Despite increasing evidence suggests that serotonin (5-HT) can influence neurogenesis, neuronal migration and circuitry formation, the precise role of 5-HT on central nervous system (CNS) development ...is only beginning to be elucidated. Moreover, how changes in serotonin homeostasis during critical developmental periods may have etiological relevance to human mental disorders, remains an unsolved question. In this study we address the consequences of 5-HT synthesis abrogation on CNS development using a knock-in mouse line in which the tryptophan hydroxylase 2 (Tph2) gene is replaced by the eGFP reporter. We report that lack of brain 5-HT results in a dramatic reduction of body growth rate and in 60% lethality within the first 3 weeks after birth, with no gross anatomical changes in the brain. Thanks to the specific expression of the eGFP, we could highlight the serotonergic system independently of 5-HT immunoreactivity. We found that lack of central serotonin produces severe abnormalities in the serotonergic circuitry formation with a brain region- and time- specific effect. Indeed, we observed a striking reduction of serotonergic innervation to the suprachiasmatic and thalamic paraventricular nuclei, while a marked serotonergic hyperinnervation was found in the nucleus accumbens and hippocampus of Tph2∷eGFP mutants. Finally, we demonstrated that BDNF expression is significantly up-regulated in the hippocampus of mice lacking brain 5-HT, mirroring the timing of the appearance of hyperinnervation and thus unmasking a possible regulatory feedback mechanism tuning the serotonergic neuronal circuitry formation. On the whole, these findings reveal that alterations of serotonin levels during CNS development affect the proper wiring of the brain that may produce long-lasting changes leading to neurodevelopmental disorders.
Highlights • Monitoring children movement competence is fundamental. • Inertial sensors can be useful for an effective, objective, widespread screening. • An instrumented version of the TGMD-2 ...locomotor subtest was developed. • The proposed method was validated on tests performed by 45 children aged 6–10 years. • Results support the use of inertial sensors in this field as valid and reliable.
A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International ...Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney‐centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new‐onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion‐based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion‐based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.
This article summarizes the opinion‐based recommendations from an international consensus meeting of experts in the field of posttransplantation diabetes mellitus, with the aim to review previous guidelines in light of emerging clinical data and to guide the direction of future research.
Abstract
The aim of the work was to compare the hormonal and the metabolic mechanisms involved in weight loss and remission of T2DM one year after Roux-en-Y gastric bypass (RYGB) and vertical sleeve ...gastrectomy (VSG) in morbidly obese type 2 diabetic (T2DM) patients. Insulin sensitivity, insulin secretion, and the gastrointestinal (GI) hormone response to a mixed meal test (MMT) were evaluated before and one year after BS (14 RYGB and 19 VSG). RYGB and VSG groups had similar characteristics at baseline. Weight loss at one year was similar in the 2 groups (ΔBMI%: − 32±10 and − 30±7%, p=0.546). Insulin sensitivity and insulin secretion improved similarly after either procedures with a similar rate in T2DM remission (86% in RYGB and 76% in VSG). Meal-stimulated GLP-1 levels increased after both procedures reaching significantly higher levels after RYGB (p=0.0001). GIP response to MMT decreased to a similar extent after the 2 interventions (p=0.977). Both fasting and post-meal ghrelin concentrations were markedly suppressed after VSG and significantly lower than RYGB (p=0.013 to p=0.035). The improvement of insulin sensitivity and beta-cell function was significantly associated with weight loss (p=0.014 to p=0.035), while no relation was found with the changes in GI hormones. In conclusion, in morbidly obese T2DM patients, RYGB and VSG result in similar improvements of the glucose status in the face of different GI hormonal pattern. Weight loss is the key determinant of diabetes remission one year after surgery.
Abstract
Objective
The aim of this observational study was to investigate the evolution of scleroderma microangiopathy throughout different nailfold videocapillaroscopy (NVC) patterns (‘early’, ...‘active’, ‘late’) as well as the prevalence of organ involvement in SSc patients during a 12-year follow-up.
Methods
Thirty-four SSc patients showing at baseline (first capillaroscopic analysis) the ‘early’ NVC pattern of microangiopathy were enrolled and followed for 12 years (s.d. 2). Complete NVC analysis and clinical and serological findings were collected. Patients were in a standard therapeutic care setting. Statistical analysis was carried out by non-parametric tests.
Results
After a 12-year follow-up, the ‘early’ NVC pattern changed from baseline in 76% of the patients. The NVC pattern was found to be ‘active’ in 9 patients (26%), ‘late’ in 13 (38%) and characterized by non-specific capillary abnormalities in 4 (12%). In the subgroup whose microangiopathy progressed from the ‘early’ to the ‘late’ NVC pattern, the median time of progression from the ‘early’ to the ‘active’ pattern was significantly shorter (11 months) when compared with patients who progressed from the ‘early’ to the ‘active’ NVC pattern (55 months) (P = 0.002). The median time of progression between NVC patterns was significantly shorter in SSc patients showing either a nucleolar ANA pattern or Scl70 autoantibodies (P = 0.048). Organ involvement was progressively greater in SSc patients with ‘early’, ‘active’ and ‘late’ NVC patterns, respectively.
Conclusions
This longitudinal study confirms over a 12-year follow-up the evolution of specific NVC patterns associated with the progressive severity of organ involvement in SSc patients in a standard clinical care setting.
Aims
To assess the glucose‐stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes.
Methods
We conducted a double‐blind, randomized, placebo‐controlled study in 33 patients ...with type 2 diabetes glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol), who were drug‐naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose‐stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response incremental area under the curve (iAUC)0–45 min and insulin secretion rate (ISR) calculated from C‐peptide deconvolution. β‐cell glucose sensitivity at steady state (second phase: 25–45 min), hepatic insulin extraction and insulin clearance were also calculated.
Results
Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0‐45, p = 0.035), first‐phase ISR by +110% (p = 0.034) and second‐phase ISR by +29% (p = 0.031). Imeglimin improved β‐cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (−13%; p = 0.056). Imeglimin did not affect glucagon secretion.
Conclusions
In patients with type 2 diabetes, imeglimin improves β‐cell function, which may contribute to the glucose‐lowering effect observed with imeglimin in clinical trials.
New‐onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation, but therapeutic strategies remain underexplored. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors ...selectively foster insulin secretion without inducing hypoglycemia, which might be advantageous in kidney transplant recipients (KTRs) with NODAT. We conducted a randomized, double‐blind, placebo‐controlled, phase II trial to assess safety and efficacy of the DPP‐4 inhibitor vildagliptin. Intraindividual differences in oral glucose tolerance test (OGTT)‐derived 2‐h plasma glucose (2HPG) from baseline to 3 months after treatment served as primary endpoint. Among secondary outcomes, we evaluated HbA1c, metabolic and safety parameters, as well as OGTTs at 1 month after drug discontinuation. Of 509 stable KTRs who were screened in our outpatient clinic, 63 (12.4%) had 2HPG ≥200 mg/dL, 33 of them were randomized and 32 completed the study. In the vildagliptin group 2HPG and HbA1c were profoundly reduced in comparison to placebo (vildagliptin: 2HPG = 182.7 mg/dL, HbA1c = 6.1%; placebo: 2HPG = 231.2 mg/dL, HbA1c = 6.5%; both p ≤ 0.05), and statistical significance was achieved for the primary endpoint (vildagliptin: 2HPG‐difference −73.7 ± 51.3 mg/dL; placebo: −5.7 ± 41.4 mg/dL; p < 0.01). Adverse events were generally mild and occurred at similar rates in both groups. In conclusion, DPP‐4 inhibition in KTRs with overt NODAT was safe and efficient, providing a novel treatment alternative for this specific form of diabetes.
In this randomized controlled trial, the authors report that vildagliptin significantly improves blood glucose metabolism and is safe in patients with newly diagnosed diabetes after kidney transplantation.
Abstract Background and aim Until recently, very few intervention studies have investigated the effects of whole-grain cereals on postprandial glucose, insulin and lipid metabolism, and the existing ...studies have provided mixed results. The objective of this study was to evaluate the effects of a 12-week intervention with either a whole-grain-based or a refined cereal-based diet on postprandial glucose, insulin and lipid metabolism in individuals with metabolic syndrome. Methods and results Sixty-one men and women age range 40–65 years, with the metabolic syndrome were recruited to participate in this study using a parallel group design. After a 4-week run-in period, participants were randomly assigned to a 12-week diet based on whole-grain products (whole-grain group) or refined cereal products (control group). Blood samples were taken at the beginning and end of the intervention, both fasting and 3 h after a lunch, to measure biochemical parameters. Generalized linear model (GLM) was used for between-group comparisons. Overall, 26 participants in the control group and 28 in the whole-grain group completed the dietary intervention. Drop-outs (five in the control and two in the whole-grain group) did not affect randomization. After 12 weeks, postprandial insulin and triglyceride responses (evaluated as average change 2 and 3 h after the meal, respectively) decreased by 29% and 43%, respectively, in the whole-grain group compared to the run-in period. Postprandial insulin and triglyceride responses were significantly lower at the end of the intervention in the whole-grain group compared to the control group ( p = 0.04 and p = 0.05; respectively) whereas there was no change in postprandial response of glucose and other parameters evaluated. Conclusions A twelve week whole-grain cereal-based diet, compared to refined cereals, reduced postprandial insulin and triglycerides responses. This finding may have implications for type 2 diabetes risk and cardiovascular disease.
Capturing agricultural heterogeneity through the analysis of farm typologies is key with regard to the design of sustainable policies and to the adoptability of new technologies. An optimal balance ...needs to be found between, on the one hand, the requirement to consider local stakeholder and expert knowledge for typology identification, and on the other hand, the need to identify typologies that transcend the local boundaries of single studies and can be used for comparisons. In this paper, we propose a method that supports expert-driven identification of farm typologies, while at the same time keeping the characteristics of objectivity and reproducibility of statistical tools. The method uses a range of multivariate analysis techniques and it is based on a protocol that favours the use of stakeholder and expert knowledge in the process of typology identification by means of visualization of farm groups and relevant statistics. Results of two studies in Zimbabwe and Kenya are shown. Findings obtained with the method proposed are contrasted with those obtained through a parametric method based on latent class analysis. The method is compared to alternative approaches with regard to stakeholder-orientation and statistical reliability.
Background:
Microvascular damage is a frequent feature in connective tissue diseases (CTDs) and can be easily detected trough nailfold videocapillaroscopy (NVC) (1,2). Mixed and Undifferentiated ...connective tissue diseases (MCTD and UCTD) do not show a specific and unique NVC pattern (3). However, a variety of microvascular abnormalities can occur in these two CTDs, both non-specific or specific for the scleroderma like-pattern (3-5).
Objectives:
To retrospectively assess and compare nailfold microangiopathy observed by NVC in MCTD and stable UCTD versus primary Raynaud’s phenomenon (PRP) (6). In addition, the aim was to correlate NVC findings with serum levels of autoantibodies (Abs) against extractable nuclear antigen (ENA) detected in UCTD.
Methods:
Files of fourty-six MCTD patients (Kasukawa’s criteria) (mean age 42.8±16 SD years), fourty-seven UCTD patients (mean age 47.7±16.1 SD years), fifty-one PRP (mean age 45.9±17.3 SD years) were retrospectively evaluated in the study. Among UCTD and MCTD patients 95% of both showed Raynaud’s phenomenon. Main NVC parameters (i.e. dilated capillaries, giant capillaries, microhemorrhages, abnormal shapes and number of capillaries) and related semiquantitative scale (score 0–3 for every parameter), were analyzed and compared between the two distinct CTD groups and PRP. Furthermore, ENA Abs (in particular, Ro/SSA, La/SSB, Scl70 and Jo1) were evaluated. The CTD patients were receiving different immunosuppressive treatments. Statistical analysis was performed by non-parametric tests.
Results:
Among UCTD group, 36% of patients showed a normal NVC pattern, 53% had non-specific NVC abnormalities and 11% had a scleroderma like-pattern. The latter was significantly more frequent in MCTD than in UCTD (p<0.001), in fact 22 out of 46 (48%) MCTD patients presented a scleroderma-like pattern. On the other hand, normal pattern or non-specific NVC abnormalities were respectively found in 9% and 43% MCTD patients. Therefore, CTD patients showing giant capillaries, abnormal shapes (i.e. angiogenesis) and lower capillary density were significantly more affected by MCTD than UCTD (p<0.001). Finally, the absolute number of capillaries was found significantly lower in MCTD versus UCTD patients (mean 7±1.7 SD vs mean 9.2±1 SD, respectively, p<0.001). Not any statistical correlation was observed between NVC parameters and specific Abs ENA in UCTD. PRP showed a normal NVC pattern in 2% and non-specific capillary abnormalities in 98%, (including dilated capillaries and microhemorrhages).
Conclusion:
NVC features in UCTD patients seem very close to the pattern observed in PRP (mostly non-specific capillary abnormalities), conversely in MCTD the scleroderma-like pattern was found significantly prevalent together with a significant capillary number reduction. The transition from the scleroderma-like to the scleroderma pattern (mean systemic sclerosis) is matter of actual investigation.
References:
1Cutolo M. et al. Best Pract Res Clin Rheumatol 2008; 22:1093-108.
2Sulli A, Ann Rheum Dis. 2008;67:885-7.
3Smith V. et al. Autoimmunity Reviews 2020; 19:102458.
4De Holanda Mafaldo DA, et al. Lupus. 2007; 16:254–8.
5Smith V, et al. Ann Rheum Dis 2010; 69: 1092-96.
6Antunes M, et al. RMD Open. 2019, 26;4.
Disclosure of Interests:
None declared
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