Immunological characteristic of children vertically infected with HIV: a case-control study

HIV infection in children causes a serious immunodeficiency with special characteristics that distinguish it from the adult, causing a global immune deficit. This is a case-control study between Cuban paediatric patients infected with HIV by vertical transmission and a control group of supposedly healthy children. Both groups were characterized from the clinical point of view and markers were used for evaluating the immunologic and virologycal state. Clinically 75% of patients present a pattern of precocious progression; from the total, only two stayed asymptomatic. All HIV-infected children receive antirretroviral treatment and three of them present values of viral load bigger than 100,000 cp/mL. The immune alterations found in the HIV-infected children compared with healthy children were: a cellular immune depletion with diminished counts of lymphocyte subsets T CD4+, CD16+/CD56+ and CD19+, an increase in subsets of CD3+, CD8+, CD8+/CD38+, CD3+/ CD95+ and a hypergammaglobulinemia due to prevalence of immunoglobulin gamma IgG (p < 0.05). On the other hand, there were not significantly differences in the serum levels of both C3 and C4, as well as in the haemolytic activity of the classic and alternate activation pathways of the complement system. This finding allowed better attention and treatment of paediatric HIV patients.     

CYP1A1 and CYP1B1 in blood-brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells.

Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.     

Vision-related quality-of-life in Jamaican glaucoma patients at Kingston Public Hospital

AIM: To determine the vision-related quality-of-life of glaucoma patients and the association between clinical and socioeconomic factors, and vision-related quality-of-life. METHODS: This was a cross-sectional study. Consecutive patients with glaucoma were interviewed using a modified 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) by a single interviewer. Statistical analysis was done to find associations between patient variables and vision-related quality-of-life scores. Confidentiality and anonymity were maintained. RESULTS: Ninety-six participants were recruited in the study. There were 44 males and the mean age for males and females was 65.7 and 69.5y, respectively. The mean composite score was 71.2 (with a maximum possible score of 100), with the highest mean score in the colour vision subscale (89.8) and the lowest mean score in the driving subscale (34.0). Worse visual acuity (P<0.001), longer duration of glaucoma (P<0.001) and higher number of glaucoma medications (P<0.001) were associated with a worse composite score. Female participants and those who lived in urban areas had significantly better scores than male participants (P=0.002) and those who lived in rural areas (P=0.017), respectively. CONCLUSION: The vision-related quality-of-life in Jamaican glaucoma patients is comparable to that of glaucoma patients in the Barbados Eye Study and other international studies using the VFQ-25 questionnaire. Worse quality-of-life scores are associated with poorer visual acuity, longer duration of glaucoma, more glaucoma medications, and sociodemographic factors such as male gender and rural residence.     

Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates

Recent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is uncertain whether this principle holds in primates. Here we identify which cells contain peptidoglycan (PGN) in multiple sclerosis brain and in two nonhuman primate experimental autoimmune encephalomyelitis (EAE) models with different disease courses: acute (rhesus monkey) versus chronic disease (marmoset). Because persistence of TLR ligands in the central nervous system might be consequential for disease progression, we also determined the expression of two major PGN-degrading enzymes, ie, lysozyme and N-acetylmuramyl-l-alanine amidase. Distinct phagocyte subsets, including granulocytes, macrophages, and dendritic cells, contained PGN in the brain and coexpressed the inflammatory cytokine interleukin-12. The number of phagocytes carrying PGN increased in acute and chronic EAE compared with control animals, with the highest number of PGN-containing cells in acute EAE brain. Lytic enzymes were scarcely expressed in monkey and multiple sclerosis brain, favoring PGN persistence. PGN stimulated interleukin-12p70 release by leukocytes from all three primate species. The presence of PGN in the inflamed brain may have major implications because TLR2/Nod ligation potentially promotes inflammation and disease progression.     

Assessment of the Induction of Dormant Ring Stages in Plasmodium falciparum Parasites by Artemisone and Artemisone Entrapped in Pheroid Vesicles In Vitro

The in vitro antimalarial activities of artemisone and artemisone entrapped in Pheroid vesicles were compared, as was their ability to induce dormancy in Plasmodium falciparum. There was no increase in the activity of artemisone entrapped in Pheroid vesicles against multidrug-resistant P. falciparum lines. Artemisone induced the formation of dormant ring stages similar to dihydroartemisinin. Thus, the Pheroid delivery system neither improved the activity of artemisone nor prevented the induction of dormant rings.     

Housing accessibility and its associations with participation among older adults living with long-standing spinal cord injury

Objectives: To describe the housing situation and aspects of participation among older adults living with long-standing spinal cord injury (SCI) with attention to SCI severity, and to examine whether and how objective housing accessibility (based on objectively measurable criteria) is associated with aspects of participation.

Design: Cross-sectional study utilizing the assessment tools Impact on Participation and Autonomy (IPA) and Housing Enabler (HE). Adjusting for demographic, social and injury related data, associations between objective housing accessibility and aspects of participation were analyzed by means of ordinal regression models.

Setting: Home and community settings.

Participants: Older adults (≥ 50 years) (N?=?123), with a traumatic or non-traumatic SCI for at least 10 years. To make comparisons within the sample, three groups of SCI severity were formed using the American Spinal Injury Association (ASIA) Impairment Scale.

Results: Housing adaptations and environmental barriers were common and differed between SCI severity groups; those with AIS D injuries had fewer adaptations and more environmental barriers indoors. A majority of the participants in the total sample perceived their participation as good or very good in most of the IPA activities studied. Accessibility indoors was significantly associated with autonomy indoors (P?=?0.009), family role (P?=?0.002) and participation problems (P?=?0.004); more accessibility problems were associated with less participation and more participation problems.

Conclusion: This study indicates that optimizing the housing environment for older adults with SCI can potentially increase their participation and make them more autonomous. Further studies based on longitudinal data are needed to determine the causality of the associations identified.     

Effect of using frozen–thawed bovine semen contaminated with lumpy skin disease virus on in vitro embryo production

Lumpy skin disease (LSD) is an important transboundary animal disease of cattle with significant economic impact because of the implications for international trade in live animals and animal products. LSD is caused by a Capripoxvirus, LSD virus (LSDV), and results in extensive hide and udder damage, fever and pneumonia. LSDV can be shed in semen of infected bulls for prolonged periods and transmitted venereally to cows at high doses. This study examined the effects of LSDV in frozen‐thawed semen on in vitro embryo production parameters, including viral status of media and resulting embryos. Bovine oocytes were harvested from abattoir‐collected ovaries and split into three experimental groups. After maturation, the oocytes were fertilized in vitro with frozen‐thawed semen spiked with a high (HD) or a lower (LD) dose of LSDV, or with LSDV‐free semen (control). Following day 7 and day 8 blastocyst evaluation, PCR and virus isolation were performed on all embryonic structures. After completing sufficient replicates to reach 1,000 inseminated oocytes, further in vitro fertilization (IVF) runs were performed to provide material for electron microscopy (EM) and embryo washing procedures. Overall, in vitro embryo yield was significantly reduced by the presence of LSDV in frozen‐thawed semen, irrespective of viral dose. When semen with a lower viral dose was used, significantly lower oocyte cleavage rates were observed. LSDV could be detected in fertilization media and all embryo structures, when higher doses of LSDV were present in the frozen‐thawed semen used for IVF. Electron microscopy demonstrated LSDV virions inside blastocysts. Following the International Embryo Transfer Society washing procedure resulted in embryos free of viral DNA; however, this may be attributable to a sampling dilution effect and should be interpreted with caution. Further research is required to better quantify the risk of LSDV transmission via assisted reproductive procedures.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Radiation with reticulation marks the origin of a major malaria vector

Advances in genomics have led to an appreciation that introgression is common, but its evolutionary consequences are poorly understood. In recent species radiations the sharing of genetic variation across porous species boundaries can facilitate adaptation to new environments and generate novel phenotypes, which may contribute to further diversification. Most Anopheles mosquito species that are of major importance as human malaria vectors have evolved within recent and rapid radiations of largely nonvector species. Here, we focus on one of the most medically important yet understudied anopheline radiations, the Afrotropical Anopheles funestus complex (AFC), to investigate the role of introgression in its diversification and the possible link between introgression and vector potential. The AFC comprises at least seven morphologically similar species, yet only An. funestus sensu stricto is a highly efficient malaria vector with a pan-African distribution. Based on de novo genome assemblies and additional whole-genome resequencing, we use phylogenomic and population genomic analyses to establish species relationships. We show that extensive interspecific gene flow involving multiple species pairs has shaped the evolutionary history of the AFC since its diversification. The most recent introgression event involved a massive and asymmetrical movement of genes from a distantly related AFC lineage into An. funestus, an event that predated and plausibly facilitated its subsequent dramatic geographic range expansion across most of tropical Africa. We propose that introgression may be a common mechanism facilitating adaptation to new environments and enhancing vectorial capacity in Anopheles mosquitoes.

Once considered a rare anthropogenic aberration in animals, interspecific hybridization is now recognized to be both taxonomically widespread and pervasive, particularly in rapidly diversifying groups (1–3). Moreover, mounting genome-scale evidence suggests that introgression, the genetic exchange between species through hybridization and backcrossing, is also prevalent and may be consequential for evolution. Examples from fish, birds, mammals, and insects—including Anopheles mosquitoes—have shown that introgressed variation favored by natural selection can facilitate adaptation, enhance fitness, and drive evolutionary innovation and diversification (4–7). It has been postulated that introgressive hybridization is most prevalent in species-rich and rapidly diversifying radiations (2, 3, 8). Introgression in these groups may solely be opportunistic, given the multiplicity of young species in geographic proximity, but the process may also favor adaptive radiation through the generation of completely novel phenotypes (6, 9, 10).There are three to four dozen Anopheles mosquito species that are of major importance as human malaria vectors, and all have evolved within recent and rapid radiations of morphologically cryptic species (informally classified as species complexes) (11, 12). Most members of these species complexes play no or very minor roles in disease transmission. The repeated de novo origin of major malaria vectors across these independent species radiations therefore holds clues about the nature of key evolutionary innovations that confer the ability to transmit disease widely and efficiently. However, most Anopheles species complexes are understudied. This is especially true of the secondary or nonvector species for which genomic resources are lacking, and basic knowledge of distribution, ecology, and behavior is scant.Until now, the single best-studied group has been the Anopheles gambiae complex, composed of at least eight morphologically indistinguishable species that diversified rapidly and recently, likely within the last half-million years (7, 13, 14). Phylogenomic analysis revealed widespread genealogical discordance (7). Some discordance was due to incomplete lineage sorting as a result of both rapid radiation and large effective population sizes (7), but the majority was caused by massive introgression between the main vector species, involving both the autosomes and the centromere-proximal region of the X chromosome. So extensive was its impact that the inferred species branching order was evident in only 2% of the genome—mostly on the distal portion of the X chromosome, which is protected from introgression by a succession of fixed chromosomal inversion differences.One of the most medically important of the understudied Anopheles species complexes is the Afrotropical Anopheles funestus complex (AFC). The AFC comprises at least seven morphologically similar species (15–18), yet only An. funestus sensu stricto (hereafter, An. funestus) is a highly efficient malaria vector, rivaled in importance solely by An. gambiae and its sister species Anopheles coluzzii in the An. gambiae complex (19–22). Comparative genomics of these two complexes may therefore be instructive with regard to malaria vectorial capacity. Both groups diversified in sub-Saharan Africa and may have experienced common geographic, ecoclimatic, and anthropogenic forces that shaped their history. In addition, the primary vector An. funestus broadly shares several characteristics with primary vectors in the An. gambiae complex: a geographic range that encompasses most of tropical Africa (Fig. 1A), high levels of chromosomal inversion polymorphism (23–25), large effective population size, and little population genetic structure across the continent (26, 27). Furthermore, the discovery of two very distantly related mitochondrial DNA (mtDNA) haplotypes (clades 1 and 2) segregating in An. funestus (27) raises the prospect of historical introgression analogous to that documented for An. gambiae, prompting an intriguing question: Can introgression be a source of evolutionary novelty leading to augmented vectoral capacity?Open in a separate windowFig. 1.Distribution and genetic variation in the AFC. Color coding of species is consistent across panels. (A) Location and distribution of sampled species, adapted from ref. 21. Approximate sample locations for An. funestus are indicated by a black star. For full sample information, see SI Appendix, Table S1. (B) Phylogeny of complete mtDNA genomes constructed using BEAST2 indicating divergent clades of An. funestus (red shading) and An. funestus-like (green shading) (see SI Appendix, Fig. S12 for phylogeny with outgroup). (C) Neighbor-joining phylogeny averaged over the complete nuclear genome. (D) Summary evolutionary history displaying three introgression events as inferred by the methods described in the main text. Introgression events shown as green horizontal arrows between pairs of species indicate the majority direction of introgression. Median divergence and introgression times are displayed in millions of years ago (Mya). See SI Appendix, Table S11 for details. An. funestus (Fun), An. funestus-like (Lik), An. longipalpis C (Lon), An. parensis (Par), and An. vaneedeni (Van), An. rivulorum (Riv).Here, we examine the role of introgression in the evolution of the AFC, using recent methods of phylogenetic network reconstruction that allow for divergence and reticulation to be inferred jointly. We use a combination of phylogenomic and population genomic analyses, based on de novo genome assemblies and additional whole genome resequencing, to: 1) establish species relationships, 2) determine the direction, extent, and genomic architecture of introgression across the complex, and 3) assess the role of introgression in the evolution of the primary vector An. funestus. We show that extensive interspecific gene flow involving multiple species pairs has shaped the evolutionary history of the AFC since its diversification ∼216 thousand years ago (Kya). The most recent introgression event ∼13 Kya involved a massive and asymmetrical movement of genes from a distantly related AFC lineage into An. funestus, an event that predated and plausibly facilitated its subsequent dramatic geographic range expansion across most of tropical Africa. We propose that introgression may be a common mechanism facilitating adaptation to new environments and enhancing vectorial capacity in Anopheles mosquitoes.     

Enhanced immune response in Mycobacterium bovis bacille calmette guerin (BCG)-infected IL-10-deficient mice.

The role of the endogenous interleukin-10 (IL-10) in the control of Mycobacterium bovis Bacille Calmette Guerin (BCG) infection was assessed using IL-10-deficient (IL-10-/-) mice. Similar to wild-type (WT) mice, IL-10-/- mice were resistant to intravenous challenge with Mycobacterium bovis BCG. Significantly higher plasma concentrations of IL-12 and tumour necrosis factor (TNF) indicated an elevated protective immune response of IL-10-/- mice. Determination of bacilli burden in IL-10-/- mice showed accelerated clearance in the lungs, spleen and the liver in comparison to WT mice. Enhanced inflammation and a vigorous granulomatous response accompanied accelerated mycobacterial clearance. Immunohistochemical analysis of hepatic granulomas from IL-10-/- mice revealed augmented lymphocyte recruitment and macrophage activation, such as increased major histocompatibility complex (MHC) class II and inducible nitric oxide synthase (iNOS) expression. Further, it was found that enlarged granulomas persisted subsequent to mycobacterial clearance and failed to resolve in the absence of IL-10. In conclusion, endogenous IL-10 dampens the cell-mediated immune response to mycobacterial infection.