To evaluate the effects of probiotics Bifidobacterium bifidum G9-1 (BBG9-1) on gastrointestinal symptoms in patients with Type 2 diabetes mellitus (T2DM) with diarrhoea or constipation. In a 12-week open-label randomised controlled trial, 100 participants were randomized 1:1 to a control or BBG9-1 group, with 12 mg of Bifidobacterium administered daily. The primary endpoint was the change in total Gastrointestinal Symptom Rating Scale (GSRS) score (range: 1-7) in the full analysis set (BBG9-1: n = 43; control: n = 51). BBG9-1 intake significantly improved the GSRS total score (from 2.22 ± 0.67 to 1.83 ± 0.62) compared with control (from 2.08 ± 0.67 to 2.06 ± 0.63; between-group difference, -0.34 [95% CI: -0.55 to -0.14; p = 0.001]). Subgroup analyses indicated greater GSRS total score improvement in women, participants with constipation, aged ≥ 65 years, and BMI < 25 kg/m2. Among the GSRS subscales, BBG9-1 showed a significantly greater mean reduction in constipation scores than control (-0.79 ± 1.38 vs. -0.13 ± 1.04; p = 0.013). Although the mean change in diarrhoea scores did not differ significantly (-0.42 ± 1.14 vs. -0.06 ± 1.08; p = 0.14), the follow-up diarrhoea score was significantly lower with BBG9-1 (2.04 ± 1.00 vs. 2.58 ± 1.44; p = 0.049). Through gut microbiota analysis, the relative abundance of genera Phocaeicola increased significantly in the BBG9-1 group (from 15.98 ± 13.75 to 19.56% ± 14.79% vs. from 18.14 ± 14.17 to 18.21 ± 13.58, p = 0.042). Assessment of faecal short-chain fatty acids (SCFAs) revealed no significant changes associated with BBG9-1 administration. The incidence of adverse effects were similar between the groups. BBG9-1 administration significantly improved gastrointestinal symptoms in patients with T2DM. Japan Registry of Clinical Trials (jRCTs051220127).
Osteoarthritis patients undergoing THA or TKA were studied to compare the cumulative incidence of revision after perioperative denosumab versus alendronate. Denosumab was not associated with differences in the incidence of revision after THA but was associated with a higher revision incidence after TKA, mainly driven by aseptic tibial loosening. Osteoarthritis is highly prevalent, and the number of total hip (THA) and knee arthroplasties (TKA) continues to rise. This study aimed to evaluate the risk of revision associated with perioperative exposure to denosumab versus alendronate in patients undergoing THA or TKA for osteoarthritis. This retrospective cohort study used data from the Emilia-Romagna Registry of Orthopedic Prosthetic Implants (RIPO). Patients undergoing primary THA or TKA for osteoarthritis between 2011 and 2023 were included. Perioperative exposure was defined as at least one dispensing of denosumab or alendronate within 180 days before or after surgery. The primary outcome was first revision. Revision risk was analysed using cumulative incidence functions, treating death and emigration as competing events, and groups were compared using Gray's test. The THA cohort comprised 129 denosumab and 922 alendronate users. Revision occurred in 4 denosumab (3.1%) and 21 alendronate patients (2.3%); no significant difference was observed in competing risk analyses (Gray's p = 0.623). In the TKA cohort, 117 denosumab and 940 alendronate users were analysed. Here 8 denosumab patients (6.8%) and 18 alendronate patients (1.9%) required revision, with a significant difference in cumulative incidence (Gray's p = 0.002). Revisions in denosumab users were mainly due to aseptic tibial loosening. Perioperative denosumab exposure was associated with a higher cumulative incidence of revision after TKA in this cohort. These findings should be interpreted cautiously and do not imply causality. The observed pattern may reflect complex interactions between antiresorptive therapy and joint-specific biomechanical factors, which warrant further investigation.
Background and Clinical Significance: Neurosarcoidosis (NS) is a rare manifestation of systemic sarcoidosis involving the central nervous system, with highly variable neurological and endocrine presentations. Among these, anterior pituitary dysfunction is particularly uncommon and diagnostically challenging. Case Presentation: We report the case of a 37-year-old woman with a 4-year history of secondary amenorrhoea and an initially suspected pituitary microadenoma, who was ultimately diagnosed with probable NS presenting with multiaxial anterior pituitary insufficiency. Early magnetic resonance imaging (MRI) revealed a small pituitary lesion and isolated pituitary stalk thickening, without other central nervous system abnormalities. Subsequent imaging demonstrated contrast-enhancing lesions involving the meninges and cranial nerves, along with progression of pituitary stalk involvement and loss of the posterior pituitary bright spot. Further evaluation confirmed systemic sarcoidosis. High-dose corticosteroid therapy led to partial clinical and radiological improvement; however, relapse necessitated methotrexate, and persistent pituitary hormone deficiencies required long-term hormonal replacement. Conclusions: This case highlights the diagnostic complexity of NS presenting with isolated endocrine dysfunction and subtle imaging findings. It underscores the need to consider systemic sarcoidosis in patients with unexplained hypopituitarism.
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In heart failure (HF), patients' quality of life (QoL) is influenced not only by cardiac function but also by coexisting conditions. Despite the widespread use of QoL assessments, the role of patient-related factors as determinants of QoL remains not fully elucidated. This study aims to assess the relative impact of different factors on QoL in HF patients, also its impact on mortality in this group. The study was based on the national registry - HEart failuRe ObsErvational Study of the Polish Cardiac Society, where QoL was assessed at baseline (Kansas City Cardiomyopathy Questionnaire [KCCQ]-12), and follow-up data on all-cause mortality were obtained. Adjusted linear regression was used to identify factors associated with KCCQ-12. The study included 1397 patients with a mean KCCQ-12 score = 47.92 (28.65-72.92). Higher New York Heart Association class had consistently significantly lower values of all KCCQ-12 domains and KCCQ-12 overall score (85 [69-93] vs. 65 [46-79] vs. 35 [23-49] vs. 21 [10-38]; all P <0.001). Hospitalized patients had significantly lower KCCQ-12 overall score, with a significant difference between patients hospitalized for HF or non-cardiac reasons and patients hospitalized for other cardiac conditions. Apart from visit type, individual factors, cardiovascular conditions, and non-cardiac conditions were independently associated with KCCQ-12. KCCQ-12 also significantly influenced all-cause mortality (hazard ratio per 1 point increase = 0.976; 95% confidence interval, 0.970-0.981; P <0.001). Individual factors with both cardiac and non-cardiac comorbidities are independently associated with QoL in patients with HF. The KCCQ-12 integrates all of these factors and may serve as a simple, easily accessible tool for prognostic assessment.
Turner syndrome (TS) may involve tissue-restricted mosaicism, undetectable in standard peripheral blood karyotyping. This poses a diagnostic challenge, particularly when occult Y-chromosome material increases gonadoblastoma risk. We report an 18-year-old girl with TS (45,X), short stature on recombinant human growth hormone (rhGH) and severe intellectual disability, who developed virilization at age 12. Laboratory testing showed hypergonadotropic hypogonadism with elevated testosterone. Imaging failed to detect gonads. Bilateral gonadectomy revealed streak gonad tissue and testicular tissue with intratubular germ cell neoplasia and focal gonadoblastoma. High-resolution cytogenetics confirmed gonadal mosaicism with unbalanced Y/7 translocation, absent in lymphocytes. This case highlights that unexplained virilization in TS warrants immediate evaluation and that high-resolution genomic methods and timely gonadectomy are essential for cancer risk reduction.
Type 1 diabetes (T1D) progresses from genetic risk to metabolic disease. Anti-β-cell antibodies (AABs), alongside clinical features, define the stages of T1D and enable identification of presymptomatic individuals. To describe the natural history of patients with ≥1 positive AAB, analyzing progression to stage 3 T1D and clinical severity at diagnosis. Single-center retrospective cohort study (February 2012-April 2025). One-hundred and six patients with ≥1 AAB-positive enrolled in a structured follow-up program. progression to stage 3 T1D and occurrence of diabetic ketoacidosis (DKA) at diagnosis. During a median follow-up of 4 years, 19 of 106 AAB-positive patients progressed to stage 3 T1D, none of whom presented with DKA at diagnosis. The 5-year cumulative risk of progression was 16.6% (95% CI: 10.0%-26.9%). Patients with multiple AAB positivity at baseline had a significantly higher 5-year risk than those with a single positive AAB (40.4% vs 8.3%; P = .0002). Glutamic acid decarboxylase (GAD) autoantibody positivity was associated with an increased 5-year risk of progression (25.7% vs 2.8% in GAD-negative children; P = .0063) and remained independently associated with T1D onset in multivariable analysis. Persistent autoantibody positivity, particularly for GAD, is strongly associated with progression to stage 3 T1D. Children identified through AAB monitoring show a milder clinical presentation at diagnosis, with no cases of DKA. These data support screening and structured follow-up of at-risk children, which may help prevent DKA and facilitate identification of candidates for disease-modifying interventions.
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Background: Diabetic neuropathy manifests as symmetric distal and autonomic neuropathy, including cardiovagal dysfunction. Small-fiber involvement can occur, leading to neuropathic pain and dysautonomia. The diagnostic gold standard of these two conditions comprehends skin biopsy and cardiovascular autonomic reflex tests (CARTs), respectively. Non-invasive diagnostic tools, such as laser-evoked potentials (LEPs), show promise in detecting small-fiber damage, though correlations between LEP abnormalities and cardiovascular autonomic dysfunction remain poorly investigated. Methods: We retrospectively evaluated LEPs (from hands and feet stimulation) in 33 diabetic patients, comparing them to a cohort of 33 age-matched healthy subjects, to highlight any significant abnormalities in the diabetic cohort. We further analyzed the LEP results in T2DM cohort with clinical, laboratory variables and CARTs to explore potential correlations and to assess whether any association between LEPs and CARTs could be identified. Results: N2/P2 complex amplitude was significantly reduced in diabetic patients compared to healthy subjects, with greater involvement in the lower limbs. While no association between LEP abnormalities and abnormal CARTs was observed, LEP amplitude reductions were notably associated with elevated glycated hemoglobin levels and longer disease duration, which appeared to be the strongest predictor of LEP reduction. Conclusions: Our findings corroborated literature data regarding length-dependent LEP alterations detectable even in initial diabetic stages. The lack of correlation between LEP abnormalities and autonomic dysfunction may stem from the predominant involvement of C fibers in autonomic neuropathy, which are not adequately assessed by currently used LEPs.
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The clinical relevance of HER2 expression profile in solid cancers has expanded with the evolving landscape of HER2 targeting agents. This systematic review and meta-analysis aim to detail the prevalence of HER (over)expression in prostate cancer and identify patient/disease subgroups with enriched HER2 overexpression. Literature searches of five databases were performed. HER2 scores with cross-tabulation of clinicopathological parameters were extracted for pooled prevalence and odds ratio analyses. Study quality, heterogeneity, and publication bias were assessed by the CASP checklist, I2 index, and LFK index. In total, 16 studies were included with 1258 cases. There were 669 (53.18%), 269 (21.38%), 250 (19.87%), and 70 (5.56%) of HER2 Scores 0/1/2/3, respectively. Pooled analysis indicated a prevalence of 4.9% (95% CI 3.0%-7.2%) for HER2 Score 3 and 42.0% (95% CI 29.0%-55.6%) for HER2 non-negative (Scores 1-3). Subgroup analysis comparing HER2 negative (0, 1) and HER2 overexpression (3) indicated higher Gleason score (OR = 0.061, 95% CI: 0.010-0.359, p < 0.001), higher disease stage (OR = 0.063, 95% CI: 0.016-0.252, p < 0.001) and biopsies from metastatic site (OR: > 100, 95% C.I.: > 100-> 100, p < 0.001) favoring HER overexpression, without significant differences for patient age or prostate-specific antigen (PSA) level. I2 was 91.63% with meta-regression analysis showing study quality as a source of heterogeneity (p = 0.043). LFK index was 1.93 (moderate publication bias risk, p = 0.054). HER2 overexpression is rare in prostatic carcinomas but nearly half show HER2 expression of Score 1 or above. Cases with higher Gleason score and advanced disease stage are more likely to overexpress HER2.
This study investigated the prevalence and clinical correlates of renal phenotypes in two cohorts of type 2 diabetes (T2D) patients, assessed temporal trends, and evaluated associations with treatment regimens. These figures were compared to those previously recorded in a similar, real world cohort 15 years earlier in Italy. Clinical data from 378 914 T2D patients attending the AMD network in 2023 in Italy were retrieved and compared to a similar cohort of prevalent patients in 2009. Renal phenotypes were classified as isolated albuminuria, isolated reduced eGFR (<60 ml/min/1.73 m²), or both. Multivariate logistic regression identified factors associated with these phenotypes. In the 2023 study cohort, 51.3% of patients showed preserved renal function, 17.9% had isolated low eGFR, 17.4% had isolated albuminuria, and 13.3% exhibited both conditions. Female gender was independently associated with isolated low eGFR (OR = 1.28), whereas male gender was linked to albuminuria. Age was significantly related to both renal abnormalities, while longer diabetes duration increased the likelihood of low eGFR. Compared with the 2009 cohort, the prevalence of CKD in T2D remains stable in 2023, with albuminuric phenotypes decreasing and isolated low eGFR phenotypes increasing. These trends may reflect the aging population and evolving treatment practices, including a growing use of nephroprotective agents such as RAS inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists as well as better control of blood pressure. Longitudinal ad hoc studies are needed to address changing clinical scenarios.
Dysmorphic syndromes are characterised by congenital anomalies affecting craniofacial features, body proportions, and organ structure. They are frequently caused by complex genetic alterations, including deletions, duplications, and microdeletions, which impede optimal growth regulation. The objective of this paper is to present a synopsis of selected dysmorphic syndromes associated with excessive growth, with particular emphasis on syndromes with confirmed or strongly suspected chromosomal aetiology or associated with DNA methylation disorders (epigenetic disorders) with dynamic mutation. The following aspects are discussed in this text: the pathogenesis of the condition, its inheritance, the characteristic clinical symptoms, the diagnostic approach and potential treatment options. The following essay will provide a comprehensive overview of the relevant literature on the subject. A thorough search of various databases yielded 50,385 scientific studies. After applying strict criteria for quality and relevance, 36 studies were selected for final analysis. The selection focused on the most recent peer-reviewed studies and case studies published in English. This review identified several key chromosomal abnormalities, dynamic mutations and methylation defects linked to overgrowth syndromes. The findings consistently associated these aberrations with core clinical features such as macrocephaly, developmental delay, and musculoskeletal abnormalities. Furthermore, the study confirmed that mosaic forms and specific genetic mechanisms, such as those found in hemihyperplasia, contribute significantly to the phenotypic variability of these disorders. Overgrowth syndromes are a heterogeneous group of disorders characterised by excessive growth and additional congenital anomalies. Diagnosis relies on clinical evaluation supported by molecular genetic testing. Effective management requires ongoing, collaborative care from a diverse team to promote the patient's health and development throughout their life.
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The epithelial sodium channel ENaC consists of the subunits α, β, and γ and is activated at an individual channel level by proteolytic processing. Murine γENaC contains a distal polybasic tract 186RKRK mediating proteolytic ENaC activation by serine proteases in vitro. The relevance of ENaC activation at this cleavage site for sodium homeostasis in vivo is unknown. Mice were generated carrying a mutation of the distal polybasic tract (RKRK186QQQQ or γENaCki/ki) using CRISP/Cas9. Sodium homeostasis and proteolytic processing of γENaC were investigated under a low sodium diet, pharmacological ENaC blockade, and induction of nephrotic syndrome. Under control conditions, the response to bolus amiloride was reduced in γENaCki/ki mice compared to γENaCwt/wt mice. Under a low sodium diet for 4 days, urinary sodium excretion was similarly lowered in both genotypes; however, γENaCki/ki mice required significantly higher plasma aldosterone concentrations. Both genotypes were similarly tolerant to amiloride exposure for 4 days and developed similar sodium retention and body weight gain after induction of nephrotic syndrome. Proteolytic processing of γENaC leading to increased expression of distally cleaved γENaC at ~54 kDa was stimulated in both γENaCwt/wt and γENaCki/ki mice under all interventions without an appreciable difference in the migration pattern. Mice harboring the RKRK186QQQQ mutation of the distal polybasic tract develop hyperaldosteronism under a low sodium diet, pointing to the relevance of this tract for sodium preservation. However, proteolytical processing of γENaC in these mice appears to be compensated for by the involvement of other adjacent cleavage sites.