Use of community-based participatory research in preparing low income and homeless minority populations for future HIV vaccines

We conducted Community-Based Participatory Research (CBPR), using a qualitative focus group design, to assess factors that might impact participation of high-risk impoverished adults in future HIV Vaccine Trials (HIVVTs). The participants were 40 homeless and low-income adults recruited from subsidized apartments and homeless shelters in Los Angeles. Findings revealed that the participants expressed both concerns and interest in future HIVVTs. Concerns centered on the impact of the vaccine on their physical health, the possibility of seroconverting and its associated stigma. While distrust of the government was pervasive, the participants were interested in receiving more information about the vaccine from the researchers. They also wished to have their voices heard by the researchers early in the design of the vaccines. Motivating factors were also discovered, and included altruism, compensation and access to care. Perception that risk behaviors might increase among some as a result of participation in a future HIVVT was likewise revealed. Implications of the study reveal that while impoverished populations are interested in participating in future HIVVTs, the researchers must address concerns early on. Moreover, the importance of ongoing education and counseling to warn about hazards of engaging in risky behavior while participating in a future HIVVT was critical.     

Indian hedgehog stimulates periarticular chondrocyte differentiation to regulate growth plate length independently of PTHrP

In the developing growth plate, periarticular chondrocytes proliferate, differentiate into columnar chondrocytes, and then further differentiate into postmitotic hypertrophic chondrocytes. Parathyroid hormone-related (PTH-related) protein (PTHrP), regulated by Indian hedgehog (Ihh), prevents premature hypertrophic differentiation, thereby maintaining the length of columns. Ihh regulates cartilage development through PTHrP-independent pathways as well. Here we show that Ihh stimulates differentiation of periarticular to columnar chondrocytes (periarticular chondrocyte differentiation) and thereby regulates the length of columns independently of PTHrP. Mosaic ablation of the PTH/PTHrP receptor in the growth plate caused upregulation of Ihh action, PTHrP upregulation, acceleration of periarticular chondrocyte differentiation, and elongation of the columnar region. Decreasing Ihh action in these mice reduced elongation of columns, whereas decreasing PTHrP showed only a modest effect on column length. Overexpression of Ihh caused PTHrP upregulation, elongation of columns, and acceleration of periarticular chondrocyte differentiation. PTHrP heterozygosity in this model had a minimal effect on the elongation of columns. Moreover, the elongation of columns and stimulation of periarticular chondrocyte differentiation in these models were still observed when PTHrP signaling was maintained so that it remained constant. These results demonstrate that Ihh acts on periarticular chondrocytes to stimulate their differentiation, thereby regulating the columnar cell mass independently of PTHrP.     

The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development

Skeletal development and turnover occur in close spatial and temporal association with angiogenesis. Osteoblasts are ideally situated in bone to sense oxygen tension and respond to hypoxia by activating the hypoxia-inducible factor alpha (HIF alpha) pathway. Here we provide evidence that HIF alpha promotes angiogenesis and osteogenesis by elevating VEGF levels in osteoblasts. Mice overexpressing HIF alpha in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of Vegf and developed extremely dense, heavily vascularized long bones. By contrast, mice lacking Hif1a in osteoblasts had the reverse skeletal phenotype of that of the Vhl mutants: long bones were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Mice lacking both Vhl and Hif1a had a bone phenotype intermediate between those of the single mutants, suggesting overlapping functions of HIFs in bone. These studies suggest that activation of the HIF alpha pathway in developing bone increases bone modeling events through cell-nonautonomous mechanisms to coordinate the timing, direction, and degree of new blood vessel formation in bone.     

ERα Signaling in GHRH/Kiss1 Dual-Phenotype Neurons Plays Sex-Specific Roles in Growth and Puberty

Gonadal steroids modulate growth hormone (GH) secretion and the pubertal growth spurt via undefined central pathways. GH-releasing hormone (GHRH) neurons express estrogen receptor α (ERα) and androgen receptor (AR), suggesting changing levels of gonadal steroids during puberty directly modulate the somatotropic axis. We generated mice with deletion of ERα in GHRH cells (GHRH^ΔERα), which displayed reduced body length in both sexes. Timing of puberty onset was similar in both groups, but puberty completion was delayed in GHRH^ΔERα females. Lack of AR in GHRH cells (GHRH^ΔAR mice) induced no changes in body length, but puberty completion was also delayed in females. Using a mouse model with two reporter genes, we observed that, while GHRH^tdTom neurons minimally colocalize with Kiss1^hrGFP in prepubertal mice, ∼30% of GHRH neurons coexpressed both reporter genes in adult females, but not in males. Developmental analysis of Ghrh and Kiss1 expression suggested that a subpopulation of ERα neurons in the arcuate nucleus of female mice undergoes a shift in phenotype, from GHRH to Kiss1, during pubertal transition. Our findings demonstrate that direct actions of gonadal steroids in GHRH neurons modulate growth and puberty and indicate that GHRH/Kiss1 dual-phenotype neurons play a sex-specific role in the crosstalk between the somatotropic and gonadotropic axes during pubertal transition.SIGNIFICANCE STATEMENT Late maturing adolescents usually show delayed growth and bone age. At puberty, gonadal steroids have stimulatory effects on the activation of growth and reproductive axes, but the existence of gonadal steroid-sensitive neuronal crosstalk remains undefined. Moreover, the neural basis for the sex differences observed in the clinical arena is unknown. Lack of ERα in GHRH neurons disrupts growth in both sexes and causes pubertal delay in females. Deletion of androgen receptor in GHRH neurons only delayed female puberty. In adult females, not males, a subset of GHRH neurons shift phenotype to start producing Kiss1. Thus, direct estrogen action in GHRH/Kiss1 dual-phenotype neurons modulates growth and puberty and may orchestrate the sex differences in endocrine function observed during pubertal transition.     

Would Zika virus Infection in Pregnancy Be a Sentence of Poor Neurological Prognosis for Exposed Children? Neurodevelopmental Outcomes in a Cohort from Brazilian Amazon

Infections with Flavivirus in pregnant women are not associated with vertical transmission. However, in 2015, severe cases of congenital infection were reported during the Zika virus outbreak in Brazil. More subtle infections in children born to mothers with ZIKV still remain uncertain and the spectrum of this new congenital syndrome is still under construction. This study describes outcomes regarding neurodevelopment and neurological examination in the first years of life, of a cohort of 77 children born to pregnant women with ZIKV infection in Manaus, Brazil, from 2017 to 2020. In the group of normocephalic children (92.2%), most showed satisfactory performance in neuropsychomotor development, with a delay in 29.6% and changes in neurological examination in 27.1%, with two children showing muscle-strength deficits. All microcephalic children (5.2%) evolved with severe neuropsychomotor-development delay, spastic tetraparesis, and alterations in the imaging exam. In this cohort, 10.5% of the children had macrocephaly at birth, but only 2.6% remained in this classification. Although microcephaly has been considered as the main marker of congenital-Zika-virus syndrome in previous studies, its absence does not exclude the possibility of the syndrome. This highlights the importance of clinical follow-up, regardless of the classification of head circumference at birth.