand the client, facility and health systems factors that contribute to positive and negative synergies between priority services

Task sharing in Zambia: HIV service scale-up compounds the human resource crisis

BACKGROUND: Considerable attention has been given by policy makers and researchers to the human resources for health crisis in Africa. However, little attention has been paid to quantifying health facility-level trends in health worker numbers, distribution and workload, despite growing demands on health workers due to the availability of new funds for HIV/AIDS control scale-up. This study analyses and reports trends in HIV and non-HIV ambulatory service workloads on clinical staff in urban and rural district level facilities. METHODS: Structured surveys of health facility managers, and health services covering 2005-07 were conducted in three districts of Zambia in 2008 (two urban and one rural), to fill this evidence gap. Intra-facility analyses were conducted, comparing trends in HIV and non-HIV service utilisation with staff trends. RESULTS: Clinical staff (doctors, nurses and nurse-midwives, and clinical officers) numbers and staff population densities fell slightly, with lower ratios of staff to population in the rural district. The ratios of antenatal care and family planning registrants to nurses/nurse-midwives were highest at baseline and increased further at the rural facilities over the three years, while daily outpatient department (OPD) workload in urban facilities fell below that in rural facilities. HIV workload, as measured by numbers of clients receiving antiretroviral treatment (ART) and prevention of mother to child transmission (PMTCT) per facility staff member, was highest in the capital city, but increased rapidly in all three districts. The analysis suggests evidence of task sharing, in that staff designated by managers as ART and PMTCT workers made up a higher proportion of frontline service providers by 2007. CONCLUSIONS: This analysis of workforce patterns across 30 facilities in three districts of Zambia illustrates that the remarkable achievements in scaling-up HIV/AIDS service delivery has been on the back of sustained non-HIV workload levels, increasing HIV workload and stagnant health worker numbers. The findings are based on an analysis of routine data that are available to district and national managers. Mixed methods research is needed, combining quantitative analyses of routine health information with follow-up qualitative interviews, to explore and explain workload changes, and to identify and measure where problems are most acute, so that decision makers can respond appropriately. This study provides quantitative evidence of a human resource crisis in health facilities in Zambia, which may be more acute in rural areas