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Preserving cells in a functional, non-senescent state is a major goal for extending human healthspans. Model organisms reveal that longevity and senescence are genetically controlled, but how genes control longevity in different mammalian tissues is unknown. Here, we report a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality that results from deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells. We show that GIMAP5 restricts the pathological accumulation of long-chain ceramides (CERs), thereby regulating longevity. GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases. Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration. Thus, GIMAP5 controls longevity assurance pathways crucial for immune function and healthspan in mammals.

Complement hyperactivation, angiopathic thrombosis and protein-losing enteropathy (CHAPLE disease) is a lethal disease caused by genetic loss of the complement regulatory protein CD55, leading to overactivation of complement and innate immunity together with immunodeficiency due to immunoglobulin wasting in the intestine. We report in vivo human data accumulated using the complement C5 inhibitor eculizumab for the medical treatment of patients with CHAPLE disease. We observed cessation of gastrointestinal pathology together with restoration of normal immunity and metabolism. We found that patients rapidly renormalized immunoglobulin concentrations and other serum proteins as revealed by aptamer profiling, re-established a healthy gut microbiome, discontinued immunoglobulin replacement and other treatments and exhibited catch-up growth. Thus, we show that blockade of C5 by eculizumab effectively re-establishes regulation of the innate immune complement system to substantially reduce the pathophysiological manifestations of CD55 deficiency in humans.

There are many unknowns about primary eosinophilic gastrointestinal disease (EGID) in childhood. The aim of this study is to provide data about the frequency, management, control level, and prognosis of well documented primary EGID in childhood. This study was conducted in children who underwent endoscopy and/or colonoscopy at a single center over 10-year period up to August 2018. Primary EGID was diagnosed after exclusion of secondary EGID and classified as eosinophilic gastritis (EG), eosinophilic enteritis (EE), eosinophilic gastroenteritis (EGE: eosinophilic gastritis with eosinophilic enteritis) and eosinophilic colitis (EC) according to histopathological evaluation. The pathological number of eosinophil counts were accepted as >30 hpf for gastric mucosa in 5 hpf area, =20/hpf for duodenal, jejunal, and ileal mucosa, >50/hpf for right colonic mucosa, >35/hpf for transverse colonic mucosa, and >25/hpf for left colonic mucosa. Presenting symptoms, signs, management, follow-up, disease control level, and remission were analyzed. Remission is defined if the patient is controlled with all clinical, endoscopic/colonoscopic, and histopathologic parameters without any treatments or diet for at least a year. During the study period, 7457 biopsies were taken in 8262 endoscopy and/or colonoscopy procedures. Primary and secondary EGID frequencies were found 0.23% (n = 17 patients) and 0.1% (n =8 patients) per procedure with biopsy in children, respectively. Endoscopy/colonoscopy procedures were not able to performed in 9 patients because of short follow-up period (n = 6) or patients leaving follow-up (n = 3). Nine of the primary EGID patients had esophageal eosinophilia (EsE) at the time of diagnosis, 5 of them were previously managed as EoE. The median follow-up period of primary EGID patients excluding the ones without a control endoscopy/colonoscopy procedure was 3.35 years (min-max: 1.1–9.0 years). Proton pump inhibitors (PPI) were the most frequently used treatment alone or in combination with diet, systemic and/or topical corticosteroids. Disease control was evaluated in 8 of 17 patients and it was uncontrolled in 4, partially controlled in 1, and controlled in 3 patients. Remission was achieved in 2 patients. The frequency of primary EGID beyond eosinophilic esophagitis (EoE) in children is low. It may be difficult to achieve control in children with primary EGID in the long-term follow-up.

A case of a 5 and a half year old male is described whose clinical and laboratory features included characteristic facial appearance, eczema, recurrent pneumonia and consistently increased serum IgE levels,. These are recognized as the main features of the hyper IgE syndrome. Apart from these features the patient has distended abdomen and hepatomegaly and splenomegaly. Laboratory studies revealed positive serum anti-endomysium and tissue transglutaminase antibodies. Small intestinal biopsy showed subtotal villous atrophy compatible with gluten-sensitive enteropathyIn conclusion we suggest that this case is the first with co-existence of hyper IgE syndrome and celiac disease. Keywords: Hyper-IgE syndromes | Celiac Disease | Coexistence, Introduction Hyperimmunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by a high level of serum immunoglobulin E, chronic eczema, recurrent staphylococcal infections, pneumatocele, malfunctioning neutrophil chemotaxis and abnormalities [...]

Cost-effectiveness studies about rotavirus (RV) vaccination programs were performed in many countries due to the severe economic burden of RV infections. This study is an economic evaluation performed to assess the potential for introducing the RV vaccine to the Turkish National Immunization Program.

Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient’s tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue’s vascular lesions.

Hepatoportal sclerosis (HPS) is a syndrome of obscure etiology, and is one of the causes of noncirrhotic portal hypertension (PH). We aimed to investigate this heterogeneous group of patients whose presentation showed cholestatic features, histopathologically. Between 1999 and 2009, 12 children diagnosed with HPS were retrospectively evaluated. HPS was diagnosed with evidence of PH, noncirrhotic liver biopsy with typical histopathologic findings, and exclusion of other possible causes of PH. The data was obtained from pathology reports and microscopic slides. In histopathological re-evaluation fibrosis state, aberrant portal vessels, portal tract dilation and inflammation, ductular reaction, regenerative nodular hyperplasia, acinar transformation, presence of bile pigment, and cholangitis were noted. Serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl, alkaline phosphatase, bilirubin, and albumin levels, presentation patterns, and radiologic findings were assessed. Familial relationship degrees were also investigated. Twelve patients (9 boys, 3 girls; 3–180 months) were re-evaluated. Two pairs of the patients were siblings. Parents of 7 patients were consanguine. The most common presenting symptom was abdominal distension. Histopathologically, all patients had hepatoportal sclerosis/intimal fibrous thickening of portal vein and periportal fibrosis, acinar transformation, and regenerative nodules not surrounded by fibrous septae. Eight patients had vascular aberrations, 7 had ductular reaction, 1 showed mild cholangitis, and 1 had canalicular bile pigment. We conclude that genetic predisposition might be a possible factor for HPS development in Turkish patients and it should be kept in mind that cholestatic features noticed in histopathological evaluation may represent a variant group in the spectrum of HPS.

The response to hepatitis A vaccine has not been studied in children with celiac disease (CD). The aim of the present study was to evaluate the immunogenicity of an inactivated hepatitis A virus (HAV) vaccine and the effect of the human leukocyte antigen (HLA) type on immunogenicity in children with CD. Thirty-three patients with CD and 62 healthy controls were enrolled in the study. Inactivated HAV vaccine (Havrix; GlaxoSmithKline Biologicals, Rixensart, Belgium) containing 720 enzyme-linked immunosorbent assay units of alum-adsorbed hepatitis A antigen was administered intramuscularly in a 2-dose schedule at 0 and 6 months. Seroconversion rates and antibody titers of HAV were measured at 1 and 7 months. At 1 month, seroconversion rates were 78.8% and 77.4% and geometric mean titers were 50.7 and 49.9 mIU/mL in the CD and control groups, respectively (P> 0.05). At 7 months, seroconversion rates were 97% and 98.4% and geometric mean titers were 138.5 and 133 mIU/mL in the CD and control groups, respectively (P> 0.05). The most frequent HLA types were HLA-DQ2, -DR3, and -DR7 alleles in patients with CD and HLA-DQ3, -DQ6, -DR11, and -DR14 in the controls. There was no association between HLA alleles and antibody titers of hepatitis A vaccine. Children with CD have a good immune response to hepatitis A vaccine, similar to healthy controls.

Octreotide has been suggested as a medical treatment option in refractory cases of primary intestinal lymphangiectasia (IL). There are few data about the long-term effect and safety of octreotide for IL in the literature. In the present article we analyzed pediatric cases of primary IL with long-term octreotide treatment and discussed its safety profile.

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

In this study, we report the case of a 2.5-day-old neonate with septicemia and meningitis due to Plesiomonas shigelloides. Culture of the cerebrospinal fluid showed Gram-negative rods, although the glucose, protein and leukocyte counts were normal. The patient was treated with meropenem and survived without any sequelae, although we were not able to identify the source of the infection. In addition, ten previously reported cases of this infection are reviewed.

Castleman disease is a rare lymphoproliferative disorder of unclear etiology. It usually presents as localized enlarged lymph nodes in children. Surgical excision is curative in localized form. Clinical findings of malabsorption are rarely reported in the literature. Herein, we describe a 14-year-old girl who presented with anemia, failure to thrive, osteoporosis, zinc, and vitamin deficiency. She was diagnosed as localized mesenteric mixed type of Castleman disease. Her clinical findings improved after surgical excision of the mass.