What is new in HIV/AIDS research in developing countries?

HIV epidemic has had greatest impact in sub‐Saharan Africa (SSA) and mainly in East and Southern Africa with HIV prevalence in some parts going up to 30%. In the recent years, considerable HIV research on prevention, treatment and care, and vaccine has been conducted in many developing countries and provided evidence‐based knowledge to control the epidemic. However, there have also been disappointing results in HIV prevention trials such as in HIV vaccine and microbicide trials. Despite these outcomes, important lessons have been learnt that help in designing future trials. This article examines the recent advances in HIV research in developing countries. The most recent HIV prevention research has demonstrated the effect of male circumcision on HIV acquisition, and lack of impact of HSV‐2 treatment on HIV transmission and acquisition. Use of HIV antiretroviral drugs (ARVs) for HIV prevention is a new area that has attracted interest and a number of trials are examining the effect of oral Pre‐Exposure Prophylaxis on HIV acquisition and also looking at the potential of ARVs in reducing infectiousness. Progress has been made in HIV treatment, monitoring treatment efficacy and toxicity as well as evaluation of different models of ART delivery. HIV vaccine research has, however, faced most challenges despite many efforts that have been put in. Looking into the future, there are ongoing trials that will hopefully generate important information to strengthen HIV policies in the next few years. There are, however, many other gaps in HIV research that need to be urgently addressed.     

What’s New in HIV/AIDS

Recently, the 15th International AIDS Conference took place in Bangkok, Thailand. This conference used to be an almost exclusively science-oriented conference reporting on new developments in diagnostic tools, drug discovery, and other medical advances, making it a "must attend" event for most scientists. In the year 2000, this congress was hosted by South Africa in Durban, for the first time in a developing country - focusing on the particular needs of poor countries and also stressing that scientific approaches are not the only relevant and important aspects of this global epidemic. While many scientist (including this author) perceived the changing emphasis of the meeting with regret ("only science will solve this problem"), the immediate view on the epidemic in areas with poor resources has proven beyond doubt that HIV is far more than just a viral infection. With the latest conference taking place in Bangkok, several particular aspects were demonstrated: after Africa, Asia is the largest hot spot in the worldwide spread of HIV with the highest increase in infections. Also, this country can serve as an admirable example of political will and successful battle to constrain the epidemic despite a serious lack of resources.     

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc- mouse model

The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/γc- (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-γ and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34(+) stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.     

MORTl/FADD is involved in liver regeneration

AIM: To explore the role of the adaptor molecule in liver regeneration after partial hepatectomy (PH). METHODS: We used transgenic mice expressing an N-terminal truncated form of MORT1/FADD under the control of the albumin promoter. As previously shown, this transgenic protein abrogated CD95- and CD120a-mediated apoptosis in the liver. Cyclin A expression was detected using Western blotting. ELISA and RT-PCR were used to detect IL-6 and IL-6 mRNA, respectively. DNA synthesis in liver tissue was measured by BrdU staining. RESULTS: Resection of 70% of the liver was followed by a reduced early regenerative response in the transgenic group at 36 h. Accordingly, 36 h after hepatectomy, cyclin A expression was only detectable in wild-type animals. Consequently, the onset of liver mass restoration was retarded as measured by MRI volumetry and mortality was significantly higher in the transgenic group. CONCLUSION: Our data demonstrate for the first time an involvement of the death receptor molecule MORT1/ FADD in liver regeneration, beyond its well described role as part of the intracellular death signaling pathway.     

Advances in the study of circ RNA in myocardial ischemia/reperfusion injury

Myocardial ischemia-reperfusion injury(I/R) is a disease in which acute ischaemic myocardium is not restored or even worsened after reperfusion therapy,resulting in arrhythmias and restricted systolic function of the heart. circular RNAs are a class of stable non-coding RNAs with a circular structure. circRNAs are involved in the pathogenesis of I/R and have great potential to become new therapeutic targets. This paper, we will review the relationship between the different pathogenesis of I/R an...     

What’s New in HIV/AIDS

In the face of a global epidemic of HIV/AIDS with the majority of individuals living in the developing countries, a protective vaccine seem the foremost goal. As this is not within imminent reach, the other option would be immunotherapy that prolongs the asymptomatic phase of infection. The basis for such a therapy is to understand the correlates of protective immunity against HIV. Here we present the most recent advances regarding selected parts of the immune response towards HIV.     

Mutational Analysis of WTX Gene in Wnt/ β-Catenin Pathway in Gastric, Colorectal, and Hepatocellular Carcinomas

A recent study of Wilms’ tumors discovered a new X chromosome gene, Wilms’ tumor gene on the X chromosome (WTX), which was found to harbor small deletions and point mutations. WTX protein negatively regulates Wnt/ β-catenin signaling, and is considered a tumor-suppressor gene. One of the questions about the WTX gene is whether the genetic alterations of the WTX gene are specific to only Wilms’ tumors. To see whether somatic point mutations of WTX occur in other malignancies, we analyzed the WTX gene for the detection of mutations in 141 cancer tissues by a single-strand conformation polymorphism assay. The cancer tissues consisted of 47 gastric adenocarcinomas, 47 colorectal adenocarcinomas, and 47 hepatocellular carcinomas. Overall, we detected one WTX mutation in the colorectal carcinomas (1/47; 2.1%), but there was no WTX mutation in other cancers analyzed. The detected mutation was a missense mutation (c. 1117G > A (p.Ala373Thr)). Although the WTX mutation is common in Wilms’ tumors, our data indicate that it is rare in colorectal, gastric, and hepatocellular carcinomas. The data also suggest that deregulation of Wnt/ β-catenin signaling by WTX gene mutation may be a rare event in the pathogenesis of colorectal, gastric, and hepatocellular carcinomas.     

Downregulation of MIP-1α/CCL3 with praziquantel treatment in Schistosoma haematobium and HIV-1 co-infected individuals in a rural community in Zimbabwe

Background  

Chemokines have been reported to play an important role in granulomatous inflammation during Schistosoma mansoni infection. However there is less information on their role in Schistosoma haematobium infection, or on the effect of concurrent HIV-1 infection, as a potential modifying influence.     

Pro12Ala polymorphism in PPAR-γ2 and dementia in Chinese nonagenarians/centenarians

We examined the existence of a relationship between polymorphism and dementia in subjects aged 90 years and above. The sample included 732 unrelated Chinese nonagenarians/centenarians (aged 90–108 years, mean age 93.68 years; 67.5% women). The Pro12Ala variant was examined using polymerase chain reaction restriction fragment length polymorphism. Cognitive function was measured with 30-item mini-mental state examination. The genotype frequencies of the Pro12Ala polymorphism were 0% Ala12Ala, 9.1% Pro12Ala, and 90.9% Pro12Pro. The prevalence rates of dementia were 64.9% in the whole sample (45.0% for men and 74.5% for women). In both men and women, between subjects with and without 12Ala carriers, there was no significant difference in cognitive function scores and also no significant difference in prevalence of dementia; there was no significant difference in frequency of 12Ala carriers between subjects with and without dementia. Multiple logistic regression was performed by adjusting clinical factors that are thought to be associated with cognitive function or with 12Ala carriers. We found that 12Ala is not a risk factor for dementia. We found that Pro12Ala polymorphism in PPAR-γ2 was not directly correlated with dementia among Chinese nonagenarians and centenarians.     

Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats

AIM To explore the exact interaction between Notch and transforming growth factor(TGF)-β signaling in liver fibrosis. METHODS We established a rat model of liver fibrosis induced by concanavalin A. Peripheral blood mononuclear cells(PBMCs) were isolated from the modeled rats, and cultured with γ-secretase inhibitor DAPT and TGF-β inhibitor for 24 h. The m RNA levels of Notch and TGF-β signaling were detected by quantitative real-time polymerase chain reaction. Expression of Notch and TGF-β proteins was analyzed by western blotting.RESULTS Compared to control rats, Notch and TGF-β signaling was activated in PBMCs of model rats. Administration of DAPT and TGF-β inhibitor suppressed Notch and TGF-β signal transducer in PBMCs of model rats. DAPT reduced m RNA and protein expression of TGF-β signaling, such as TGF-β1 and Smad3. TGF-β inhibitor also downregulated Notch1, Hes1 and Hes5, and m RNA and protein expression of the Notch signaling pathway.CONCLUSION Notch and TGF-β signaling play a role in liver fibrosis. TGF-β signaling upregulates Notch signaling, which promotes TGF-β signaling.     

Lag in maturation of the brain’s intrinsic functional architecture in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood, and there is great interest in understanding its neurobiological basis. A prominent neurodevelopmental hypothesis proposes that ADHD involves a lag in brain maturation. Previous work has found support for this hypothesis, but examinations have been limited to structural features of the brain (e.g., gray matter volume or cortical thickness). More recently, a growing body of work demonstrates that the brain is functionally organized into a number of large-scale networks, and the connections within and between these networks exhibit characteristic patterns of maturation. In this study, we investigated whether individuals with ADHD (age 7.2–21.8 y) exhibit a lag in maturation of the brain’s developing functional architecture. Using connectomic methods applied to a large, multisite dataset of resting state scans, we quantified the effect of maturation and the effect of ADHD at more than 400,000 connections throughout the cortex. We found significant and specific maturational lag in connections within default mode network (DMN) and in DMN interconnections with two task positive networks (TPNs): frontoparietal network and ventral attention network. In particular, lag was observed within the midline core of the DMN, as well as in DMN connections with right lateralized prefrontal regions (in frontoparietal network) and anterior insula (in ventral attention network). Current models of the pathophysiology of attention dysfunction in ADHD emphasize altered DMN–TPN interactions. Our finding of maturational lag specifically in connections within and between these networks suggests a developmental etiology for the deficits proposed in these models.Attention-deficit/hyperactivity disorder (ADHD) is a serious neuropsychiatric disorder characterized by inattention, hyperactivity, and impulsivity. One influential neurodevelopmental model of the disorder posits a lag in the maturational trajectories of key features of the brain (1–4). This model has mostly been investigated by examining developmental pathways of structural features of the brain (3, 5–8). In recent years, however, theorists have increasingly used resting state functional MRI (fMRI)—scanning participants in a task-free resting state—to explore the brain’s functional architecture. This work has led to the recognition that the human brain is organized into several large-scale intrinsic connectivity networks (ICNs), each associated with specific neurocognitive functions (9, 10). ICNs have been shown to undergo significant maturation from childhood to early adulthood, with individual ICNs exhibiting spatially specific reliable patterns of integration (increased connectivity with age) and segregation (decreased connectivity with age) with other ICNs (11–17). These advances raise possibilities for investigating maturational lag in ADHD in the developing ICN architecture of the brain (18).Independent lines of research suggest that attention dysfunction in ADHD is linked to altered ICN interrelationships. According to current theoretical models (19, 20), inattention in ADHD involves altered competitive balance between (i) default network, an ICN implicated in internally directed mentation (21, 22); and (ii) several task-positive ICNs (TPNs), including dorsal attention network (DAN), ventral attention network (VAN), and frontoparietal network (FPN), which are involved in cognitively demanding externally focused processing. Consistent with these models, previous resting state fMRI studies in ADHD have reliably found abnormalities in functional connections within DMN (23, 24) and in its interconnections with TPNs (25–27). Importantly, however, it is not currently known whether these abnormalities reliably observed in ADHD are linked to maturational lag. The current study sought to investigate this question. Based on current network models of ADHD, we hypothesized that maturational lag in ADHD in the brain’s intrinsic functional architecture would be focused within DMN and in its interconnections with three TPNs: DAN, VAN, and FPN.To test this hypothesis, we used recently developed whole-brain connectomic methods (28–30). Traditional seed-based strategies examine connectivity using a single or a handful of regions of interest (ROIs) or average connectivity values across entire ICNs. However, recent work demonstrates that ICN interrelationships are not unitary; rather, connectivity alterations during maturation in DMN and TPNs are highly variable across individual connections within ICNs (13, 14, 31, 32). Thus, conventional seed-based strategies are likely to produce summary measures that do not capture underlying fine-grained patterns of variation or can miss trends that are detectable only when looking across large populations of connections. Connectomic methods remedy this problem by examining connectivity patterns among hundreds of seeds. To produce comprehensive connectomic maps, we placed 907 ROIs at regular intervals throughout the cortex and calculated connectivity between each pair of ROIs (410,871 unique connections). Using a multiple regression approach, we then calculated the effect of age and the effect of ADHD at each connection of the connectome, controlling for nuisance effects (sex, IQ, handedness, motion, and scanner site). This regression modeling yielded two comprehensive maps of effect of age and effect of ADHD, respectively. Examining patterns of spatial correspondence across populations of connections in these whole-cortex connectomic maps provides a powerful way to investigate the maturational lag hypothesis.In our connectomic framework, we operationalized maturational lag as spatial co-occurrence of effects of age and effects of ADHD at the same connections. In particular, lag exists at an individual connection when the effect of ADHD at that connection opposes the effect of maturation. The presence of lag in a population of connections can be tested statistically by using a count-based framework that compares the number of observed lagged connections to a suitable chance distribution. Alternatively, a correlation-based framework can be used to investigate whether the strength of the effect of maturation is proportionately opposed by the effect of ADHD. That is, to the extent that a connection tends to more strongly integrate with age (i.e., effect of age is more positive), then its connectivity should be correspondingly reduced in ADHD relative to typically developing controls (TDCs). Conversely, to the extent that a connection tends to more strongly segregate with age (i.e., effect of age is more negative), then its connectivity should be correspondingly increased in ADHD relative to TDCs.We used both correlation- and count-based tests to investigate the spatial co-occurrence of effects of age and opposed effects of ADHD that is predicted by the maturational lag hypothesis. ICNs exhibit substantial intra- and internetwork dependency across connections. Thus, we assessed the significance of all statistical tests with nonparametric permutation tests, which are robust to deviations from independence and normality assumptions of conventional tests (33). We calculated estimates of effect of age and effect of ADHD used in these tests from participants in the ADHD-200 sample (34). This sample consisted of 481 TDCs and 275 children with ADHD and, after demographic and quality control exclusions, encompassed 421 participants (288 TDC and 135 ADHD). In addition, we also performed a partially independent second analysis. In particular, the preceding connectomic analyses were done a second time using effect of age estimates derived from a different sample, 155 TDC participants from the multisite Autism Brain Image Date Exchange (ABIDE) sample (35). The effect of ADHD estimates were derived from the ADHD-200 sample, and thus it bears emphasis that this second analysis is not completely independent from the first. Results were remarkably similar in this second analysis, and (with the exception of a single statistical test) all significant statistical tests reported below from the first analysis were also statistically significant in the second analysis (SI Results). Although not a fully independent replication, this second analysis nonetheless provides additional support for the reliability of our findings.