Case number 3 : Prune Belly Syndrome aka Eagle Barrett Syndrome

HM, male Severe bilateral hydronephrosis was noted at 20 weeks gestation with normal liquor at the time. The baby was delivered by elective C-section at 39 weeks gestation and very little liquor was noted. He was noted to have deficient abdominal wall musculature and cryptorchidism and prune-belly syndrome was suspected. A renal US confirmed bilateral severe hydroureteronephrosis with no evidence of posterior urethral valves or vesico-ureteric reflux on micturating cystourethrogram. A DTPA scan excluded outflow tract obstruction and a DMSA scan showed a non-functioning left kidney. His creatinine was noted to be 228umol/l (normal creatinine at this age 20-30umol/l). An ultrasound of the brain and back revealed no spinal anomalies and an echocardiogram showed a normal heart. Over the first few months of life he was managed conservatively on medications for chronic kidney disease. At the age of 1 year he underwent a left orchidopexy and a right first stage Fowler Stephen’s procedure. The second stage was performed a few months later.peer-reviewe

Molecular mechanisms of the sleep wake cycle : therapeutic applications to insomnia

The aim of this review is to explore the molecular mechanism and genetic components of the sleepwake cycle and insomnia. Moreover, we wanted to review the correlation between primary insomnia and its comorbidities. With this aim, a systematic review of recent evidence of the molecular and genetic mechanisms involved in the causation of primary insomnia, along with associations between primary insomnia and other diseases were conducted. Primary insomnia is a complex disorder which accounts for 25% of total chronic insomnia and has several effects other than on sleep. It is manifested by a variety of genetic, cultural, social, psychological and environmental factors. Chronic insomnia has been shown to be 24-hour hyperarousal with reduced relative metabolism in the prefrontal cortex while awake. Insomnia can cause various physiological effects and memory capacity alterations; with chronic activation of the hypothalamic–pituitary–adrenal axis also leading to the development of depression and anxiety. Orexins and melatonin are important regulators of sleep and wakefulness. Detailed mechanisms of alterations to the neuroendocrine components highlight the therapeutic potential of orexin antagonists, as well as exogenous melatonin and melatonin receptor agonists. Genetics plays an important role in the development of insomnia, with several single nucleotide polymorphisms implicated in sleep regulation. Further research is crucial to aid understanding of this common disorder and enhance treatment options.peer-reviewe

The 5'-3' exoribonuclease pacman is required for epithelial sheet sealing in Drosophila and genetically interacts with the phosphatase puckered

Background information. Ribonucleases have been well studied in yeast and bacteria, but their biological significance to developmental processes in multicellular organisms is not well understood. However, there is increasing evidence that specific timed transcript degradation is critical for regulation of many cellular processes, including translational repression, nonsense-mediated decay and RNA interference. The Drosophila gene pacman is highly homologous to the major yeast exoribonuclease XRN1 and is the only known cytoplasmic 5′–3′ exoribonuclease in eukaryotes. To determine the effects of this exoribonuclease in development we have constructed a number of mutations in pacman by P-element excision and characterized the resulting phenotypes. Results. Mutations in pacman resulted in flies with a number of specific phenotypes, such as low viability, dull wings, crooked legs, failure of correct dorsal/thorax closure and defects in wound healing. The epithelial sheet movement involved in dorsal/thorax closure is a conserved morphogenetic process which is similar to that of hind-brain closure in vertebrates and wound healing in humans. As the JNK (c-Jun N-terminal kinase) signalling pathway is known to be involved in dorsal/thorax closure and wound healing, we tested whether pacman affects JNK signalling. Our experiments demonstrate that pacman genetically interacts with puckered, a phosphatase that negatively regulates the JNK signalling pathway. Conclusions. These results reveal that the 5′–3′ exoribonuclease pacman is required for a critical aspect of epithelial sheet sealing in Drosophila. Since these mutations result in specific phenotypes, our data suggest that the exoribonuclease Pacman targets a specific subset of mRNAs involved in this process. One of these targets could be a member of the JNK signalling pathway, although it is possible that a parallel pathway may instead be affected. The exoribonuclease pacman is highly conserved in all eukaryotes, therefore it is likely that it is involved in similar morphological processes, such as wound healing in human cells

Evaluating comparative effectiveness of psychosocial interventions adjunctive to opioid agonist therapy for opioid use disorder: A systematic review with network meta-analyses.

BackgroundGuidelines recommend that individuals with opioid use disorder (OUD) receive pharmacological and psychosocial interventions; however, the most appropriate psychosocial intervention is not known. In collaboration with people with lived experience, clinicians, and policy makers, we sought to assess the relative benefits of psychosocial interventions as an adjunct to opioid agonist therapy (OAT) among persons with OUD.MethodsA review protocol was registered a priori (CRD42018090761), and a comprehensive search for randomized controlled trials (RCT) was conducted from database inception to June 2020 in MEDLINE, Embase, PsycINFO and the Cochrane Central Register of Controlled Trials. Established methods for study selection and data extraction were used. Primary outcomes were treatment retention and opioid use (measured by urinalysis for opioid use and opioid abstinence outcomes). Odds ratios were estimated using network meta-analyses (NMA) as appropriate based on available evidence, and in remaining cases alternative approaches to synthesis were used.ResultsSeventy-two RCTs met the inclusion criteria. Risk of bias evaluations commonly identified study limitations and poor reporting with regard to methods used for allocation concealment and selective outcome reporting. Due to inconsistency in reporting of outcome measures, only 48 RCTs (20 unique interventions, 5,404 participants) were included for NMA of treatment retention, where statistically significant differences were found when psychosocial interventions were used as an adjunct to OAT as compared to OAT-only. The addition of rewards-based interventions such as contingency management (alone or with community reinforcement approach) to OAT was superior to OAT-only. Few statistically significant differences between psychosocial interventions were identified among any other pairwise comparisons. Heterogeneity in reporting formats precluded an NMA for opioid use. A structured synthesis was undertaken for the remaining outcomes which included opioid use (n = 18 studies) and opioid abstinence (n = 35 studies), where the majority of studies found no significant difference between OAT plus psychosocial interventions as compared to OAT-only.ConclusionsThis systematic review offers a comprehensive synthesis of the available evidence and the limitations of current trials of psychosocial interventions applied as an adjunct to OAT for OUD. Clinicians and health services may wish to consider integrating contingency management in addition to OAT for OUD in their settings to improve treatment retention. Aside from treatment retention, few differences were consistently found between psychosocial interventions adjunctive to OAT and OAT-only. There is a need for high-quality RCTs to establish more definitive conclusions.Trial registrationPROSPERO registration CRD42018090761

Evaluating comparative effectiveness of psychosocial interventions adjunctive to opioid agonist therapy for opioid use disorder: a systematic review with network meta-analyses.

BACKGROUND: Guidelines recommend that individuals with opioid use disorder (OUD) receive pharmacological and psychosocial interventions; however, the most appropriate psychosocial intervention is not known. In collaboration with people with lived experience, clinicians, and policy makers, we sought to assess the relative benefits of psychosocial interventions as an adjunct to opioid agonist therapy (OAT) among persons with OUD. METHODS: A review protocol was registered a priori (CRD42018090761), and a comprehensive search for randomized controlled trials (RCT) was conducted from database inception to June 2020 in MEDLINE, Embase, PsycINFO and the Cochrane Central Register of Controlled Trials. Established methods for study selection and data extraction were used. Primary outcomes were treatment retention and opioid use (measured by urinalysis for opioid use and opioid abstinence outcomes). Odds ratios were estimated using network meta-analyses (NMA) as appropriate based on available evidence, and in remaining cases alternative approaches to synthesis were used. RESULTS: Seventy-two RCTs met the inclusion criteria. Risk of bias evaluations commonly identified study limitations and poor reporting with regard to methods used for allocation concealment and selective outcome reporting. Due to inconsistency in reporting of outcome measures, only 48 RCTs (20 unique interventions, 5,404 participants) were included for NMA of treatment retention, where statistically significant differences were found when psychosocial interventions were used as an adjunct to OAT as compared to OAT-only. The addition of rewards-based interventions such as contingency management (alone or with community reinforcement approach) to OAT was superior to OAT-only. Few statistically significant differences between psychosocial interventions were identified among any other pairwise comparisons. Heterogeneity in reporting formats precluded an NMA for opioid use. A structured synthesis was undertaken for the remaining outcomes which included opioid use (n = 18 studies) and opioid abstinence (n = 35 studies), where the majority of studies found no significant difference between OAT plus psychosocial interventions as compared to OAT-only. CONCLUSIONS: This systematic review offers a comprehensive synthesis of the available evidence and the limitations of current trials of psychosocial interventions applied as an adjunct to OAT for OUD. Clinicians and health services may wish to consider integrating contingency management in addition to OAT for OUD in their settings to improve treatment retention. Aside from treatment retention, few differences were consistently found between psychosocial interventions adjunctive to OAT and OAT-only. There is a need for high-quality RCTs to establish more definitive conclusions

Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord

International audienceAberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce.We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration.We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases.Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially