Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Behavioral and antioxidant activity of a tosylbenz[g]indolamine derivative. A proposed better profile for a potential antipsychotic agent

BACKGROUND: Tardive dyskinesia (TD) is a major limitation of older antipsychotics. Newer antipsychotics have various other side effects such as weight gain, hyperglycemia, etc. In a previous study we have shown that an indolamine molecule expresses a moderate binding affinity at the dopamine D(2 )and serotonin 5-HT(1A )receptors in in vitro competition binding assays. In the present work, we tested its p-toluenesulfonyl derivative (TPBIA) for behavioral effects in rats, related to interactions with central dopamine receptors and its antioxidant activity. METHODS: Adult male Fischer-344 rats grouped as: i) Untreated rats: TPBIA was administered i.p. in various doses ii) Apomorphine-treated rats: were treated with apomorphine (1 mg kg(-1), i.p.) 10 min after the administration of TPBIA. Afterwards the rats were placed individually in the activity cage and their motor behaviour was recorded for the next 30 min The antioxidant potential of TPBIA was investigated in the model of in vitro non enzymatic lipid peroxidation. RESULTS: i) In non-pretreated rats, TPBIA reduces the activity by 39 and 82% respectively, ii) In apomorphine pretreated rats, TPBIA reverses the hyperactivity and stereotype behaviour induced by apomorphine. Also TPBIA completely inhibits the peroxidation of rat liver microsome preparations at concentrations of 0.5, 0.25 and 0.1 mM. CONCLUSION: TPBIA exerts dopamine antagonistic activity in the central nervous system. In addition, its antioxidant effect is a desirable property, since TD has been partially attributed, to oxidative stress. Further research is needed to test whether TPBIA may be used as an antipsychotic agent

Wits Transplant Unit Annual Report 2022: Adult and paediatric liver transplantation

In 2022, the Wits Transplant Unit performed 57 liver transplants: 33/57 adult (58%) and 24/57 paediatric (42%) recipients. At the beginning of 2022, 28 candidates were on the adult waitlist. Forty-six candidates were added to the waitlist during the year. Sixty-five percent of waitlisted candidate were transplanted. Adult candidates remained on the waitlist for longer than previous years, with 52% of them waitlisted for less than one year before undergoing liver transplantation. There was a decrease in adult pretransplant mortality to 9% in 2021 from 25% in 2020. The most common aetiology in waitlist candidates was alcoholic steatohepatitis (ASH)/non-alcoholic steatohepatitis (NASH) (36%) and in recipients cholestatic (primary sclerosing cholangitis (PSC) and primary biliary sclerosis (PBC)) (40%). Most adult recipients received a deceased donor graft (79%). Unadjusted recipient one- and three-year survivals were 75% (95% confidence interval (CI) 65 - 83) and 74% (95% CI 65 - 81), respectively. In the paediatric population, the most common aetiologies for both pretransplant candidates and transplant recipients remained cholestatic disease and acute liver failure. There was a decrease in paediatric pretransplant mortality from 27% in 2017 to 6% in 2021. Unlike the adult cohort, most paediatric recipients received a living donor graft (79%). Unadjusted one-year and three-year survival rates were 85% (95% CI 75 - 92) and 68% (95% CI 56 - 77), respectively.

The paediatric liver transplant experience in Johannesburg, South Africa: A broad overview and update

Background: The Wits Transplant Unit performed its first paediatric liver transplant in 2005. Initial experiences from the unit were published in 2012 and 2014. Since then, significant progress has been made in capacity-building the unit, improving outcomes and enhancing service delivery. This paper presents a broad overview and update of the unit’s 17-year experience.   Methods: We conducted a retrospective review of all paediatric liver transplants performed in Johannesburg from 1 January 2005 to 31 December 2021 with a minimum one-year follow-up. Data were accessed from the Wits Donald Gordon Medical Centre Paediatric Liver Transplant Research Database (University of the Witwatersrand Human Research Ethics approval: M190749). The following data were collected: donor and recipient sociodemographic and clinical characteristics, details of transplant procedures, donor grafts and recipient outcomes (post-operative complications, graft and recipient survival).   Results: A total of 270 transplants were performed during the review period. Two thirds of recipients (n=180, 67%) were younger than 5 years at time of transplant and half (n=135, 50%) received a living donor graft. The most common indication for liver transplant was biliary atresia, followed by acute liver failure. Unadjusted recipient survival was 80% (95% CI: 75-85%) at one year, and 68% (95% CI: 59-75%) at five years. Waiting list mortality decreased from 27.3% in 2017 to 5.9% in 2021. One hundred and fifty-four (57.0%) recipients experienced at least one type of intervention requiring surgical complication - the most common being biliary in nature (n = 91; 33.7%).   Conclusion: Over last seventeen years, a sustainable paediatric liver transplantation service has been established in Johannesburg. Living donor, split and ABO incompatible liver transplants have been incorporated in response to the severe organ shortage in South Africa. However, our outcomes can be improved. Additionally, a national transplant initiative to coordinate timeous referrals and expand access to liver transplantation for children with severe acute and chronic liver failure is advised

Hydrothermal vents and methane seeps: rethinking the sphere of influence

Although initially viewed as oases within a barren deep ocean, hydrothermal vents and methane seep chemosynthetic communities are now recognized to interact with surrounding ecosystems on the sea floor and in the water column, and to affect global geochemical cycles. The importance of understanding these interactions is growing as the potential rises for disturbance of the systems from oil and gas extraction, seabed mining and bottom trawling. Here we synthesize current knowledge of the nature, extent and time and space scales of vent and seep interactions with background systems. We document an expanded footprint beyond the site of local venting or seepage with respect to elemental cycling and energy flux, habitat use, trophic interactions, and connectivity. Heat and energy are released, global biogeochemical and elemental cycles are modified, and particulates are transported widely in plumes. Hard and biotic substrates produced at vents and seeps are used by "benthic background" fauna for attachment substrata, shelter, and access to food via grazing or through position in the current, while particulates and fluid fluxes modify planktonic microbial communities. Chemosynthetic production provides nutrition to a host of benthic and planktonic heterotrophic background species through multiple horizontal and vertical transfer pathways assisted by flow, gamete release, animal movements, and succession, but these pathways remain poorly known. Shared species, genera and families indicate that ecological and evolutionary connectivity exists among vents, seeps, organic falls and background communities in the deep sea: the genetic linkages with inactive vents and seeps and background assemblages however, are practically unstudied. The waning of venting or seepage activity generates major transitions in space and time that create links to surrounding ecosystems, often with identifiable ecotones or successional stages. The nature of all these interactions is dependent on water depth, as well as regional oceanography and biodiversity. Many ecosystem services are associated with the interactions and transitions between chemosynthetic and background ecosystems, for example carbon cycling and sequestration, fisheries production, and a host of non-market and cultural services. The quantification of the sphere of influence of vents and seeps could be beneficial to better management of deep-sea environments in the face of growing industrialization

Angiogenesis in Interstitial Lung Diseases: a pathogenetic hallmark or a bystander?

The past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells. A hallmark of tumorigenesis is the production of new blood vessels to facilitate tumor growth and mediate organ-specific metastases. On the other hand several chronic fibroproliferative disorders including fibrotic lung diseases are associated with aberrant angiogenesis. Angiogenesis, the process of new blood vessel formation is under strict regulation determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively. While numerous studies have examined so far the interplay between aberrant vascular and matrix remodeling the relative role of angiogenesis in the initiation and/or progression of the fibrotic cascade still remains elusive and controversial. The current article reviews data concerning the pathogenetic role of angiogenesis in the most prevalent and studied members of ILD disease-group such as IIPs and sarcoidosis, presents some of the future perspectives and formulates questions for potential further research

Emerging Roles of PAR-1 and PAFR in Melanoma Metastasis

Melanoma growth, angiogenesis and metastatic progression are strongly promoted by the inflammatory tumor microenvironment due to high levels of cytokine and chemokine secretion by the recruited inflammatory and stromal cells. In addition, platelets and molecular components of procoagulant pathways have been recently emerging as critical players of tumor growth and metastasis. In particular, thrombin, through the activity of its receptor protease-activated receptor-1 (PAR-1), regulates tumor cell adhesion to platelets and endothelial cells, stimulates tumor angiogenesis, and promotes tumor growth and metastasis. Notably, in many tumor types including melanoma, PAR-1 expression directly correlates with their metastatic phenotype and is directly responsible for the expression of interleukin-8, matrix metalloproteinase-2 (MMP-2), vascular endothelial growth factor, platelet-derived growth factor, and integrins. Another proinflammatory receptor–ligand pair, platelet-activating factor (PAF) and its receptor (PAFR), have been shown to act as important modulators of tumor cell adhesion to endothelial cells, angiogenesis, tumor growth and metastasis. PAF is a bioactive lipid produced by a variety of cells from membrane glycerophospholipids in the same reaction that releases arachidonic acid, and can be secreted by platelets, inflammatory cells, keratinocytes and endothelial cells. We have demonstrated that in metastatic melanoma cells, PAF stimulates the phosphorylation of cyclic adenosine monophosphate response element-binding protein (CREB) and activating transcription factor 1 (ATF-1), which results in overexpression of MMP-2 and membrane type 1-MMP (membrane type 1-MMP). Since only metastatic melanoma cells overexpress CREB/ATF-1, we propose that metastatic melanoma cells are better equipped than their non-metastatic counterparts to respond to PAF within the tumor microenvironment. The evidence supporting the hypothesis that the two G-protein coupled receptors, PAR-1 and PAFR, contribute to the acquisition of the metastatic phenotype of melanoma is presented and discussed

Natural flavonoids as potential multifunctional agents in prevention of diabetic cataract

Cataract is one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Mechanisms related to glucose toxicity, namely oxidative stress, processes of non-enzymatic glycation and enhanced polyol pathway significantly contribute to the development of eye lens opacity under conditions of diabetes. There is an urgent need for inexpensive, non-surgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in the prevention of cataract since flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of diabetic cataract. In the present paper, natural flavonoids are reviewed as potential agents that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification. In addition, the bioavailability of flavonoids for the lens is considered