Incidence of AIDS-Defining Opportunistic Infections and Mortality during Antiretroviral Therapy in a Cohort of Adult HIV-Infected Individuals in Hanoi, 2007-2014

Background

Although the prognosis for HIV-infected individuals has improved after antiretroviral therapy (ART) scale-up, limited data exist on the incidence of AIDS-defining opportunistic infections (ADIs) and mortality during ART in resource-limited settings.

Methods

HIV-infected adults in two large hospitals in urban Hanoi were enrolled to the prospective cohort, from October 2007 through December 2013. Those who started ART less than one year before enrollment were assigned to the survival analysis. Data on ART history and ADIs were collected retrospectively at enrollment and followed-up prospectively until April 2014.

Results

Of 2,070 cohort participants, 1,197 were eligible for analysis and provided 3,446 person-years (PYs) of being on ART. Overall, 161 ADIs episodes were noted at a median of 3.20 months after ART initiation (range 0.03–75.8) with an incidence 46.7/1,000 PYs (95% confidence interval [CI] 39.8–54.5). The most common ADI was tuberculosis with an incidence of 29.9/1,000 PYs. Mortality after ART initiation was 8.68/1,000 PYs and 45% (19/45) died of AIDS-related illnesses. Age over 50 years at ART initiation was significantly associated with shorter survival after controlling for baseline CD4 count, but neither having injection drug use (IDU) history nor previous ADIs were associated with poor survival. Semi-competing risks analysis in 951 patients without ADIs history prior to ART showed those who developed ADIs after starting ART were at higher risk of death in the first six months than after six months.

Conclusion

ADIs were not rare in spite of being on effective ART. Age over 50 years, but not IDU history, was associated with shorter survival in the cohort. This study provides in-depth data on the prognosis of patients on ART in Vietnam during the first decade of ART scale-up.     

Human Leukocyte Antigen and Systemic Sclerosis in Japanese: The Sign of the Four Independent Protective Alleles,DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01

ObjectiveSeveral studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies.MethodsAssociations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls.ResultsWe found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29–0.73), DRB1*14:06 (P = 6.60X10^-5, Pc = 0.0020, OR 0.05, 95%CI 0.01–0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40–0.79), and DPB1*02:01 (P = 5.16X10^-6, Pc = 8.77X10^-5, OR 0.52, 95%CI 0.39–0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA.ConclusionThus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets.     

Community Attitudes and Practices of Urban Residents Regarding Predation by Pet Cats on Wildlife: An International Comparison

International differences in practices and attitudes regarding pet cats'' interactions with wildlife were assessed by surveying citizens from at least two cities in Australia, New Zealand, the UK, the USA, China and Japan. Predictions tested were: (i) cat owners would agree less than non-cat owners that cats might threaten wildlife, (ii) cat owners value wildlife less than non-cat owners, (iii) cat owners are less accepting of cat legislation/restrictions than non-owners, and (iv) respondents from regions with high endemic biodiversity (Australia, New Zealand, China and the USA state of Hawaii) would be most concerned about pet cats threatening wildlife. Everywhere non-owners were more likely than owners to agree that pet cats killing wildlife were a problem in cities, towns and rural areas. Agreement amongst non-owners was highest in Australia (95%) and New Zealand (78%) and lowest in the UK (38%). Irrespective of ownership, over 85% of respondents from all countries except China (65%) valued wildlife in cities, towns and rural areas. Non-owners advocated cat legislation more strongly than owners except in Japan. Australian non-owners were the most supportive (88%), followed by Chinese non-owners (80%) and Japanese owners (79.5%). The UK was least supportive (non-owners 43%, owners 25%). Many Australian (62%), New Zealand (51%) and Chinese owners (42%) agreed that pet cats killing wildlife in cities, towns and rural areas was a problem, while Hawaiian owners were similar to the mainland USA (20%). Thus high endemic biodiversity might contribute to attitudes in some, but not all, countries. Husbandry practices varied internationally, with predation highest where fewer cats were confined. Although the risk of wildlife population declines caused by pet cats justifies precautionary action, campaigns based on wildlife protection are unlikely to succeed outside Australia or New Zealand. Restrictions on roaming protect wildlife and benefit cat welfare, so welfare is a better rationale.     

Effects of nutrient limitation on sperm and seminal fluid: a systematic review and meta‐analysis

Theory predicts that costly sexual traits should be reduced when individuals are in poor condition (i.e. traits should exhibit condition‐dependent expression). It is therefore widely expected that male ejaculate traits, such as sperm and seminal fluid, will exhibit reduced quantity and quality when dietary nutrients are limited. However, reported patterns of ejaculate condition dependence are highly variable, and there has been no comprehensive synthesis of underlying sources of such variation in condition‐dependent responses. In particular, it remains unclear whether all ejaculate traits are equally sensitive to nutrient intake, and whether such traits are particularly sensitive to certain dietary nutrients, respond more strongly to nutrients during specific life stages, or respond more strongly in some taxonomic groups. We systematically reviewed these potential sources of variation through a meta‐analysis across 50 species of arthropods and vertebrates (from 71 papers and 348 effect sizes). We found that overall, ejaculate traits are moderately reduced when dietary nutrients are limited, but we also detected substantial variation in responses. Seminal fluid quantity was strongly and consistently condition dependent, while sperm quantity was moderately condition dependent. By contrast, aspects of sperm quality (particularly sperm viability and morphology) were less consistently reduced under nutrient limitation. Ejaculate traits tended to respond in a condition‐dependent manner to a wide range of dietary manipulations, especially to caloric and protein restriction. Finally, while all major taxa for which sufficient data exist (i.e. arthropods, mammals, fish) showed condition dependence of ejaculate traits, we detected some taxonomic differences in the life stage that is most sensitive to nutrient limitation, and in the degree of condition dependence of specific ejaculate traits. Together, these biologically relevant factors accounted for nearly 20% of the total variance in ejaculate responses to nutrient limitation. Interestingly, body size showed considerably stronger condition‐dependent responses compared to ejaculate traits, suggesting that ejaculate trait expression may be strongly canalised to protect important reproductive functions, or that the cost of producing an ejaculate is relatively low. Taken together, our findings show that condition‐dependence of ejaculate traits is taxonomically widespread, but there are also many interesting, biologically relevant sources of variation that require further investigation. In particular, further research is needed to understand the differences in selective pressures that result in differential patterns of ejaculate condition dependence across taxa and ejaculate traits.     

N’-acyl-N-methylphenylenediamine as a novel proximity labeling agent for signal amplification in immunohistochemistry

We synthesized novel phenylenediamine derivatives and evaluated them as labeling agents to label proteins in close proximity to a single electron transfer catalyst. We found that N’-acyl-N-methylphenylenediamine labels tyrosine effectively in a model experiment using tris(bipyridine)ruthenium (Ru(bpy)₃²⁺) as the single electron transfer catalyst. By changing the substituents on the nitrogen atom of the phenylenediamine derivatives, the electrochemical properties of the labeling agent can be drastically changed. On the other hand, horseradish peroxidase (HRP) also catalyzes the reaction with almost the same oxidation potential as Ru(bpy)₃²⁺ (～+1.1?V). HRP proximity labeling is applicable to signal amplification in immunohistochemistry. We evaluated the phenylenediamine derivatives as labeling agents for HRP proximity labeling and signal amplification, and found that N’-acyl-N-methylphenylenediamine is a novel and efficient agent for signal amplification using HRP in immunohistochemistry.     

Tet-on inducible system combined with in ovo electroporation dissects multiple roles of genes in somitogenesis of chicken embryos

The in ovo electroporation technique in chicken embryos has enabled investigators to uncover the functions of numerous developmental genes. In this technique, the ubiquitous promoter, CAGGS (CMV base), has often been used for overexpression experiments. However, if a given gene plays a role in multiple steps of development and if overexpression of this gene causes fatal consequences at the time of electroporation, its roles in later steps of development would be overlooked. Thus, a technique with which expression of an electroporated DNA can be controlled in a stage-specific manner needs to be formulated. Here we show for the first time that the tetracycline-controlled expression method, "tet-on" and "tet-off", works efficiently to regulate gene expression in electroporated chicken embryos. We demonstrate that the onset or termination of expression of an electroporated DNA can be precisely controlled by timing the administration of tetracycline into an egg. Furthermore, with this technique we have revealed previously unknown roles of RhoA, cMeso-1 and Pax2 in early somitogenesis. In particular, cMeso-1 appears to be involved in cell condensation of a newly forming somite by regulating Pax2 and NCAM expression. Thus, the novel molecular technique in chickens proposed in this study provides a useful tool to investigate stage-specific roles of developmental genes.     

Stable integration and conditional expression of electroporated transgenes in chicken embryos

The in ovo electroporation in chicken embryos has widely been used as a powerful tool to study roles of genes during embryogenesis. However, the conventional electroporation technique fails to retain the expression of transgenes for more than several days because transgenes are not integrated into the genome. To overcome this shortcoming, we have developed a transposon-mediated gene transfer, a novel technique in chicken manipulations. It was previously reported that the transposon Tol2, originally found in medaka fish, facilitates an integration of a transgene into the genome when co-acting with Tol2 transposase. In this study, we co-electroporated a plasmid containing a CAGGS-EGFP cassette cloned in the Tol2 construct along with a transposase-encoding plasmid into early presomitic mesoderm or optic vesicles of chicken embryos. This resulted in persistent expression of EGFP at least until embryonic day 8 (E8) and E12 in somite-derived tissues and developing retina, respectively. The integration of the transgene was confirmed by genomic Southern blotting using chicken cultured cells. We further combined this transposon-mediated gene transfer with the tetracycline-dependent conditional expression system that we also developed recently. With this combined method, expression of a stably integrated transgene could be experimentally induced upon tetracycline administration at relatively late stages such as E6, where a variety of organogenesis are underway. Thus, the techniques proposed in this study provide a novel approach to study the mechanisms of late organogenesis, for which chickens are most suitable model animals.     

Specific role of the truncated betaIV-spectrin Sigma6 in sodium channel clustering at axon initial segments and nodes of ranvier

At axon initial segments and nodes of Ranvier in neurons, the spectrin membrane skeleton plays roles in physically stabilizing the plasma membrane integrity and in clustering voltage-gated sodium channels for proper conduction of the action potential. betaIV-Spectrin, an essential component of the membrane skeleton at these sites, has an N-terminal-truncated isoform, Sigma6, which is expressed at much higher levels than the full-length isoform Sigma1. To investigate the role of betaIV-spectrin Sigma6, we generated Sigma1-deficient mice with a normal level of Sigma6 expression (Sigma1(-/-) mice), and compared their phenotypes with those of previously generated mice lacking both Sigma1 and Sigma6(Sigma1Sigma6(-/-) mice). The gross neurological defects observed in Sigma1Sigma6(-/-) mice, such as hindleg contraction, were apparently ameliorated in Sigma1(-/-) mice. At cellular levels, Sigma1Sigma6(-/-) and Sigma1(-/-) neurons similarly exhibited waving and swelling of the plasma membrane at axon initial segments and nodes of Ranvier. By contrast, the levels of ankyrin G and voltage-gated sodium channels at these sites, which are significantly reduced in Sigma1Sigma6(-/-) mice, were substantially recovered in Sigma1(-/-) mice. We conclude that the truncated betaIV-spectrin isoform Sigma6 plays a specific role in clustering voltage-gated sodium channels, whereas it is dispensable for membrane stabilization at axon initial segments and nodes of Ranvier.     

Effective tempo of the step test for dynamic balance ability in the elderly

This study aimed to examine the reliability and sex- and age-related differences of step tests with stipulated tempos as well as to clarify useful test parameters and tempos. One hundred forty elderly people and fifty young adults conducted tapping and stepping tests, matching the tempo provided by a metronome. Both tests involve movements where the subject touches a sheet with both the right and left hands or right and left legs at a designated spot. Evaluation parameters were the time difference between the beep sound and the time at which the sheet was touched in both tests as well as two-leg support and one-leg support times in the step test. The trial-to-trial reliability of the parameters in both tests was high. The time differences of both 40 bpm tests in the elderly were larger in males than in females. In the step test, the time difference and two-leg support times of the elderly were larger, in the order of 40, 60, and 120 bpm, and the one-leg support time was less in 40 bpm than 60 bpm or 120 bpm. The one-leg support time of the young subjects was larger, in the order of 40, 60, and 120 bpm. A significant age-related difference was found in the 40 bpm and 60 bpm test, and the time difference and two-leg support time were larger in the elderly while the one-leg support time was larger in the young subjects. The time difference at 40 bpm in the elderly was larger in the step test than in the tap test. There was no significant difference between both tests in the young subjects. In conclusion, the step test with the slow tempo, because it requires a long one-leg support phase, is effective for evaluating dynamic balance in the elderly. The time difference and two-leg and one-leg support times are effective evaluation parameters of the step test.