Neuronal Spike Shapes (NSS): A straightforward approach to investigate heterogeneity in neuronal excitability states

The mammalian brain exhibits a remarkable diversity of neurons, contributing to its intricate architecture and functional complexity. The analysis of multimodal single-cell datasets enables the investigation of cell types and states heterogeneity. In this study, we introduce the Neuronal Spike Shapes (NSS), a straightforward approach for the exploration of excitability states of neurons based on their Action Potential (AP) waveforms. The NSS method describes the AP waveform based on a triangular representation complemented by a set of derived electrophysiological (EP) features. To support this hypothesis, we validate the proposed approach on two datasets of murine cortical neurons, focusing it on GABAergic neurons. The validation process involves a combination of NSS-based clustering analysis, features exploration, Differential Expression (DE), and Gene Ontology (GO) enrichment analysis. Results show that the NSS-based analysis captures neuronal excitability states that possess biological relevance independently of cell subtype. In particular, Neuronal Spike Shapes (NSS) captures, among others, a well-characterized fast-spiking excitability state, supported by both electrophysiological and transcriptomic validation. Gene Ontology Enrichment Analysis reveals voltage-gated potassium (K+) channels as specific markers of the identified NSS partitions. This finding strongly corroborates the biological relevance of NSS partitions as excitability states, as the expression of voltage-gated K+ channels regulates the hyperpolarization phase of the AP, being directly implicated in the regulation of neuronal excitabilit

Effect of Metformin on Glucagon-Like Peptide 1 (GLP-1) and Leptin Levels in Obese Nondiabetic Subjects

OBJECTIVE—To evaluate the effects of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels. RESEARCH DESIGN AND METHODS—A total of 10 obese nondiabetic male patients were studied before and after a 14-day treatment with 2,550 mg/day metformin and were compared with 10 untreated obese control subjects. On days 0 and 15, leptin and GLP-1(7–36)amide/(7–37) levels were assessed before and after an oral glucose load during a euglycemic hyperinsulinemic clamp to avoid the interference of variations of insulinemia and glycemia on GLP-1 and leptin secretion. The effects of metformin on GLP-1(7–36)amide degradation in human plasma and in a buffer solution containing dipeptidyl peptidase IV (DPP-IV) were also studied. RESULTS—Leptin levels were not affected by the oral glucose load, and they were not modified after metformin treatment. Metformin induced a significant (P < 0.05) increase of GLP-1(7–36)amide/(7–37) at 30 and 60 min after the oral glucose load (63.8 ± 29.0 vs. 50.3 ± 15.6 pmol/l and 75.8 ± 35.4 vs. 46.9 ± 20.0 pmol/l, respectively), without affecting baseline GLP-1 levels. No variations of GLP-1 levels were observed in the control group. In pooled human plasma, metformin (0.1–0.5 μg/ml) significantly inhibited degradation of GLP-1(7–36)amide after a 30-min incubation at 37°C; similar results were obtained in a buffer solution containing DPP-IV. CONCLUSIONS—Metformin significantly increases GLP-1 levels after an oral glucose load in obese nondiabetic subjects; this effect could be due to an inhibition of GLP-1 degradation

Vitamin D therapy in adults with diabetes mellitus

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Ezetimibe + simvastatin versus doubling the dose of simvastatin in high cardiovascular risk diabetics: a multicenter, randomized trial (the LEAD study)

Abstract Background The primary goal of therapy in patients with hypercholesterolemia and coronary heart disease (CHD) is reducing low-density lipoprotein cholesterol (LDL-C). This was a multicenter, randomized, double-blind, double-dummy study in patients with type 2 diabetes mellitus (T2DM). Methods Adult patients with T2DM and CHD (N = 93) on a stable dose of simvastatin 20 mg with LDL-C ≥ 2.6 mmol/L (100 mg/dL) and ≤ 4.1 mmol/L (160 mg/dL) were randomized to ezetimibe 10 mg plus simvastatin 20 mg (EZ + simva 10/20 mg) or simvastatin 40 mg for 6 weeks. Percent change in LDL-C, high-density lipoprotein cholesterol, and triglycerides was assessed. Results EZ + simva 10/20 mg produced a significantly greater change from treated baseline compared with simvastatin 40 mg in LDL-C (-32.2% vs -20.8%; p Conclusions These results demonstrate that EZ + simva 10/20 mg may provide a superior alternative for LDL-C lowering vs doubling the dose of simvastatin to 40 mg in hyperlipidemic patients with T2DM and CHD. In addition, the combination therapy may provide an alternative treatment for patients who require further LDL-C reduction than they can achieve with simvastatin 20 mg alone.</p

Metachronous colorectal cancer have a similar microsatellite instability frequency but a lower infiltration of lymphomononuclear cells than primary lesions

Background: An increased risk of metachronous colorectal cancer is usually associated with microsatellite instability occurring in Lynch syndrome. However, not all patients with metachronous colorectal cancer have microsatellite instability. The density of tumor-infiltrating lymphocytes is an independent predictor of outcome in patients with colorectal cancer, and a fascinating hypothesis is that they can be involved in the onset of metachronous colorectal cancer. The aim of this study was to analyze the tumor microenvironment and tumor mutation frequency in sporadic and metachronous colorectal cancer. Methods: The clinical and pathological records of a series of consecutive colorectal cancer patients who were operated on from 2015 to 2019 were retrieved for this retrospective study. We defined metachronous colorectal cancer as a second colorectal cancer that appeared at least 1 year after the primary one, and sporadic colorectal cancer as those that did not have a metachronous colorectal cancer. Histology for the infiltration of intratumoral lymphomononuclear cells, immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, and mutational analysis of BRAF, KRAS, and NRAS were all performed. Sporadic colorectal cancer and metachronous colorectal cancer were compared. Nonparametric tests were used for small sample size comparison. Results: In the study, 238 patients were operated on for colorectal cancer at the General Surgery Unit of the Azienda Ospedaliera di Padova from 2015 to 2019. We identified 26 patients with metachronous colorectal cancer, and only 3 of them had had adjuvant therapy after the primary colorectal cancer. No difference was observed in terms of cancer stage between metachronous and sporadic colorectal cancer. Mismatch repair gene deficiencies and microsatellite instability frequency was similar in metachronous colorectal cancer and in sporadic colorectal cancer (P = .77). Likewise, the mutation frequency of BRAF and KRAs was similar in the 2 groups (P = .75 and P = .21, respectively). To the contrary, the absence of infiltration of lymphomononuclear cells within the tumor (P = .004) in patients with metachronous colorectal cancer was more frequent and they tended to have a higher frequency of NRAS mutation (P = .06). Conclusion: Our study showed that, rather unexpectedly, microsatellite instability frequency was similar in metachronous and sporadic colorectal cancer. Moreover, our data suggest that an altered immune microenvironment may be a crucial factor, permitting the occurrence of metachronous colorectal cancer. In fact, the absence of lymphomononuclear cells can be the substrate for a weak immune response to cancer neoantigens, opening the way to a second primary colorectal cancer

Crohn's disease-related stoma complications and their impact on postsurgical course

Introduction: Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. The diversion through a colostomy or an ileostomy is sometimes required for disease control. In these patients, common stoma-related complications sum up with CD-related complications and often require revisional surgery. Methods: The aim of the study was to assess stoma morbidity after surgery for CD and to identify the burden of CD-related complications. Details of past medical history, surgery and follow up of 54 consecutive patients operated on for CD with any sort of stoma were retrieved from the stoma therapist prospectively maintained database. Results: In our series, 23 patients had a colostomy, and 31 an ileostomy. CD-related complications arose in 8 patients (including pyoderma gangrenosus in 3 patients, peristomal fistulae in 2, granulomas in 2, and peristomal abscess in 1). Patients with CD-related complications had shorter disease duration (p=0.07) and, more frequently end-stoma (p=0.006). In this cohort, 11 cases had to be surgically treated for peristomal fistulae or abscess, parastomal hernia, prolapse, pyoderma gangrenosus and recurrent CD. Discussion/conclusions: In patients with CD, stoma creation is burdened by a high rate of postoperative complication and a relevant rate is specifically related to CD. Often these patients required to be re-operated on to re-do the stoma. Moreover, end stoma configuration and aggressive CD phenotype are associated to a higher rate of complications