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Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic-pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 μg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention × group × drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS.

The rate of disease progression in autosomal-dominant (AD) polycystic kidney disease (PKD) exhibits high intra-familial variability suggesting that environmental factors may play a role. We hypothesized that a prevalent form of renal insult may accelerate cystic progression and investigated tubular crystal deposition. We report that calcium oxalate (CaOx) crystal deposition led to rapid tubule dilation, activation of PKD-associated signaling pathways, and hypertrophy in tubule segments along the affected nephrons. Blocking mTOR signaling blunted this response and inhibited efficient excretion of lodged crystals. This mechanism of \"flushing out\" crystals by purposefully dilating renal tubules has not previously been recognized. Challenging PKD rat models with CaOx crystal deposition, or inducing calcium phosphate deposition by increasing dietary phosphorous intake, led to increased cystogenesis and disease progression. In a cohort of ADPKD patients, lower levels of urinary excretion of citrate, an endogenous inhibitor of calcium crystal formation, correlated with increased disease severity. These results suggest that PKD progression may be accelerated by commonly occurring renal crystal deposition which could be therapeutically controlled by relatively simple measures.

Objectives:The diameters of the vertebral arteries (VAs) are very often unequal. Therefore, this study investigated if unequal VA flow contributes to the development of basilar artery (BA) curvature and if it is a link to the laterality of pontine or cerebellar infarcts occurring around the vertebrobasilar junction.Methods:Radiological factors were analysed (infarct laterality, VA dominance, BA curvature and their directional relationships) in 91 patients with acute unilateral pontine or posterior inferior cerebellar artery (PICA) territory infarcts. The “dominant” VA side was defined as either that the VA was larger in diameter or the VA was connected with the BA in more of a straight line, if both VAs looked similar in diameter on CT angiography. Multiple regression analysis was performed to predict moderate to severe BA curvature.Results:The dominant VA was more frequent on the left side (p<0.01). Most patients had an opposite directional relationship between the dominant VA and BA curvature (p<0.01). Pontine infarcts were opposite to the side of BA curvature (p<0.01) and PICA infarcts were on the same side as the non-dominant VA side (p<0.01). The difference in VA diameters was the single independent predictor for moderate to severe BA curvature (OR per 1 mm, 2.70; 95% CI 1.22 to 5.98).Conclusions:Unequal VA flow is an important haemodynamic contributor of BA curvature and development of peri-vertebrobasilar junctional infarcts.

To assess corneal microarchitecture and regional epithelial thickness profile in eyes with keratoconus, postoperative corneal ectasia (ectasia), and normal unoperated eyes (controls) using spectral-domain optical coherence tomography (SD-OCT). Regional corneal epithelial thickness profiles were measured with anterior segment SD-OCT (Optovue RTVue-100, Optovue Inc., Fremont, CA). Epithelial thickness was assessed at 21 points, 0.5 mm apart, across the central 6-mm of the corneal apex in the horizontal and vertical meridians. One hundred twenty eyes were evaluated, including 49 eyes from 29 patients with keratoconus, 32 eyes from 16 patients with ectasia, and 39 eyes from 21 control patients. Average epithelial thickness at the corneal apex was 41.18 ± 6.47 μm (range: 30 to 51 μm) for keratoconus, 46.5 ± 6.72 μm for ectasia (range: 34 to 60 μm), and 50.45 ± 3.92 μm for controls (range: 42 to 55 μm). Apical epithelial thickness was significantly thinner in eyes with keratoconus (P < .0001) and ectasia (P = .0007) than in controls. Epithelial thickness ranges in all other areas varied widely for keratoconus (range: 21 to 101 μm) and ectasia (range: 30 to 82 μm) compared to controls (range: 43 to 64) (P = .0063). SD-OCT demonstrated significant central and regional epithelial thickness profile differences between keratoconus, ectasia, and control eyes, with significant variability and unpredictability in ectatic eyes. This regional irregularity may necessitate direct epithelial thickness measurement for treatments where underlying stromal variations may be clinically relevant, including corneal collagen cross-linking or topography-guided ablations.

The adult heart responds to excessive neurohumoral signaling and workload by a pathological growth response characterized by hypertrophy of cardiomyocytes and activation of a fetal program of cardiac gene expression. These responses culminate in diminished pump function, ventricular dilatation, wall thinning, and fibrosis, and can result in sudden death. Myocyte enhancer factor-2 (MEF2) transcription factors serve as targets of the signaling pathways that drive pathological cardiac remodeling, but the requirement for MEF2 factors in the progression of heart disease in vivo has not been determined. MEF2A and MEF2D are the primary MEF2 factors expressed in the adult heart. To specifically determine the role of MEF2D in pathological cardiac remodeling, we generated mice with a conditional MEF2D allele. MEF2D-null mice were viable, but were resistant to cardiac hypertrophy, fetal gene activation, and fibrosis in response to pressure overload and beta-chronic adrenergic stimulation. Furthermore, we show in a transgenic mouse model that forced overexpression of MEF2D was sufficient to drive the fetal gene program and pathological remodeling of the heart. These results reveal a unique and important function for MEF2D in stress-dependent cardiac growth and reprogramming of gene expression in the adult heart.

Objectives To identify useful features to predict hidden pancreatic malignancies in patients with main pancreatic duct (MPD) abrupt cutoff and dilatation, but without visible focal pancreatic lesions on CT. Methods This retrospective study included 92 patients (mean age, 63.4 ± 10.6 years, 63 men and 29 women) with MPD abrupt cutoff and dilatation, but without visible focal pancreatic lesion on contrast-enhanced CT between 2009 and 2021. Two radiologists independently evaluated the CT imaging features. Multivariable logistic regression analysis was performed to identify clinical and CT imaging features for hidden pancreatic malignancies. A nomogram was developed based on these results and assessed its performance. Results Thirty-eight (41.3%) and 54 (58.7%) were classified into the malignant and benign groups, respectively. In the multivariable analysis, CA19-9 elevation (odds ratio [OR] 7.5, p = 0.003), duct cutoff site at the head/neck (OR 7.6, p = 0.006), parenchymal contour abnormality at the duct cutoff site (OR 13.7, p < 0.001), and presence of acute pancreatitis (OR 11.5, p = 0.005) were independent predictors of pancreatic malignancy. A combination of any two significant features showed an accuracy of 77.2%, and a combination of any three features exhibited a specificity of 100%. The CT-based nomogram showed an area under the curve (AUC) of 0.84 (95% confidence interval, 0.77–0.90). Conclusions The three CT imaging features and CA19-9 elevation translated into a nomogram permit a reliable estimation of hidden pancreatic malignancies in patients with MPD abrupt cutoff without visible focal pancreatic lesion. It may facilitate determining whether to proceed to further diagnostic tests. Key Points • Isoattenuating pancreatic ductal adenocarcinoma can manifest only as an isolated main pancreatic duct (MPD) dilatation with abrupt cutoff, making it difficult to distinguish from benign strictures. • Along with the serum CA 19-9 elevation, MPD cutoff site at the pancreas head or neck, parenchymal contour abnormality at the duct cutoff site, and associated acute pancreatitis indicated a higher probability of the malignant MPD strictures. • The CT-based nomogram provided excellent diagnostic performance (AUC of 0.84) for hidden pancreatic malignancies in patients with MPD abrupt cutoff and dilatation.

Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas.

Objective This study aims to elucidate the relationship between gastric mucosal atrophy, cystic dilatation, and their associated histopathological characteristics. Methods A comprehensive analysis was conducted on endoscopic biopsy specimens from 527 cases exhibiting gastric mucosal cystic dilatation. Detailed histological observations and immunohistochemical analysis were performed. Results This study included 527 endoscopic biopsy and ESD samples, with a male predominance of 313 cases (59.4%) and 214 female cases (40.6%). The age distribution was as follows: 207 cases (39.3%) were ≤ 60 years, while 320 cases (60.7%) were > 60 years. Regarding cystic dilatation types, 287 cases (54.5%) were identified as simple cystic dilatation, and 240 cases (45.5%) were classified as compound cystic dilatation. Gastric mucosal atrophy was observed in all cases of cystic dilatation, with the atrophic process initially disrupting the structural integrity of the gastric glands. This led to increased interstitial tissue and widening of glandular septa, followed by compensatory hyperplasia and cystic cavity formation. Simple cystic dilatation (54.5%) and compound cystic dilatation (45.5%) were distinguished based on the extent of cellular and structural changes. Simple cystic dilatation could progress to early gastric cancer, presenting as gastric papillary cystadenocarcinoma, while compound cystic dilatation could lead to tubular papillary adenocarcinoma. The progression from simple to complex lesions involved low- and high-grade intraepithelial neoplasia, ultimately resulting in mixed cystadenocarcinoma-glandular tube papillary carcinoma, indicative of early-stage gastric cancer. Conclusion The classification, grading, and histopathological characteristics of cystic dilatation in the gastric mucosa are crucial for guiding clinicians in precise treatment and vigilant monitoring of malignant transformation. This approach is significant for the prevention and control of gastric cancer progression.

Objective:To establish a classification of bicuspid aortic valve (BAV) that includes both leaflet morphology and aortic shape.Setting:Two academic medical centres of the University of Washington, Seattle.Patients:191 adult patients with BAV.Interventions:Review of clinical data and transthoracic echocardiograms.Main outcome measures:Assessment of leaflet morphology; valve function; aortic shape and dimensions.Results:We identified three morphologies: type 1, fusion of right and left coronary cusp (n = 152); type 2, right and non-coronary fusion (n = 39); and type 3, left and non-coronary fusion (n = 1). Comparing type 1 and 2 BAV, there were no significant differences in age, height, weight, blood pressure or aortic valve function. Type 1 was more common in men (69 vs 45%). The aortic sinuses were larger in type 1, while type 2 had larger arch dimensions. Myxomatous mitral valves were more common in type 2 BAV (13% vs 2.6%, p<0.05). Three aortic shapes were defined: normal (N), sinus effacement (E), and ascending dilatation (A). Comparing type 1 to type 2 BAV, shape N was more common in type 1 (60% vs 32%), and type A was more common in type 2 (35% vs 54%,); type E was rare (p<0.01 across all groups).Conclusion:A comprehensive BAV phenotype includes aortic shape. Type 1 BAV is associated with male gender and normal aortic shape but a larger sinus diameter. Type 2 leaflet morphology is associated with ascending aorta dilatation , larger arch dimensions and higher prevalence of myxomatous mitral valve disease.

ObjectiveThis study aimed to determine aortic disease severity in patients with Loeys–Dietz syndrome (LDS).MethodsThirty-three patients with LDS diagnosed and followed up at our unit were included. After reviewing all family trees, 25 deceased family members with clear clinical suspicion of having had LDS were also included. Clinical presentation, aortic dilation rate by echocardiography and age at aortic surgery, dissection or death were determined.ResultsMedian aortic diameter at diagnosis was 36 mm, 43% of the patients aged >40 years had a z-score <2. Median aortic root dilation rate was 0.67 mm/year (maximum 2.0 mm/year) over a median follow-up of 2 years (IQR 1.0–4.0). In the global cohort, 31/58 patients reached a clinical endpoint; 19% death, median age: 52 years; 14% dissection, median age: 36 years; 21% aortic surgery, median age: 53 years. As expected, probands had a higher z-score (2.9 vs 1.5, p=0.019) and more often required aortic surgery (33.4% vs 18.2%, p=0.035) compared with family members. TGFBR2 carriers had a higher z-score compared with TGFBR1 carriers (3.2 vs 1.5, p=0.034) and younger age at aortic surgery (HR 4.9, 95% CI 1.5 to 123, p=0.026). Craniofacial severity index was inversely correlated with age at first event (r=−0.765, p=0.045).ConclusionsAlthough paediatric patients were not properly represented in our cohort, our patients with LDS presented a significant heterogeneity in the severity of aortic disease with large intrafamilial and interfamilial variability, aortic root aneurysm were less frequent and aortic complications less premature than previously depicted. Furthermore, aortic dilation rate was similar to that reported in Marfan syndrome and aortic root diameters appear to be larger in TGFBR2 carriers.