Gambling in Sub-Saharan Africa: Traditional Forms and Emerging Technologies.

Purpose of Review: The gambling industry in Africa has seen substantial growth and evolution over recent years with a growing body of literature describing these shifts. Here, we provide a narrative synthesis of the extant literature on the origins, trends and consequences of the expansion and intensification of the commercial gambling industry in sub-Saharan Africa with a reference for future research on gambling as a growing public health concern. Recent Findings: The historical shift and permeation of gambling in sub-Saharan Africa is diverse with evidence of certain countries following a neo-colonial logic. Advances in technology have made gambling more accessible and created new markets in Africa. A key motive driving gambling on the continent is a lack of stable employment. While the intensification and growth of Africa's gambling industry has brought economic benefits to some African investors and individuals, this has been accompanied by a range of gambling harms. Legislation and policies designed to better regulate the gambling industry and redress these harms are needed. In this context, a small number of services and campaigns designed to mitigate gambling harms demonstrate promise, but more research is needed in this area. Summary: The gambling industry in sub-Saharan Africa has undergone a dramatic transformation. While it is true that the growth of the African gambling industry has provided an additional revenue stream to governments, it is also necessary to acknowledge the concurrent rise in gambling addiction and the health-related and social harms that it elicits. As such, designing effective regulatory measures and policy interventions that can reduce the public health burden of gambling harms is vital. However, these interventions need to take in to account the significance of cultural differences that exist among countries on the continent.

Deconstructing the functional neuroanatomy of the choroid plexus: an ontogenetic perspective for studying neurodevelopmental and neuropsychiatric disorders.

The choroid plexus (CP) is a delicate and highly vascularized structure in the brain comprised of a dense network of fenestrated capillary loops that help in the synthesis, secretion and circulation of cerebrospinal fluid (CSF). This unique neuroanatomical structure is comprised of arachnoid villi stemming from frond-like surface projections-that protrude into the lumen of the four cerebral ventricles-providing a key source of nutrients to the brain parenchyma in addition to serving as a 'sink' for central nervous system metabolic waste. In fact, the functions of the CP are often described as being analogous to those of the liver and kidney. Beyond forming a barrier/interface between the blood and CSF compartments, the CP has been identified as a modulator of leukocyte trafficking, inflammation, cognition, circadian rhythm and the gut brain-axis. In recent years, advances in molecular biology techniques and neuroimaging along with the use of sophisticated animal models have played an integral role in shaping our understanding of how the CP-CSF system changes in relation to the maturation of neural circuits during critical periods of brain development. In this article we provide an ontogenetic perspective of the CP and review the experimental evidence implicating this structure in the pathophysiology of neurodevelopmental and neuropsychiatric disorders.

Gambling Patterns and Problem Gambling Among Youth in Sub-Saharan Africa: A Systematic Review.

Mounting evidence suggests that youth in sub-Saharan Africa (SSA) find themselves increasingly drawn to gambling related activities; an issue, that if left unchecked, can lead to adverse consequences including financial difficulties, crime and mental health problems. To better understand the psychosocial mechanisms underlying problem gambling, there is a pressing need to conduct more research on gambling related disorders amongst this vulnerable stratum of society. Against this background, the present review explores gambling patterns, attitudes and behaviors among youth in SSA-in a manner aligning with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We systematically searched 8 databases including PubMed, Science Direct, Scopus, ProQuest, Wiley Online, Google Scholar, PsycINFO and PsycARTICLES for published research articles up until July 2019. A total of 1624 articles were screened, of which, only 13 studies met inclusion criteria. All of these studies were cross-sectional in nature and the quality of each study was evaluated using the Newcastle-Ottawa Scale. Studies varied considerably ranging from neuropsychological and personality trait assessment to application of item response theory. Due to this study heterogeneity we could not conduct a meta-analysis. The results presented here suggest that the existing body of evidence pertaining to patterns of gambling-related harm among youth in SSA is weak. This study highlights the need for additional good quality studies focusing on gambling related behaviors and prevalence levels among the continent's youth. Additionally, the findings reported herein emphasise the need for implementing social policies alongside effective public health interventions to tackle gambling addiction.

The health and economic burden of the coronavirus in sub-Saharan Africa.

The current coronavirus (COVID-19) pandemic continues to overwhelm healthcare systems and to exert a negative influence on the global economy. Of particular concern is the impact of COVID-19 in low-income settings - especially in terms of their capacity to mitigate a surge in COVID-19 cases. Indeed, response measures currently in place to tackle the spread of COVID-19 in geographic regions predominantly consisting of low-income nations, such as Sub-Saharan Africa (SSA), remain tenuous and will require context-appropriate interventions. Control measures to tackle COVID-19 in SSA should therefore be informed through lessons learned from past outbreaks and emergencies on the continent. These lessons will represent a key source of guidance for the strategic implementation and promotion of public health interventions to assist scale-up of COVID-19 case management, infection prevention and control. Importantly, as governments in SSA continue to combat the spread of COVID-19, there will be a need to expand the coverage of social safety net programs and fiscal policy responses to tackle the socio-economic and health impact of COVID-19.

Implications of early life stress on fetal metabolic programming of schizophrenia: A focus on epiphenomena underlying morbidity and early mortality.

The fetal origin of adult disease hypothesis postulates that a stressful in utero environment can have deleterious consequences on fetal programming, potentially leading to chronic disease in later life. Factors known to impact fetal programming include the timing, intensity, duration and nature of the external stressor during pregnancy. As such, dynamic modulation of fetal programming is heavily involved in shaping health throughout the life course, possibly by influencing metabolic parameters including insulin action, hypothalamic-pituitary-adrenal activity and immune function. The ability of prenatal insults to program adult disease is likely to occur as a result of reduced functional capacity in key organs-a "thrifty" phenotype-where more resources are re-allocated to preserve critical organs such as the brain. Notably, it has been postulated that the manifestation of neuropsychiatric disorders in individuals priorly exposed to prenatal stress may arise from the interaction between hereditary factors and the intrauterine environment, which together precipitate disease onset by disrupting the trajectory of normal brain development. In this review we discuss the evidence linking prenatal programming to neuropsychiatric disorders, mainly schizophrenia, via a "Thrifty psychiatric phenotype" concept. We start by outlining the conception of the thrifty psychiatric phenotype. Next, we discuss the convergence of potential mechanistic pathways through which prenatal insults may trigger epigenetic changes that contribute to the increased morbidity and early mortality observed in neuropsychiatric disorders. Finally, we touch on the public health importance of fetal programming for these disorders. We conclude by providing a brief outlook on the future of this evolving field of research.

A conceptualized model linking matrix metalloproteinase-9 to schizophrenia pathogenesis.

Matrix metalloproteinase 9 (MMP-9) is an extracellularly operating zinc-dependent endopeptidase that is commonly expressed in the brain, other tissues. It is synthesized in a latent zymogen form known as pro-MMP-9 that is subsequently converted to the active MMP-9 enzyme following cleavage of the pro-domain. Within the central nervous system, MMP-9 is localized and released from neurons, astrocytes and microglia where its expression levels are modulated by cytokines and growth factors during both normal and pathological conditions as well as by reactive oxygen species generated during oxidative stress. MMP-9 is involved in a number of key neurodevelopmental processes that are thought to be affected in schizophrenia, including maturation of the inhibitory neurons that contain the calcium-binding protein parvalbumin, developmental formation of the specialized extracellular matrix structure perineuronal net, synaptic pruning, and myelination. In this context, the present article provides a narrative synthesis of the existing evidence linking MMP-9 dysregulation to schizophrenia pathogenesis. We start by providing an overview of MMP-9 involvement in brain development and physiology. We then discuss the potential mechanisms through which MMP-9 dysregulation may affect neural circuitry maturation as well as how these anomalies may contribute to the disease process of schizophrenia. We conclude by articulating a comprehensive, cogent, and experimentally testable hypothesis linking MMP-9 to the developmental pathophysiologic cascade that triggers the onset and sustains the chronicity of the illness.

A strategy to analyse activity-based profiling of tyrosine kinase substrates in OCT-embedded lung cancer tissue.

The use of optimal cutting temperature (OCT) medium has served to improve the long-term preservation of surgical tissue specimens. Unfortunately, the presence of polymers in OCT has been found to generate signal interference in proteomic-based techniques. Indeed the presence of OCT medium in tissue lysates precludes the analysis of activity based proteomic profiles obtained from lung adenocarcinoma (LuAdCa) resection specimens. In order to probe this question further tissue lysates were prepared from 47 lung non-neoplastic and tumour, node, metastasis (TNM) stage 1 LuAdCa resection specimens embedded with or without OCT, and data of activity based multiplex profiles of protein tyrosine kinase peptide substrates were obtained. We found that changes in overall phosphorylation level coincided with the use of OCT and subsequently developed an OCT per peptide median correcting strategy by performing median centering on the values of each peptide. Application of this post-analytical strategy not only can identify changes in kinase activity but can also assist in identifying novel targets for therapeutic intervention against LuAdCa.

Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma.

INTRODUCTION: Alterations of the tumor suppressor Neurofibromatosis type II (NF2) have been reported in about 40% of Malignant pleural mesothelioma (MPM) patients. NF2 (Merlin) deficiency leads to alterations of the Hippo pathway; resulting in activation of the oncogenic Yes Associated Protein-1 (YAP1). Our aim was to investigate the association between these alterations and clinical outcomes. MATERIAL AND METHODS: Tissue microarrays composed of MPM tumors derived from 2 independent MPM cohorts were employed for this study. Immunohistochemical expression of Merlin, YAP1 and its target genes, Survivin and connective tissue growth factor (CTGF) were assessed in nuclear and cytoplasmic fractions. Cohort 1 was comprised of 145 patients intended to be treated with chemotherapy (CTX) followed by extrapleural pneumonectomy (EPP), thus both pre- and post-CTX tissues were available. Cohort 2 was comprised of 59 patients treated with EPP followed by intraoperative hyperthermic cisplatin and/or adjuvant CTX and/or radiotherapy. Marker expression was quantified by means of labeling index (%) for nuclear Survivin and by H-score for the other markers. The dichotomized marker expression was tested for the association with overall survival (OS) and freedom from recurrence (FFR). RESULTS: Kaplan-Meier survival curves revealed a significant association between low cytoplasmic Merlin expression in pre-induction CTX tissues of cohort 1 with shorter FFR (p = 0.02) and OS (p = 0.03). The same tendency was observed in the chemotherapy naïve tissues obtained during EPP of cohort 2. Low nuclear Merlin expression in post-CTX tissues (available from cohort 1 only) was associated with shorter FFR (p = 0.04) and OS (p = 0.05). High nuclear Survivin labeling indices in both pre- and post-CTX tissues of cohort 1 was associated with shorter FFR (p = 0.02). In cohort 2, this was associated with both FFR and OS (p = 0.046 and p = 0.002, respectively). In multivariate analysis, low expression of cytoplasmic Merlin remained an independent prognosticator for shorter FFR of cohort 1 [hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.3-0.9, p = 0.001] and OS [HR = 0.5, 95% CI = 0.3-1, p = 0.04]. High Survivin labeling index was an independent prognostic factor for shorter FFR in patients from cohort 1 [HR = 3.4, 95% CI = 1.7-6.8, p = 0.006] and shorter OS in patients from cohort 2 [HR = 2.35, 95% CI = 1.27-4.33, p = 0.006]. CONCLUSIONS: Our findings uncover the significance of Merlin protein expression and Survivin labeling index as prognosticators for poor clinical outcome in two independent MPM cohorts. If confirmed, these markers may be used to identify subgroups of patients benefitting from additional treatment.

Weaving a Net of Neurobiological Mechanisms in Schizophrenia and Unraveling the Underlying Pathophysiology.

Perineuronal nets (PNNs) are enigmatic structures composed of extracellular matrix molecules that encapsulate the soma, dendrites, and axon segments of neurons in a lattice-like fashion. Although most PNNs condense around parvalbumin-expressing gamma-aminobutyric acidergic interneurons, some glutamatergic pyramidal cells in the brain are also surrounded by PNNs. Experimental findings suggest pivotal roles of PNNs in the regulation of synaptic formation and function. Also, an increasing body of evidence links PNN abnormalities to schizophrenia. The number of PNNs progressively increases during postnatal development until plateauing around the period of late adolescence and early adulthood, which temporally coincides with the age of onset of schizophrenia. Given the established role of PNNs in modulating developmental plasticity, the PNN represents a possible candidate for altering the onset and progression of schizophrenia. Similarly, the reported function of PNNs in regulating the trafficking of glutamate receptors places them in a critical position to modulate synaptic pathology, considered a cardinal feature of schizophrenia. We discuss the physiologic role of PNNs in neural function, synaptic assembly, and plasticity as well as how they interface with circuit/system mechanisms of cognition. An integrated understanding of these neurobiological processes should provide a better basis to elucidate how PNN abnormalities influence brain function and contribute to the pathogenesis of neurodevelopmental disorders such as schizophrenia.

Transcriptional dysregulation of γ-aminobutyric acid transporter in parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia.

Parvalbumin (PV)-containing neurons are functionally compromised in schizophrenia. Using double in situ hybridization in postmortem human prefrontal cortex, we found that the messenger RNA (mRNA) for the γ-aminobutyric acid (GABA) transporter GAT-1 was undetectable in 22-41% of PV neurons in layers 3-4 in schizophrenia. In the remaining PV neurons with detectable GAT-1 mRNA, transcript expression was decreased by 26% in layer 3. Hence, the dysfunction of PV neurons involves the molecular dysregulation of presynaptic GABA reuptake.

Perineuronal nets and schizophrenia: the importance of neuronal coatings.

Schizophrenia is a complex brain disorder associated with deficits in synaptic connectivity. The insidious onset of this illness during late adolescence and early adulthood has been reported to be dependent on several key processes of brain development including synaptic refinement, myelination and the physiological maturation of inhibitory neural networks. Interestingly, these events coincide with the appearance of perineuronal nets (PNNs), reticular structures composed of components of the extracellular matrix that coat a variety of cells in the mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been associated with schizophrenia. Here, we review the emerging evidence linking PNNs to schizophrenia. Future studies aimed at further elucidating the functions of PNNs will provide new insights into the pathophysiology of schizophrenia leading to the identification of novel therapeutic targets with the potential to restore normal synaptic integrity in the brain of patients afflicted by this illness.

PI3K/mTOR signaling in mesothelioma patients treated with induction chemotherapy followed by extrapleural pneumonectomy.

INTRODUCTION: The prognostic significance of activity biomarkers within the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway was assessed in two independent cohorts of malignant pleural mesothelioma (MPM) patients uniformly treated with a multimodal approach. We specifically assessed expression signatures in a unique set of pre- and postchemotherapy tumor samples. METHODS: Biomarker expression was assessed in samples of two independent cohorts of 107 (cohort 1) and 46 (cohort 2) MPM cases uniformly treated with platinum-based induction chemotherapy followed by extrapleural pneumonectomy from two different institutions, assembled on tissue microarrays. Expression levels of phosphatase and tensin homologue (PTEN), phospho-mTOR, and p-S6 in addition to marker of proliferation (Ki-67) and apoptosis (cleaved caspase-3) were evaluated by immunohistochemistry and correlated with overall survival (OAS) and progression-free survival (PFS). To assess PTEN genomic status, fluorescence in situ hybridization was performed. RESULTS: Survival analysis showed that high p-S6 and Ki-67 expression in samples of treatment naïve patients of cohort 1 was associated with shorter PFS (p = 0.02 and p = 0.04, respectively). High Ki-67 expression after chemotherapy remained associated with shorter PFS (p = 0.03) and OAS (p = 0.02). Paired comparison of marker expression in samples before and after induction chemotherapy of cohort 1 revealed that decreased cytoplasmic PTEN and increased phospho-mTOR expression was associated with a worse OAS (p = 0.04 and p = 0.03, respectively). CONCLUSIONS: These novel data reveal a prognostic significance of expression changes of PI3K/mTOR pathway components during induction chemotherapy if confirmed in other patient cohorts and support the growing evidence to target the PI3K/mTOR pathway in the treatment of MPM.

Oxidative stress in schizophrenia: an integrated approach.

Oxidative stress has been suggested to contribute to the pathophysiology of schizophrenia. In particular, oxidative damage to lipids, proteins, and DNA as observed in schizophrenia is known to impair cell viability and function, which may subsequently account for the deteriorating course of the illness. Currently available evidence points towards an alteration in the activities of enzymatic and nonenzymatic antioxidant systems in schizophrenia. In fact, experimental models have demonstrated that oxidative stress induces behavioral and molecular anomalies strikingly similar to those observed in schizophrenia. These findings suggest that oxidative stress is intimately linked to a variety of pathophysiological processes, such as inflammation, oligodendrocyte abnormalities, mitochondrial dysfunction, hypoactive N-methyl-d-aspartate receptors and the impairment of fast-spiking gamma-aminobutyric acid interneurons. Such self-sustaining mechanisms may progressively worsen producing the functional and structural consequences associated with schizophrenia. Recent clinical studies have shown antioxidant treatment to be effective in ameliorating schizophrenic symptoms. Hence, identifying viable therapeutic strategies to tackle oxidative stress and the resulting physiological disturbances provide an exciting opportunity for the treatment and ultimately prevention of schizophrenia.

Sensorimotor gating and vigilance-dependent choice accuracy: a within-subject correlative analysis in wild-type C57BL/6 mice.

Deterioration in attention and related processes is an early sign in schizophrenia predictive of disease development. Amongst the various translational paradigms for assessing attention in rodents, it is not known if they are equivalent in detecting individual differences. Answers here are pertinent to their use in the general human population for identifying individuals at high risk of developing schizophrenia. The present study employed a within-subject approach to examine in mice two common paradigms for assessing attention that differ markedly in their implementation. An operant-based two-choice visual discrimination task (2-CVDT) that depends on effortful attention to brief visual cues was contrasted with prepulse inhibition (PPI) of the acoustic startle reflex, a well-established test of pre-attentive gating whereby processing of a startle-eliciting stimulus is inhibited by a preceding weak prepulse stimulus. Here, we revealed a correlation showing that individual mice with low PPI tended to perform poorly in the 2-CVDT in terms of choice accuracy but not response speed. This specific positive correlation suggests that the two readouts might be regulated via common attentional mechanisms, which might be critically dependent on normal muscarinic and N-methyl-d-asparate receptor functions. As demonstrated here, blockade of either receptor type by scopolamine or dizocilpine impaired 2-CVDT performance at doses that have been shown to disrupt PPI in mice. Further studies contrasting these two paradigms would be warranted to characterize the possible underlying psychological constructs that give rise to this correlation and to clarify whether the two paradigms may effectively capture schizophrenia-related cognitive deficits belonging to orthogonal domains.

Late prenatal immune activation in mice leads to behavioral and neurochemical abnormalities relevant to the negative symptoms of schizophrenia.

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Cognitive impairment following prenatal immune challenge in mice correlates with prefrontal cortical AKT1 deficiency.

Accumulating evidence indicates that genetically determined deficiency in the expression of the cytoplasmic serine-threonine protein kinase AKT1 may contribute to abnormal prefrontal cortical structure and function relevant to the cognitive disturbances in schizophrenia. However, it remains essentially unknown whether prefrontal AKT1 expression may also be influenced by environmental factors implicated in the aetiology of this mental illness. One of the relevant environmental risk factors of schizophrenia and related disorders is prenatal exposure to infection and/or immune activation. This study therefore explored whether prenatal immune challenge may lead to prefrontal AKT1 deficiency and associated changes in cognitive functions attributed to the prefrontal cortex. For these purposes, we used a well-established experimental mouse model of prenatal exposure to a viral-like acute phase response induced by the synthetic analogue of double-stranded RNA, polyriboinosinic-polyribocytidilic acid (PolyI:C). We found that adult offspring born to PolyI:C-treated mothers showed delay-dependent impairments in spatial working memory and recognition memory together with a marked reduction of AKT1-positive cells in the prefrontal cortex. These effects emerged in the absence of concomitant changes in prefrontal catechol-O-methyltransferase (COMT) density. Correlative analyses further demonstrated a significant positive correlation between the number of AKT1-positive cells in distinct prefrontal cortical subregions and cognitive performance under high storage load in the temporal domain. Our findings thus highlight that schizophrenia-related alterations in AKT1 signalling and associated cognitive dysfunctions may not only be precipitated by genetically determined factors, but may also be produced by (immune-associated) environmental insults implicated in the aetiology of this disabling brain disorder.

Zinc: the brain's dark horse.

Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.