Missed Opportunities for Early Access to Care of HIV-Infected Infants in Burkina Faso

Objective

The World Health Organization (WHO) has recommended a universal antiretroviral therapy (ART) for all HIV-infected children before the age of two since 2010, but this implies an early identification of these infants. We described the Prevention of Mother-to-Child HIV Transmission (PMTCT) cascade, the staffing and the quality of infrastructures in pediatric HIV care facilities, in Ouagadougou, Burkina Faso.

Methods

We conducted a cross-sectional survey in 2011 in all health care facilities involved in PMTCT and pediatric HIV care in Ouagadougou. We assessed them according to their coverage in pediatric HIV care and WHO standards, through a desk review of medical registers and a semi-structured questionnaire administered to health-care workers (HCW).

Results

In 2011, there was no offer of care in primary health care facilities for HIV-infected children in Ouagadougou. Six district hospitals and two university hospitals provided pediatric HIV care. Among the 67 592 pregnant women attending antenatal clinics in 2011, 85.9% were tested for HIV. The prevalence of HIV was 1.8% (95% Confidence Interval: 1.7%–1.9%). Among the 1 064 HIV-infected pregnant women attending antenatal clinics, 41.4% received a mother-to-child HIV transmission prevention intervention. Among the HIV-exposed infants, 313 (29.4%) had an early infant HIV test, and 306 (97.8%) of these infants tested received their result within a four-month period. Among the 40 children initially tested HIV-infected, 33 (82.5%) were referred to a health care facility, 3 (9.0%) were false positive, and 27 (90.0%) were initiated on ART. Although health care facilities were adequately supplied with HIV drugs, they were hindered by operational challenges such as shortage of infrastructures, laboratory reagents, and trained HCW.

Conclusions

The PMTCT cascade revealed bottle necks in PMTCT intervention and HIV early infant diagnosis. The staffing in HIV care and quality of health care infrastructures were also insufficient in 2011 in Ouagadougou.     

IgG1 and IgG4 Antibody Responses to the Anopheles gambiae Salivary Protein gSG6 in the Sympatric Ethnic Groups Mossi and Fulani in a Malaria Hyperhendemic Area of Burkina Faso

Human antibody response to the Anopheles gambiae salivary protein gSG6 has recently emerged as a potentially useful tool for malaria epidemiological studies and for the evaluation of vector control interventions. However, the current understanding of the host immune response to mosquito salivary proteins and of the possible crosstalk with early response to Plasmodium parasites is still very limited. We report here the analysis of IgG1 and IgG4 subclasses among anti-gSG6 IgG responders belonging to Mossi and Fulani from Burkina Faso, two ethnic groups which are known for their differential humoral response to parasite antigens and for their different susceptibility to malaria. The IgG1 antibody response against the gSG6 protein was comparable in the two groups. On the contrary, IgG4 titers were significantly higher in the Fulani where, in addition, anti-gSG6 IgG4 antibodies appeared in younger children and the ratio IgG4/IgG1 stayed relatively stable throughout adulthood. Both gSG6-specific IgG1 and IgG4 antibodies showed a tendency to decrease with age whereas, as expected, the IgG response to the Plasmodium circumsporozoite protein (CSP) exhibited an opposite trend in the same individuals. These observations are in line with the idea that the An. gambiae gSG6 salivary protein induces immune tolerance, especially after intense and prolonged exposure as is the case for the area under study, suggesting that gSG6 may trigger in exposed individuals a Th2-oriented immune response.     

Malaria Incidence in Children in South-West Burkina Faso: Comparison of Active and Passive Case Detection Methods

Background

The aim of this study was to determine the incidence and seasonal pattern of malaria in children in South-West Burkina Faso, and to compare, in a randomized trial, characteristics of cases detected by active and passive surveillance. This study also enabled the planning of a malaria vaccine trial.

Methods

Households with young children, located within 5 kilometers of a health facility, were randomized to one of two malaria surveillance methods. In the first group, children were monitored actively. Each child was visited twice weekly; tympanic temperature was measured, and if the child had a fever or history of fever, a malaria rapid diagnostic test was performed and a blood smear collected. In the second group, children were monitored passively. The child’s parent or caregiver was asked to bring the child to the nearest clinic if he was unwell. Follow up lasted 13 months from September 2009.

Results

Incidence of malaria (Fever with parasitaemia ≥5,000/µL) was 1.18 episodes/child/year in the active cohort and 0.89 in the passive cohort (rate ratio 1.32, 95% CI 1.13–1.54). Malaria cases in the passive cohort were more likely to have high grade fever; but parasite densities were similar in the two groups. Incidence was highly seasonal; when a specific case definition was used, about 60% of cases occurred within the 4 months June-September.

Conclusion

Passive case detection required at least a 30%–40% increase in the sample size for vaccine trials, compared to active detection, to achieve the same power. However we did not find any evidence that parasite densities were higher with passive than with active detection. The incidence of malaria is highly seasonal and meets the WHO criteria for Seasonal Malaria Chemoprevention (SMC). At least half of the malaria cases in these children could potentially be prevented if SMC was effectively deployed.     

Novel 1,5-diphenyl-6-substituted 1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones induced apoptosis in RKO colon cancer cells

Novel 1,5-diphenyl-6-substituted-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-ones were synthesized and characterized. All compounds were screened for their anti-proliferative activities in five different cancer cell lines. The results showed that compounds 7a and 7b comprising aminoguanidino or guanidino moiety at position 6 inhibited proliferation of RKO colon cancer cells with IC₅₀ of 8 and 4?μM, respectively. Compounds 7a and 7b induced apoptosis in RKO cells, which was confirmed by TUNEL and annexin V-FITC assays. Flow cytometric analysis indicated that compounds 7a and 7b arrested RKO cells in the G1 phase and the most active compound 7b increased levels of p53, p21, Bax, ERK1/2 and reduced levels of Bcl2 and Akt. Compound 7b also activates release of cytochrome c, which is consistent with activation of caspase-9. Additionally, compound 7b increased caspase-3 activity and cleaved PARP-1 in RKO cells. Collectively, these findings could establish a molecular basis for the development of new anti-cancer agents.     

Expression of ATP6V1C1 during oral carcinogenesis

We investigated the gene and protein expressions of V-type ATPase protein subunit C1 (ATP6V1C1) in cases of oral squamous cell carcinoma (OSCC) and contralateral normal mucosa in smokers, nonsmokers and former smokers. Subjects were separated into five groups of 15: group 1, smokers with OSCC; group 2, normal contralateral mucosa of OSCC patients; group 3, chronic smokers; group 4, former smokers who had stopped smoking 1 year earlier; group 5, individuals who had never smoked. Exfoliative cytology specimens from oral mucosa of smokers, former smokers and nonsmokers showed normal gene and protein expression. We found significantly greater gene expression in the OSCC group than in the nonsmoker groups. No difference in gene expression was observed between normal contralateral mucosa and nonsmoker groups, smoker and nonsmoker groups or former smoker and nonsmoker groups. We observed intense immunostaining for ATP6V1C1 protein in all cases of OSCC and weak or no staining in smoker, former smoker and nonsmoker groups. Significantly greater expression of ATP6V1C1 protein was observed in the OSCC group compared to the other groups, which supports the role of ATP6V1C1 in effecting changes associated with oral cancer. Analysis of the mucosae of chronic smokers, former smokers and the normal contralateral mucosa of patients with OSCC showed unaltered ATP6V1C1 gene and protein expression. Early stages of carcinogenesis, represented by altered epithelium of chronic smokers, had neither gene nor protein alterations as seen in OSCC. Therefore, we infer that the changes in ATP6V1C1 occur during later stages of carcinogenesis. Our preliminary study provides a basis for future studies of using ATP6V1C1 levels for detecting early stage OSCC.     

Do distribution volumes and clearances relate to tissue volumes and blood flows? A computer simulation

Background

Thoracotomy is associated with severe pain that may persist for years. Acupuncture is a complementary therapy with a proven role in pain control. A randomized trial showed that acupuncture was effective in controlling pain after abdominal surgery, but the efficacy of this technique for the treatment of thoracotomy pain has not been established. We developed a novel technique for convenient application of acupuncture to patients undergoing thoracotomy, and in a Phase II trial evaluated the safety of this intervention and the feasibility of doing a randomized trial.

Methods

Adult patients scheduled for unilateral thoracotomy with preoperative epidural catheter placement received acupuncture immediately prior to surgery. Eighteen semi-permanent intradermal needles were inserted on either side of the spine, and four were inserted in the legs and auricles. Needles were removed after four weeks. Using a numerical rating scale, pain was measured on the first five postoperative days. After discharge, pain was assessed using the Brief Pain Inventory at 7, 30, 60 and 90 days.

Results

Thirty-six patients were treated with acupuncture. Of these, 25, 23, and 22 patients provided data at 30, 60, and 90 days, respectively. The intervention was well tolerated by patients with only one minor and transient adverse event of skin ulceration.

Conclusion

The rate of data completion met our predefined criterion for determining a randomized trial to be feasible (at least 75% of patients tolerated the intervention and provided evaluable data). This novel intervention is acceptable to patients undergoing thoracotomy and does not interfere with standard preoperative care. There was no evidence of important adverse events. We are now testing the hypothesis that acupuncture significantly adds to standard perioperative pain management in a randomized trial.     

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: Selection of the scaffold

HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC₅₀ of 3 nM against wild type HIV infected T-cells.     

Neuregulin 3 promotes excitatory synapse formation on hippocampal interneurons

Hippocampal GABAergic interneurons are crucial for cortical network function and have been implicated in psychiatric disorders. We show here that Neuregulin 3 (Nrg3), a relatively little investigated low‐affinity ligand, is a functionally dominant interaction partner of ErbB4 in parvalbumin‐positive (PV) interneurons. Nrg3 and ErbB4 are located pre‐ and postsynaptically, respectively, in excitatory synapses on PV interneurons in vivo. Additionally, we show that ablation of Nrg3 results in a similar phenotype as the one described for ErbB4 ablation, including reduced excitatory synapse numbers on PV interneurons, altered short‐term plasticity, and disinhibition of the hippocampal network. In culture, presynaptic Nrg3 increases excitatory synapse numbers on ErbB4⁺ interneurons and affects short‐term plasticity. Nrg3 mutant neurons are poor donors of presynaptic terminals in the presence of competing neurons that produce recombinant Nrg3, and this bias requires postsynaptic ErbB4 but not ErbB4 kinase activity. Furthermore, when presented by non‐neuronal cells, Nrg3 induces postsynaptic membrane specialization. Our data indicate that Nrg3 provides adhesive cues that facilitate excitatory neurons to synapse onto ErbB4⁺ interneurons.     

mIL21-SA双功能融合蛋白锚定治疗膀胱癌实验研究

目的:制备链亲合素标记的鼠白细胞介素21融合蛋白(mIL21-SA),治疗小鼠表浅膀胱癌。方法:构建mIL21-SA-pET21质粒,BL21表达,Ni-NTA纯化,透析复性,Western blot鉴定,MTT法检测其对小鼠胸腺细胞的增殖作用,流式检测其对生物素化的MB49锚定修饰率。建立小鼠MB49表浅膀胱癌模型,将mIL21-SA锚定在小鼠膀胱表面进行治疗并观察小鼠存活时间。60d后对mIL21-SA治疗后存活小鼠进行二次攻击。结果:mIL21-SA可以促进T细胞增殖,且具有SA介导的高效结合已生物素化的MB49表面的功能(修饰率98.74%)。膀胱灌注60d后,mIL21-SA组有10只(10/25)存活,二次攻击后,仍有6只(6/10)存活。与对照组比较均有统计学意义(P<0.05)。结论:该实验研制了具有双重活性的mIL21-SA,mIL21-SA锚定修饰治疗表浅膀胱癌是一种有效的免疫治疗方法。