Effects of a Lactobacillus paracasei B21060 based synbiotic on steatosis, insulin signaling and toll-like receptor expression in rats fed a high-fat diet.

Insulin resistance (IR) has been identified as crucial pathophysiological factor in the development and progression of non-alcoholic fatty liver disease (NAFLD). Although mounting evidence suggests that perturbation of gut microflora exacerbates the severity of chronic liver diseases, therapeutic approaches using synbiotic has remained overlooked. Here, we show that a synbiotic composed by Lactobacillus paracasei B21060 plus arabinogalactan and fructo-oligosaccharides lessens NAFLD progression in a rat model of high fat feeding. IR and steatosis were induced by administration of high fat diet (HFD) for 6 weeks. Steatosis and hepatic inflammation, Toll-like receptor (TLR) pattern, glucose tolerance, insulin signaling and gut permeability were studied. Liver inflammatory markers were down-regulated in rats receiving the synbiotic, along with an increased expression of nuclear peroxisome proliferator-activated receptors and expression of downstream target genes. The synbiotic improved many aspects of IR, such as fasting response, hormonal homeostasis and glycemic control. Indeed it prevented the impairment of hepatic insulin signaling, reducing the phosphorylation of insulin receptor substrate-1 in Ser 307 and down-regulating suppressor of cytokine signaling 3. Gene expression analysis revealed that in the liver the synbiotic reduced cytokines synthesis and restored the HFD-dysregulated TLR 2, 4 and 9 mRNAs toward a physiological level of expression. The synbiotic preserved gut barrier integrity and reduced the relative amount of Gram-negative Enterobacteriales and Escherichia coli in colonic mucosa. Overall, our data indicate that the L. paracasei B21060 based synbiotic is effective in reducing the severity of liver injury and IR associated with high fat intake, suggesting its possible therapeutic/preventive clinical utilization

Compatible Paths on Labelled Point Sets

Let P and Q be finite point sets of the same cardinality in R 2 , each labelled from 1 to n. Two noncrossing geometric graphs GP and GQ spanning P and Q, respectively, are called compatible if for every face f in GP , there exists a corresponding face in GQ with the same clockwise ordering of the vertices on its boundary as in f. In particular, GP and GQ must be straightline embeddings of the same connected n-vertex graph G. No polynomial-time algorithm is known for deciding whether two labelled point sets admit compatible geometric graphs. The complexity of the problem is open, even when the graphs are constrained to be triangulations, trees, or simple paths. We give polynomial-time algorithms to find compatible paths or report that none exist in three scenarios: O(n) time for points in convex position; O(n 2 ) time for two simple polygons, where the paths are restricted to remain inside the closed polygons; and O(n 2 log n) time for points in general position if the paths are restricted to be monotonePeer ReviewedPostprint (published version

Post-intubation tracheal lacerations: Risk-stratification and treatment protocol according to morphological classification

BackgroundPost-intubation tracheal laceration (PITL) is a rare condition (0.005% of intubations). The treatment of choice has traditionally been surgical repair. Following our first report in 2010 of treatment protocol tailored to a risk-stratified morphological classification there is now clear evidence that conservative therapy represents the gold standard in the majority of patients. In this paper we aim to validate our risk-stratified treatment protocol through the largest ever reported series of patients. MethodsThis retrospective analysis is based on a prospectively collected series (2003-2020) of 62 patients with PITL, staged and treated according to our revised morphological classification. ResultsFifty-five patients with Level I (#8), II (#36) and IIIA (#11) PITL were successfully treated conservatively. Six patients with Level IIIB injury and 1 patient with Level IV underwent a surgical repair of the trachea. No mortality was reported. Bronchoscopy confirmed complete healing in all patients by day 30. Statistical analysis showed age only to be a risk factor for PITL severity. ConclusionsOur previously proposed risk-stratified morphological classification has been validated as the major tool for defining the type of treatment in PITL

Luminal-like HER2-negative stage IA breast cancer: A multicenter retrospective study on long-term outcome with propensity score analysis

The benefit of adding chemotherapy (CT) to adjuvant hormone therapy (HT) in stage IA luminal-like HER2-negative breast cancer (BC) is unclear. We retrospectively evaluated predictive factors and clinical outcome of 1,222 patients from 4 oncologic centers. Three hundred and eighty patients received CT and HT (CT-cohort) and 842 received HT alone (HT-cohort). Disease-free survival (DFS) and overall survival (OS) were evaluated with univariate and multivariate analyses. We also applied the propensity score methodology. Compared with the HT-cohort, patients in the CT-cohort were more likely to be younger, have larger tumors of a higher histological grade that were Ki67-positive, and lower estrogen and progesterone receptor expression. At univariate analysis, a higher histological grade and Ki67 were significantly associated to a lower DFS. At multivariable analysis, only histological grade was predictive of DFS. The CT-cohort had a worse outcome than the HT-cohort in terms of DFS and OS, but differences disappeared when matched according to propensity score. In summary, patients with stage IA luminal-like BC had an excellent prognosis, however relapse and mortality were higher in the CT-cohort than in the HT-cohort. Longer use of adjuvant HT or other therapeutic strategies may be needed to improve outcome

Laryngopharyngeal reflux diagnosis in obstructive sleep apnea patients using the pepsin salivary test

Background: To investigate the presence of laryngopharyngeal reflux in patients with obstructive sleep apnea (OSA) employing the salivary pepsin concentration method. To compare the results of pepsin concentration with the severity of the pathology. Methods: Seventy-five OSA patients (44 males, 31 females) were enrolled in the study. For each patient, the AHI (apnea–hypopnea index) and the BMI (body mass index) were initially evaluated. All the patients enrolled were assessed using the reflux symptom index (RSI) and the reflux finding score (RFS) in order to perform a clinical diagnosis of laryngopharyngeal reflux. In all patients a salivary sample was taken to estimate the presence of pepsin and its concentration. Results: The incidence of LPR (laryngopharyngeal reflux) in OSA patients, evaluated using the salivary pepsin concentration test (PEP-test), was found to be 32% of cases. Linear regression testing did not show any correlation between AHI and pepsin concentration in salivary samples (p = 0.1). Conclusion: A high number of patients with OSA seem to show positivity for salivary pepsin, correlated to an LPR. There does not appear to be a correlation between the severity of apnea and the grade of salivary pepsin reflux. On the other hand, direct correlation between BMI and the value of pepsin in salivary specimens was observed

RANKL Cytokine: From Pioneer of the Osteoimmunology Era to Cure for a Rare Disease

Since its identification, the RANKL cytokine has been demonstrated to play a crucial role in bone homeostasis and lymphoid tissue organization. Genetic defects impairing its function lead to a peculiar form of autosomal recessive osteopetrosis (ARO), a rare genetic bone disease presenting early in life and characterized by increased bone density due to failure in bone resorption by the osteoclasts. Hematopoietic stem cell transplantation (HSCT) is the only option for the majority of patients affected by this life-threatening disease. However, the RANKL-dependent ARO does not gain any benefit from this approach, because the genetic defect is not intrinsic to the hematopoietic osteoclast lineage but rather to the mesenchymal one. Of note, we recently provided proof of concept of the efficacy of a pharmacological RANKL-based therapy to cure this form of the disease. Here we provide an overview of the diverse roles of RANKL in the bone and immune systems and review the clinical features of RANKL-deficient ARO patients and the results of our preclinical studies. We emphasize that these patients present a continuous worsening of the disease in the absence of a cure and strongly wish that the therapy we propose will be further developed

The IMPACT study: early loss of skeletal muscle mass in advanced pancreatic cancer patients

Abstract Background Pancreatic cancer (PC) patients have multiple risk factors for sarcopenia and loss of skeletal muscle mass (LSMM), which may cause greater treatment toxicities, reduced response to cancer therapy, prolonged hospitalization, impaired quality of life, and worse prognosis. Methods This is a retrospective study on advanced PC patients treated at the Department of Oncology of Udine, Italy, from January 2012 to November 2017. Among 162 patients who received chemotherapy, 94 consecutive patients with an available computed tomography (CT) scan were retrospectively analyzed. The primary objective of our study was to explore if an early LSMM ≥ 10% (measured at first radiological evaluation and compared with baseline) and/or baseline sarcopenia may impact prognosis. Baseline sarcopenia was defined according to Prado's criteria. Skeletal muscle area was measured as cross‐sectional areas (cm2) using CT scan data through the Picture archiving and communication system (PACS) image system. Results In the whole cohort, 48% of patients were ≤70 years old, and 50% had metastatic disease. At baseline, 73% of patients had sarcopenia, and 16% presented a visceral fat area ≥ 44 cm2/m2. Overall, 21% experienced an early LSMM ≥ 10%. Approximately 33% of sarcopenic patients at baseline and ~35% of patients with early LSMM ≥ 10% had a body mass index > 25 kg/m2. Of note, 71% of patients were evaluated by a nutritionist, and 56% received a dietary supplementation (oral and/or parenteral). After a median follow‐up of 30.44 months, median overall survival (OS) was 11.28 months, whereas median progression‐free survival (PFS) was 5.72 months. By multivariate analysis, early LSMM ≥ 10% was significantly associated with worse OS [hazard ratio (HR): 2.16; 95% confidence interval (CI) 1.23–3.78; P = 0.007] and PFS (HR: 2.31; 95% CI 1.30–4.09; P = 0.004). Moreover, an exploratory analysis showed that inflammatory indexes, such as neutrophil–lymphocyte ratio variation, impact early LSMM ≥ 10% (odds ratio 1.31, 95% CI 1.06–1.61, P = 0.010). Conclusions Early LSMM ≥ 10% has a negative prognostic role in advanced PC patients. Further prospective investigations are needed to confirm these preliminary data

RANK-Dependent Autosomal Recessive Osteopetrosis: Characterization of Five New Cases With Novel Mutations

Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis. © 2012 American Society for Bone and Mineral Researc

Bevacizumab-Irinotecan combination therapy in recurrent low-grade glioma, previously treated with chemo-radiotherapy: a case report

Low grade gliomas (LGGs) of pineal region are usually difficult to remove and they frequently relapse or progress after front line chemotherapy. Bevacizumab-Irinotecan (BEVIRI) combination has been successfully attempted in children with recurrent LGGs, in most cases not previously irradiated. The efficacy of bevacizumab has also been described in radiation necrosis. Considering the possible overlapping of radiation treatment effect and disease progression and difficulty in differentiating, we report on the use of BEVIRI in a case of a recurrent relapsing low-grade glioma of the pineal region, subjected to multiple neurosurgical interventions, also treated with a carboplatin-etoposide regimen and a radiation course, at present at one-year follow-up showing a stable response, with no adverse events