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The article discusses a research study on telomerase reverse transcriptase (TERT) deficiency in mice with ulcerative typhlocolitis that is associated with Helicobacter mastomyrinus. Study subjecs include interleukin-10 (IL-10) knockout (KO) mice, recombinant-activating gene (RAG) KO mice and severe combined immunodeficient (SCID) mice then helicobacter from feces were homogenized for primary isolation. Results showed distended colons of affected mice while there was granulocytic hyperplasia of the splenic hepatopoietic tissues in some mice.

Objectives: Abdominal pain (AP) in children imposes a large economic burden on the healthcare system. Currently, there are no reliable diagnostic tools to differentiate between organic and functional disorders. We hypothesized from previous research that the analysis of patients' graphic expression of subjective symptoms as well as their interactional behavior adds new ways to differentiate between functional and organic AP., Methods: Conversation analyses of physician-patient-encounters and graphical expression of AP-based pain were performed., Results: Twenty-two interactions were recorded and analyzed. Fifteen children were diagnosed with organic AP and seven with functional AP. We found marked differences between children with organic and functional AP. For example, all 15 children with organic AP saw the task of drawing a picture of the pain during the interview as a duty, whereas the seven children with functional AP took this as an opportunity to provide detailed descriptions about the nature of the pain, the circumstances, and how the AP impaired their quality of life., Conclusion: Analysis of patients' interaction strategies in response to the painting task provides relevant clues as to whether AP is functional or requires further workup for organic causes., (© 2024 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Patients carrying pathogenic variants in GNAO1 often present with early-onset central hypotonia and global developmental delay, with or without epilepsy. As the disorder progresses, a complex hypertonic and hyperkinetic movement disorder is a common phenotype. A genotype-phenotype correlation has not yet been described and there are no evidence-based therapeutic recommendations., Methods: To improve understanding of the clinical course and pathophysiology of this ultra-rare disorder, we built up a registry for GNAO1 patients in Germany. In this retrospective, multicentre cohort study, we collected detailed clinical data, treatment effects and genetic data for 25 affected patients., Results: The main clinical features were symptom onset within the first months of life, with central hypotonia or seizures. Within the first year of life, nearly all patients developed a movement disorder comprising dystonia (84%) and choreoathetosis (52%). Twelve (48%) patients suffered life-threatening hyperkinetic crises. Fifteen (60%) patients had epilepsy with poor treatment response. Two patients showed an atypical phenotype and seven novel pathogenic variants in GNAO1 were identified. Nine (38%) patients were treated with bilateral deep brain stimulation of the globus pallidus internus. Deep brain stimulation reduced hyperkinetic symptoms and prevented further hyperkinetic crises. The in silico prediction programmes did not predict the phenotype by the genotype., Conclusion: The broad clinical spectrum and genetic findings expand the phenotypical spectrum of GNAO1 -associated disorder and therefore disprove the assumption that there are only two main phenotypes. No specific overall genotype-phenotype correlation was identified. We highlight deep brain stimulation as a useful treatment option in this disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α 1 -subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3 S ), whereas a loss of ion channel function was seen in the long (Cav1.3 L ) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3 S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3 L variant results in sinus node dysfunction.

Pathogenic variants in PRRT2 , encoding the proline-rich transmembrane protein 2, have been associated with an evolving spectrum of paroxysmal neurologic disorders. Based on a cohort of children with PRRT2-related infantile epilepsy, this study aimed at delineating the broad clinical spectrum of PRRT2-associated phenotypes in these children and their relatives. Only a few recent larger cohort studies are on record and findings from single reports were not confirmed so far. We collected detailed genetic and phenotypic data of 40 previously unreported patients from 36 families. All patients had benign infantile epilepsy and harbored pathogenic variants in PRRT2 (core cohort). Clinical data of 62 family members were included, comprising a cohort of 102 individuals (extended cohort) with PRRT2-associated neurological disease. Additional phenotypes in the cohort of patients with benign sporadic and familial infantile epilepsy consist of movement disorders with paroxysmal kinesigenic dyskinesia in six patients, infantile-onset movement disorders in 2 of 40 individuals, and episodic ataxia after mild head trauma in one girl with bi-allelic variants in PRRT2 . The same girl displayed a focal cortical dysplasia upon brain imaging. Familial hemiplegic migraine and migraine with aura were reported in nine families. A single individual developed epilepsy with continuous spikes and waves during sleep. In addition to known variants, we report the novel variant c.843G>T, p.(Trp281Cys) that co-segregated with benign infantile epilepsy and migraine in one family. Our study highlights the variability of clinical presentations of patients harboring pathogenic PRRT2 variants and expands the associated phenotypic spectrum.

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG., Methods: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated., Results: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures., Conclusion: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To understand the formal roles of community representatives (CRs) in Clinical and Translational Science Awardee (CTSA) activities, to evaluate the extent of integration into the organizational and governance structures and to identify barriers to effective integration., Methods: The inventory tool was distributed to each of the 60 CTSAs using a secure web application., Results: Forty-seven (78%) completed the inventory. The mean number of CRs per CTSA is 21.4 (SD: 14.8). Most CTSAs had community advisory boards (89%) and 94% included CRs in Community Engagement (CE) cores. Only 11% reported a CR being a member of the CTSA leadership team and 19% reported that CRs advise core programs beyond CE. CRs are compensated by 79% of CTSAs. Mean annual compensation is $753 (median: $400). Compensation directly correlated with the number of hours that CRs worked in CTSA activities (r = 0.64; P = 0.001)., Conclusions: This inventory allows CTSAs to better understand how CRs have engaged in activities and brings attention to the limited representation among cores and in leadership roles. CTSAs should, with substantive input from CRs, develop strategies to provide the resources and compensation necessary to better integrate the community in CTSA activities and fully realize the goals of the CTSA vision., (© 2013 Wiley Periodicals, Inc.)

Background: The National Institutes of Health-funded Clinical and Translational Science Awards (CTSA) have increasingly focused on community-engaged research and funded investigators for community-based participatory research (CBPR). However, because CBPR is a collaborative process focused on community-identified research topics, the Harvard CTSA and its Community Advisory Board (CERAB) funded community partners through a CBPR initiative., Objectives: We describe lessons learned from this seed grants initiative designed to stimulate community-academic CBPR partnerships., Methods: The CBPR program of the Harvard CTSA and the CERAB developed this initiative and each round incorporated participant and advisory feedback toward program improvement., Lessons Learned: Although this initiative facilitated relevant and innovative research, challenges included variable community research readiness, insufficient project time, and difficulties identifying investigators for new partnerships., Conclusion: Seed grants can foster innovative CBPR projects. Similar initiatives should consider preliminary assessments of community research readiness as well as strategies for meaningful academic researcher engagement.

Objective: Clinical trials concerning cervical spine manipulation and mobilization in children and adolescents with cervicogenic headache are lacking., Methods: We performed a multicenter, prospective, randomized, placebo-controlled, and blinded trial in 52 children and adolescents (21 boys, 31 girls) aged 7-15. After prospective baseline documentation for 2 months patients were either assigned to placebo or true manipulation with another 2-month follow-up. Main outcome measures were defined as: percentage of days with headache, total duration of headache, days with school absence due to headache, consume of analgesics, intensity of headache., Results: We did not find a significant difference comparing the groups with placebo and true manipulation with respect to the defined main outcome measures., Conclusions: We were not able to show an efficacy of cervical spine manipulation in 52 children and adolescents.

Purpose: To evaluate the efficacy and tolerability of Levetiracetam (LEV) in a large pediatric cohort with drug-resistant epilepsy from a prospective multicenter observational study., Methods: We report the results of a multicenter observational survey of a cohort of 285 pediatric patients (mean: 9.9 years, range: 0; 6-17; 11) with refractory generalized and focal epilepsy who received Levetiracetam as an add-on open label treatment trial. The average duration of epilepsy was 6.0 years and the patients were treated with a mean of 7.0 antiepileptic drugs (AED) before LEV was introduced., Results: No serious persistent adverse events were reported. Reversible colitis and an apnoea syndrome in a child with phosphorylase-A-kinase-deficiency were noted. Mild to moderate side effects were reported in 128 patients (44.9%), consisting most frequently of somnolence (23.9%), general behavioral changes (15.4%), aggression (10.5%) and sleep disturbances (3.2%). In 209 patients, efficacy was analyzed over a treatment period of at least 12 weeks compared to a baseline of 2 weeks. Thirteen patients (6.2%) became seizure free, 39 (18.7%) responded with a seizure reduction of more than 50% following introduction of LEV. No response to LEV was reported in 65.1% (n=136). A decrease of initial treatment effect was seen in 37 patients (17.8%) while in 6.7% the seizure frequency doubled to the baseline (n=14). In seven patients (3.3%), the effect of LEV on seizure frequency could not be evaluated. A positive psychotropic effect was observed in 18 patients (8.6%). Mental retardation was associated with poor response and associated with more side effects and earlier discontinuation of LEV therapy., Conclusion: LEV is a well-tolerated new AED that may effectively improve seizure control as an add-on drug in resistant epilepsy in childhood with good tolerability. However, neurologically handicapped children appear at increased risk for reversible neurocognitive side effects and have a poorer treatment response.

Separation of neonatal rats from their mothers decreases, while a subsequent period of suckling (nursing) increases, serum growth hormone (GH) levels in neonatal rats. Milk-borne (humoral) factors and neural factors inherent in mother-offspring interaction have been implicated in these phenomena. Conflicting reports have demonstrated the alpha 2-adrenergic agonist clonidine to increase and to decrease serum GH levels in 10-day-old rats. The present experiments were aimed at testing whether an interaction between the alpha 2-adrenergic system and the nursing-induced changes in GH secretion could account for the discrepancy. Rat pups were treated with clonidine (150 micrograms/kg) or the alpha 2-adrenergic antagonist yohimbine (10 mg/kg), and the drug treatment was combined with separation of the mothers and nursing. Yohimbine did not affect serum GH levels in separated two-day-old pups (i.e. basal levels of the hormone), but prevented the nursing-induced increase in serum GH concentration. In two-day-old pups, clonidine had no effect on basal GH levels but, like yohimbine, prevented the increase in serum GH normally associated with nursing. Both yohimbine and clonidine prevented active sucking behavior, i.e. the pups did not search for and/or attach to the nipples of their mothers. Moreover, the pups treated with yohimbine and clonidine were cooler to the touch than the littermate controls. In eight-day-old pups, yohimbine prevented the nursing-induced increase in serum GH and decreased GH levels below the saline-injected, separated control.(ABSTRACT TRUNCATED AT 250 WORDS)

The Sxr (sex-reversed) region, a fragment of the Y chromosome short arm, can cause chromosomally female XXSxr or XSxrO mice to develop as sterile males. The original Sxr region, termed Sxra, encodes: Tdy, the primary sex-determining gene; Hya, the controlling or structural locus for the minor transplantation antigen H-Y; gene(s) controlling the expression of the serologically detected male antigen (SDMA); Spy, a gene(s) required for the survival and proliferation of A spermatogonia during spermatogenesis; Zfy-1/Zfy-2, zinc-finger-containing genes of unknown function; and Sry, which is probably identical to Tdy. A deletion variant of Sxra, termed Sxrb, which lacks Hya, SDMA expression, Spy and some Zfy-2 sequences, makes positional cloning of these genes possible. We report here the isolation of a new testis-specific gene, Sby, mapping to the DNA deleted from the Sxrb region (the delta Sxrb interval). Sby has extensive homology to the X-linked human ubiquitin-activating enzyme E1. The critical role of this enzyme in nuclear DNA replication together with the testis-specific expression of Sby suggests Sby as a candidate for the spermatogenic gene Spy.