Non-cirrhotic Ascites: A Case of Severe Alcoholic Hepatitis.

This case report presents a unique instance of ascites in acute alcoholic hepatitis (AH) occurring in a non-cirrhotic patient. Comprehensive diagnostic evaluation excluded alternative etiologies, pinpointing sinusoidal non-cirrhotic portal hypertension. Present therapeutic modalities for AH, including steroids and pentoxifylline, offer limited efficacy, necessitating ongoing investigation. Liver transplantation may be contemplated in refractory cases. This case underscores the intricate nature of AH presentations and the challenges in their management, emphasizing the imperative need for continued research to delineate optimal therapeutic strategies. Early intervention remains pivotal in addressing AH complications, underscoring the need for heightened clinical vigilance and proactive treatment approaches in such cases.

Diagnostic value of IgG antibody and stool antigen tests for chronic Helicobacter pylori infections in Ibb Governorate, Yemen.

The stool antigen test (SAT) and the serum Helicobacter pylori (H. pylori) IgG antibody assays exhibit significant utility in the clinical diagnosis of H. pylori infection and in distinguishing between acute and chronic infections. The main objective of the current study was to identify the diagnostic value of serum H. pylori IgG antibody and SAT in the detection of H. pylori infections among chronic H. pylori-infected patients residing in Ibb Governorate, Yemen. 200 patients with H. pylori infection, confirmed through positive results in the serum immunochromatographic antibody test, were selected for H. pylori infection confirmation using serum H. pylori IgG antibodies and SAT across diverse hospitals, gastroenterology, and Hepatology clinics in Ibb Governorate. After the selection of patients, blood and stool specimens were obtained from all participants and underwent analysis via the Statistical Package for the Social Sciences (SPSS). The prevalence of H. pylori infection demonstrated variability based on the confirmatory tests, with rates of 54% for SAT and 78.5% for serum H. pylori IgG antibody, contrasting with a 100% prevalence observed in the screening serum immunochromatographic antibody test. Clinically, the study categorized H. pylori infections into four stages, whereby a significant proportion of patients (40.5%) exhibited positivity for both serum H. pylori IgG antibody and SAT, indicative of active chronic infections. The majority of positive cases only manifested serum H. pylori IgG antibody presence (chronic infections) at 38%, whereas 13.5% exclusively tested positive for SAT, corresponding to acute infections. Moreover, 88% of patients did not have either serum H. pylori IgG antibody or SAT (absence of infections) during confirmatory tests. Noteworthy is the study's approach employing multiple tests for H. pylori infection detection, focusing predominantly on chronic infections-prevailing types caused by H. pylori. The results revealed a significant association between serum levels of H. pylori IgG antibody and SAT results with the presence of diverse gastrointestinal symptoms among patients, which increased with long H. pylori infection durations.

Retraction: Colonic Angiolipoma: An Extremely Rare Tumor Clinically Masquerading as Acute Appendicitis.

[This retracts the article DOI: 10.7759/cureus.20659.].

The clinical significance of some serum tumor markers among chronic patients with Helicobacter pylori infections in Ibb Governorate, Yemen.

BACKGROUND: Helicobacter pylori (H. pylori) is a carcinogenic bacterium, it is the greatest risk factor for gastric cancer (GC), according to these evidences, there may be a certain association between chronic H. pylori infections and serum levels of tumor markers. This study was conducted to determine serum levels of some tumor markers, namely carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and cancer antigen 72-4 (CA72-4) in patients with chronic H. pylori infections and evaluate the association between serum tumor marker levels and chronic patients with H. pylori infections in Ibb Governorate, Yemen. SUBJECTS AND METHODS: This study involved 200 patients who had been diagnosed with H. pylori infections using a serum immunochromatography antibody test. Stool and blood samples were collected from all patients to confirm the presence of H. pylori through detection of serum H. pylori IgG antibody and stool antigen test (SAT). Additionally, serum samples were analyzed to measurement the level of certain tumor markers CEA, CA19-9 and CA72-4. These tests were conducted at various Hospitals, Gastroenterology and Hepatology clinics in Ibb governorate, Yemen from October 2019 to November 2020. RESULTS: The findings of current study showed that the prevalence of H. pylori infections by rapid anti H. pylori test were 200 (100%), 157 (78.5%) by serum H. pylori IgG antibody and 108 (54%) by SAT. In addition, the results showed that 42 (21%) of the patients had abnormal level of CEA, 30 (15%) had abnormal level of CA19-9 and 31 (15.5%) had abnormal level of CA72-4. Most importantly, the results indicated that the serum tumor marker levels CEA, CA19-9 and CA72-4 were correlated with the levels of serum H. pylori IgG antibody as well as positive results from the SAT (P < 0.05). Furthermore, the results indicated that serum tumor marker levels were associated with different infection status. Finally, the results indicated that the serum levels of tumor markers were associated with older ages, symptomatic patients and long duration of H. pylori infections (P < 0.05). CONCLUSION: The findings of this study indicated that there is a significant association between chronic H. pylori infections and the serum levels of tumor markers (CEA, CA19-9 and CA72-4). This suggests that the patients with active chronic H. pylori infection may have an increased risk of developing GC. Therefore, monitoring and early detection of H. pylori infection and tumor markers levels in these patients may be crucial for identifying individuals at higher risk and implementing appropriate interventions.

Novel multilocus imprinting disturbances in a child with expressive language delay and intellectual disability.

Multilocus imprinting disturbances (MLID) have been associated with up to 12% of patients with Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism type 1B (PHP1B). Single-gene defects affecting components of the subcortical maternal complex (SCMC) have been reported in cases with multilocus hypomethylation defects. We present a patient with speech and language impairment with mild Angelman syndrome (AS) features who demonstrates maternal hypomethylation at 15q11.2 (SNRPN) as well as 11p15.5 (KCNQ1OT1) imprinted loci, but normal methylation at 6q24.2 (PLAGL1), 7p12.1 (GRB10), 7q32.2 (MEST), 11p15.5 (H19), 14q32.2 (MEG3), 19q13.43 (PEG3), and 20q13.32 (GNAS and GNAS-AS1). The proband also has no copy number nor sequence variants within the AS imprinting center or in UBE3A. Maternal targeted next generation sequencing did not identify any pathogenic variants in ZPF57, NLRP2, NLRP5, NLRP7, KHDC3L, PADI6, TLE6, OOEP, UHRF1 or ZAR1. The presence of very delayed, yet functional speech, behavioral difficulties, EEG abnormalities but without clinical seizures, and normocephaly are consistent with the 15q11.2 hypomethylation defect observed in this patient. To our knowledge, this is the first report of MLID in a patient with mild, likely mosaic, Angelman syndrome.

Clinical pharmacogenomic testing and reporting: A technical standard of the American College of Medical Genetics and Genomics (ACMG).

Pharmacogenomic testing interrogates germline sequence variants implicated in interindividual drug response variability to infer a drug response phenotype and to guide medication management for certain drugs. Specifically, discrete aspects of pharmacokinetics, such as drug metabolism, and pharmacodynamics, as well as drug sensitivity, can be predicted by genes that code for proteins involved in these pathways. Pharmacogenomics is unique and differs from inherited disease genetics because the drug response phenotype can be drug-dependent and is often unrecognized until an unexpected drug reaction occurs or a patient fails to respond to a medication. Genes and variants with sufficiently high levels of evidence and consensus may be included in a clinical pharmacogenomic test; however, result interpretation and phenotype prediction can be challenging for some genes and medications. This document provides a resource for laboratories to develop and implement clinical pharmacogenomic testing by summarizing publicly available resources and detailing best practices for pharmacogenomic nomenclature, testing, result interpretation, and reporting.

Cardiac phenotype in familial partial lipodystrophy.

OBJECTIVES: LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. STUDY DESIGN: Retrospective cohort study. METHODS: Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. RESULTS: Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. CONCLUSIONS: Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.

Metreleptin therapy for nonalcoholic steatohepatitis: Open-label therapy interventions in two different clinical settings.

BACKGROUND: Recombinant leptin therapy reverses nonalcoholic steatohepatitis (NASH) in leptin-deficient lipodystrophy. We inquired if leptin therapy would improve nonalcoholic steatohepatitis in more common forms of this heterogeneous condition. METHODS: Nine male patients with relative leptin deficiency (level < 25th percentile of body mass index- and gender-matched United States population) and biopsy-proven NASH and 23 patients with partial lipodystrophy and NASH were recruited for two distinctive open-label trials. Participants received leptin therapy in the form of metreleptin for 12 months. The primary endpoints were the global nonalcoholic steatohepatitis scores from paired liver biopsies scored blindly. FINDINGS: Of 9 participants recruited in the relative leptin deficiency treatment study, 7 completed 12-months of therapy. Mean global NASH scores were reduced from 8 ± 3 to 5 ± 2 (range: from 1 to 6, P = 0.004). In the partial lipodystrophy study, 19 of 22 subjects completed 12 months of treatment, and 18 completed a second liver biopsy. Global NASH scores also reduced significantly from 6 ± 2 to 5 ± 2 (range: from -2 to 4, P = 0.008). In both studies, the predominant changes were in steatosis and hepatic injury scores. CONCLUSION: Our findings show that patients with NASH associated with both relative leptin deficiency and partial lipodystrophy have reductions in hepatic steatosis and injury in response to exogenous leptin therapy. Moreover, leptin deficiency may have regulatory effects in mediating fat deposition and ensuing injury in the liver.TRIAL REGISTRATION. ClinicalTrials.gov NCT00596934 and NCT01679197.

Colonic Angiolipoma: An Extremely Rare Tumor Clinically Masquerading as Acute Appendicitis.

The clinical presentation of right iliac fossa pain, anorexia, and vomiting are the classic clinical features of acute appendicitis. However, a broad spectrum of manifestations may result in a similar clinical picture, including gastrointestinal, genitourinary, and gynecologic pathologies. Imaging studies are crucial to establishing the diagnosis. Here, we report the case of a 58-year-old man who presented to the emergency department with a one-week history of right lower quadrant abdominal pain. The pain was associated with nausea, vomiting, and frequent bowel motions. There was no history of fever or weight loss. The examination of the abdomen showed localized tenderness and guarding in the right iliac fossa. The basic laboratory investigation was within the reference range. The computed tomography scan demonstrated a well-circumscribed intraluminal mass lesion in the ascending colon with no evidence of complete obstruction. The mass was slightly heterogeneous but had fat attenuation. There was no evidence of invasion. There was no stranding of the adjacent fat. The radiological findings were consistent with colonic lipoma. The patient underwent laparoscopic surgery and had a segmental resection of the tumor with primary anastomosis. The appendix was also resected. Histopathological examination showed mature adipose cells along with thin-walled, capillary-sized vessels representing a benign angiolipoma. Further, the resected appendix was completely normal and showed no evidence of acute inflammation. Colonic angiolipoma is an extremely rare tumor. This case demonstrated that a large angiolipoma of the ascending colon may show a presenting clinical picture similar to that of acute appendicitis. Complete resection of the tumor is associated with an excellent outcome.

The SRG rat, a Sprague-Dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies.

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in existing models but displays over 90% engraftment rate in the SRG rat with uniform growth kinetics. Since rats can support much larger tumors than mice, the SRG rat is an attractive host for PDX establishment. Surgically resected NSCLC tissue from nine patients were implanted in SRG rats, seven of which engrafted and grew for an overall success rate of 78%. These developed into a large tumor volume, over 20,000 mm3 in the first passage, which would provide an ample source of tissue for characterization and/or subsequent passage into NSG mice for drug efficacy studies. Molecular characterization and histological analyses were performed for three PDX lines and showed high concordance between passages 1, 2 and 3 (P1, P2, P3), and the original patient sample. Our data suggest the SRG OncoRat is a valuable tool for establishing PDX banks and thus serves as an alternative to current PDX mouse models hindered by low engraftment rates, slow tumor growth kinetics, and multiple passages to develop adequate tissue banks.

Engineering the Surface and Mechanical Properties of Water Desalination Membranes Using Ultralong Carbon Nanotubes.

In this work, novel polysulphone (PS) porous membranes for water desalination, incorporated with commercial and produced carbon nanotubes (CNT), were fabricated and analyzed. It was demonstrated that changing the main characteristics of CNT (e.g., loading in the dope solutions, aspect ratio, and functionality) significantly affected the membrane properties and performance including porosity, water flux, and mechanical and surface properties. The water flux of the fabricated membranes increased considerably (up to 20 times) along with the increase in CNT loading. Conversely, yield stress and Young's modulus of the membranes dropped with the increase in the CNT loading mainly due to porosity increase. It was shown that the elongation at fracture for PS/0.25 wt. % CNT membrane was much higher than for pristine PS membrane due to enhanced compatibility of commercial CNTs with PS matrix. More pronounced effect on membrane's mechanical properties was observed due to compatibility of CNTs with PS matrix when compared to other factors (i.e., changes in the CNT aspect ratio). The water contact angle for PS membranes incorporated with commercial CNT sharply decreased from 73° to 53° (membrane hydrophilization) for membranes with 0.1 and 1.0 wt. % of CNTs, while for the same loading of produced CNTs the water contact angles for the membrane samples increased from 66° to 72°. The obtained results show that complex interplay of various factors such as: loading of CNT in the dope solutions, aspect ratio, and functionality of CNT. These features can be used to engineer membranes with desired properties and performance.

Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar.

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome. CASE PRESENTATION: A previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation. CONCLUSIONS: This is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation.

Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome. Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS. Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications. Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.

Spectrum of disease associated with partial lipodystrophy: lessons from a trial cohort.

CONTEXT: Partial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. OBJECTIVE: The objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DESIGN: Cross-sectional evaluation. PARTICIPANTS: Twenty-three patients (22 with familial, one acquired, 78·3% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MEASUREMENTS: Genetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. RESULTS: Seven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM002691·3: c.3199 G>A; p.E1067K). Most patients had high ratios (>1·5) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (11·3 ± 6·3%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (78·3%), hypertension (56·5%) and mood disorders (52·2%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 ± 1 and 78·3% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. CONCLUSIONS: Partial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.

Nine de novo duplications affecting both maternal and paternal chromosomes and an inherited 15q11.2 deletion, in a patient with developmental delay.

A patient with developmental delay and nine, de novo, tandem duplications affecting eight different chromosomes that arose on both maternal and paternal chromosomes indicating a vulnerable zygotic or early postzygotic period of development for these errors, potentially affected by genetic and nongenetic factors.