Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide–induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.     

Giant Extra-Adrenal Retroperitoneal Myelolipoma With Incidental Gastric Mesenchymal Neoplasias

Extra-adrenal myelolipomas are rare, benign tumors composed of adipose tissue and hematopoietic cells. Almost all myelolipomas occur within the adrenal gland. Only 50 cases of myelolipomas were described in literature and none of these were associated with gastric mesenchymal neoplasia. A 72-year-old male patient presented to a family medicine outpatient clinic with dyspnea and urinary urgency. His abdominal sonography revealed a 9-cm intra-abdominal mass. An incidental finding was 2 separate masses 1 cm each on the serosal surface of the stomach. The pathology specimen of the retroperitoneal mass revealed myelolipoma histopathology while gastric masses were reported as spindle cell mesenchymal neoplasias. The association of gastric spindle cell tumor and myelolipoma was not reported before in medical literature. Extra-adrenal myelolipomas are rare lesions, but should be considered in the differential diagnosis of fat containing retroperitoneal masses that are well circumscribed.Key words: Myelolipoma, Retroperitoneal, NeoplasiaExtra-adrenal myelolipomas are rare, benign tumors composed of adipose tissue and hematopoietic cells. When these lesions occur outside the adrenal gland, they can be confused with other soft tissue tumors. Differentiating extra-adrenal myelolipomas from well-differentiated liposarcomas, retroperitoneal myelolipomas, and extramedullary hematopoietic tumors can be difficult. There are only 50 cases of myelolipoma described in literature¹ and none of these is associated with gastric mesenchymal neoplasia.Here we present a symptomatic extra adrenal retroperitoneal myelolipoma presenting along with incidental multiple gastric stromal tumors.     

The effect of dentin hypersensitivity treatments on the shear bond strength to dentin of a composite material

This study sought to evaluate the influence of a dentin desensitizer and ozone application on the bond strength to dentin of a composite resin material. The dentin desensitizing agent and ozone treatment were applied on the cervical dentin surfaces of extracted, caries-free, erupted third molars. Dentin surfaces that received no treatment were used as control samples. A dentin bonding agent was applied according to the manufacturer's instructions and an adhesion test was performed according to ISO/TS 11405. Statistical analysis showed no significant influence of the different hypersensitivity treatments on shear bond strength to dentin (ANOVA and Tukey's tests, p > 0.05). Within the limitations of this in vitro study, it appears that the short-term use of dentin hypersensitivity treatments like ozone and dentin desensitizers containing gluteraldehyde do not further affect the shear bond strength to dentin of subsequent composite resin restorations.     

Primary antibody deficiencies in Turkey: molecular and clinical aspects

Primary antibody deficiencies (PAD) are the most common subtype of primary immunodeficiencies, characterized by increased susceptibility to infections and autoimmunity, allergy, or malignancy predisposition. PAD syndromes comprise of immune system genes highlighted the key role of B cell activation, proliferation, migration, somatic hypermutation, or isotype switching have a wide spectrum from agammaglobulinemia to selective Ig deficiency. In this study, we describe the molecular and the clinical aspects of fifty-two PAD patients. The most common symptoms of our cohort were upper and lower respiratory infections, bronchiectasis, diarrhea, and recurrent fever. Almost all patients (98%) had at least one of the symptoms like autoimmunity, lymphoproliferation, allergy, or gastrointestinal disease. A custom-made next-generation sequencing (NGS) panel, which contains 24 genes, was designed to identify well-known disease-causing variants in our cohort. We identified eight variants (15.4%) among 52 PAD patients. The variants mapped to BTK (n?=?4), CD40L (n?=?1), ICOS (n?=?1), IGHM (n?=?1), and TCF3 (n?=?1) genes. Three novel variants were described in the BTK (p.G414W), ICOS (p.G60*), and IGHM (p.S19*) genes. We performed Sanger sequencing to validate pathogenic variants and check for allelic segregation in the family. Targeted NGS panel sequencing can be beneficial as a suitable diagnostic modality for diagnosing well-known monogenic PAD diseases (only 2–10% of PADs); however, screening only the coding regions of the genome may not be adequately powered to solve the pathogenesis of PAD in all cases. Deciphering the regulatory regions of the genome and better understanding the epigenetic modifications will elucidate the molecular basis of complex PADs.

     

Correction to: Primary antibody deficiencies in Turkey: molecular and clinical aspects

Immunologic Research -     

Low Density Granulocytes and Dysregulated Neutrophils Driving Autoinflammatory Manifestations in NEMO Deficiency

Journal of Clinical Immunology - NF-κB essential modulator (NEMO, IKK-γ) deficiency is a rare combined immunodeficiency caused by mutations in the IKBKG gene. Conventionally, patients are...     

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis‐like phenotype and early onset cancer

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis‐like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12–14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis‐like group, two subjects had already developed high‐grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.