Kumaryoung2697

Mutations in theABCB4gene are associated with failure of bile acid emulsification leading to cholestatic liver disease. Presentations range from progressive familial intrahepatic cholestasis type 3 (PFIC3) in childhood, to milder forms seen in adulthood.

We sought to characterize adult disease with particular reference to histology which has been hitherto poorly defined.

Four unrelated adults (three female, mean age 39years) and three sisters presenting with cholestatic liver disease in adulthood, associated with variants in the ABCB4 gene, were identified. Clinical review and detailed blinded histopathological analysis were performed.

Two novel pathogenicABCB4variants were identified c.620T > G, p.(Ile207Arg) and c.2301dupT, p.(Thr768TyrfsTer26). Sub-phenotypes observed included low-phospholipid-associated cholelithiasis syndrome (LPAC), intrahepatic cholestasis of pregnancy (ICP), drug-induced cholestasis, idiopathic adulthood ductopenia, and adult PFIC3. Of note, 5/7 had presented with gallstone We observed a distinct histological pattern which differs from classical biliary disease and describe two novel pathogenic ABCB4 variants. ABCB4 sequencing should be considered in patients with relevant cholestatic phenotypes and/or suggestive histology; accurate diagnosis can guide potential interventions to delay progression and inform family screening.

Active Crohn's disease increases the risk of strictures, fistulas, and abscesses. Less than 30% of patients with Crohn's disease achieve endoscopic remission on any therapy. Tofacitinib may be a therapeutic option for patients with refractory Crohn's disease.

We aimed to evaluate the safety and effectiveness of off-label tofacitinib for refractory Crohn's disease.

We retrospectively assessed adverse events and clinical/endoscopic response after therapy.

Forty-four patients were included in the safety analysis and 35 were included in the clinical and/or endoscopic assessments. The mean age was 41.8years and the mean disease duration was 17.4years. All patients had prior biologic exposure. Adverse events were reported in 52.3% of patients; 13.6% had ≥ 1 serious adverse event after a median 54.6weeks of treatment. Seventy percent achieved clinical response after a mean 29.4 (SD 15.1) weeks, and 33.3% achieved clinical remission after a mean 33.4 (SD 17.6) weeks of therapy. Endoscopic improvement occurredkely reflects the severe refractory disease in this population and no new safety events were observed. Tofacitinib achieved clinical and endoscopic improvement in some patients with refractory Crohn's disease. Further research is needed to understand the long-term safety and efficacy of tofacitinib in Crohn's disease.

The clinical course of ulcerative colitis (UC) is variable. There is an unmet clinical need for biomarkers of UC disease behaviour. We aimed to evaluate the association between ex vivo human UC explant conditioned media (explant-CM) secreted protein profiles and UC disease behaviour.

UC patients undergoing endoscopy were prospectively recruited. Endoscopic biopsies were collected and explant-CM generated. Association between explant-CM protein secretion profiles and disease progression was evaluated. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent. Association between explant-CM secreted protein profiles and anti-TNF failure status was also evaluated. p values < 0.05 were considered significant in analyses.

Twenty-four UC patients were included (age [median, range]) 55 [21-72] years; 50% female. Disease progression during follow-up occurred in twelve (50%) patients. Multivs was observed in anti-TNF failure status consistent with previous reports. Ex vivo human UC explants, generated from endoscopic biopsies, have potential as precision medicine tools in inflammatory bowel disease.

The burden of hepatocellular carcinoma (HCC) is increasing, and certain groups may be at higher risk.

We analyzed trends in HCC-related mortality in the USA (1999-2018) using national death data. Age-adjusted trends in death rates (annual percentage change, APC) were calculated using joinpoint regression analysis.

HCC-related death rates increased by 2.1% (95% CI 1.9 to 2.3) annually. Hepatitis C (HCV)-related HCC death rates increased from 1999 to 2012 (8.9%, 95% CI 7.6 to 10.2) followed by a -1.3% (95% CI -3.5 to 0.9) decrease annually. For adults > 65years, HCV-related HCC death rates increased (7.3% annually, 95% CI 6.5 to 8.1), especially for rural areas (11.1% annually, 95% CI 6.9 to 15.5) with high rates among African-Americans and Hispanics. Increases in non-HCV-related HCC death rates were larger 13.5% annually (95% CI 3.6 to 24.3, 2005-2010) followed by 4.2% annually (95% CI 2.3 to 6.2, 2010-2018). Annual rates of increase were similar for men (6.8%, 95% CI 5.9 to 7.8) and women (7.0%, 95% her cancers.

The endoscopic appearance in patients with "pouchitis" after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) can be quite heterogenous. Patients with an endoscopic phenotype resembling Crohn's disease (CD) are at high risk of pouch loss.

We aimed to assess how the histopathology of colectomy specimens predicts endoscopic pouch phenotypes in UC.

We retrospectively assessed pouchoscopies from patients with UC who underwent IPAA and classified pouch findings into 7 main phenotypes (1) normal, (2) afferent limb involvement, (3) inlet involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch with fistulas noted ≥ 6months from ileostomy takedown. We assessed the clinical and pathological data including deep, focal inflammation, granulomas, and terminal ileal involvement in the colectomy specimens. Logistic regression analysis was performed to identify contributing factors to each phenotype.

This study included 1,203 pouchoscopies from 382 patients with UC. On multivariable analysis, deep inflammation was significantly associated with pouch fistulas (Odds ratio 3.27; 95% confidence interval 1.65-6.47; P = 0.0007). Of the 75 patients with deep inflammation, only two patients (2.7%) were diagnosed with CD based on pathology review. Terminal ileal involvement significantly increased the risk of afferent limb involvement (Odds ratio 2.96; 95% confidence interval 1.04-8.47; P = 0.04). There were no significant associations between other microscopic features and phenotypes.

We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.

We identify histologic features of colectomy specimens in UC that predict subsequent pouch phenotypes. Particularly, deep inflammation in the resected colon was significantly associated with pouch fistulas, a pouch phenotype with poor prognosis.Baclofen, a GABAb agonist, is used in the treatment of multiple sclerosis, a neurodegenerative disease. Currently available dosage forms to deliver baclofen are through the oral and the intrathecal routes. The disadvantage of oral baclofen is that it requires administering the drug multiple times a day, owing to baclofen's short half-life. On the other hand, intrathecal baclofen pumps are invasive and cannot be an alternative to oral baclofen. Hence, there is a need to develop a dosage form that can deliver baclofen non-invasively and for an extended period at a steady rate, increasing the dosing interval. A transdermal baclofen delivery system might be the solution to this problem. Hence, this research focuses on evaluating microneedles, iontophoresis, and a combination of microneedles-iontophoresis as transdermal delivery enhancement strategies for baclofen. In vitro permeation studies were conducted on dermatomed porcine ear skin using vertical Franz diffusion cells to evaluate transdermal baclofen delivery. Anodal iontophoresis was applied at a current density of 0.5 mA/cm2, and transdermal delivery was assessed from pH 4.5 (45.51±0.76 μg/cm2) and pH 7.4 (68.84±10.13 μg/cm2) baclofen solutions. Iontophoresis enhanced baclofen delivery but failed to reach target delivery. Maltose microneedles were used to create hydrophilic microchannels on the skin, and this technique enhanced baclofen delivery by 89-fold. Both microneedles (447.88±68.06 μg/cm2) and combination of microneedles - iontophoresis (428.56±84.33 μg/cm2) reached the target delivery range (222-1184 μg/cm2) for baclofen. The findings of this research suggest that skin could be a viable route for delivery of baclofen. Graphical Abstract.Thymoma-associated multiorgan autoimmunity (TAMA) is a rare autoimmune disorder associated with thymoma that causes a pathology similar to graft-versus-host disease (GVHD) targeting the skin, digestive organs, and liver. Herein, we report the case of a 38-year-old male with myasthenia gravis (MG) preceded by TAMA. The patient developed intractable diarrhea 2 years before admission. Subsequently, dysphagia, dysarthria, and left blepharoptosis were observed. The patient was admitted to the hospital because of fever and dyspnea, was positive for anti-AChR antibody, and chest-computed tomography revealed thymoma, which led to the diagnosis of thymoma-related MG. Biopsied specimens from the sigmoid colon revealed apoptotic colonopathy with lymphocyte-rich lamina propria. Immunohistochemical staining revealed that the infiltrating cells were predominantly labeled with anti-CD3-antibody. The patient did not show skin lesions or liver dysfunction. Therefore, TAMA limited to the gastrointestinal tract was diagnosed. selleck inhibitor Although TAMA typically has a poor prognosis, immediate multimodal immunotherapy for MG was successful, resulting in a good outcome for TAMA of this case. TAMA is caused by the inability of the thymoma to suppress self-reactive T lymphocytes, which subsequently leads to a disease that is clinically indistinguishable from GVHD. Based on the characteristics of this case, limited gastrointestinal tract involvement in TAMA without lesions in other organs may lead to a favorable prognosis. TAMA cases lacking skin lesions may present with nonspecific gastrointestinal or liver disease. If a patient with thymoma-associated MG has gastrointestinal symptoms such as diarrhea, TAMA should be considered, and the diagnosis should be made early by pathological evaluation of gastrointestinal tissues.Increasing evidence has shown that circular RNAs (circRNAs) participate in the process of cardiac remodeling. CircRNA circ_0036176 originating from the back-splicing of exon 2 to exon4 of myosin IXA (Myo9a) gene was shown to be increased in the myocardium of patients with heart failure (HF) and riched in exosomes from human AC16 cardiomyocytes with overexpression of circ_0036176. Proliferation activity was inhibited in mCFs subjected to exosomal circ_0036176 treatment and in mCFs with overexpression of circ_0036176. Interestingly, circ_0036176 contains an IRES element and an ORF of 627 nt encoding a 208-amino acid protein (termed as Myo9a-208). Myo9a-208 was shown to mediate the inhibitory effect of circ_0036176 on CFs proliferation, and miR-218-5p could inhibit Myo9a-208 expression by binding to circ_0036176, resulting in abolishing the effect of circ_0036176 on inactivating cyclin/Rb signal and suppressing CFs proliferation. Our findings suggest that circ_0036176 inhibits mCFs proliferation by translating Myo9a-208 protein to suppress cyclin/Rb pathway.