Titratable fixed-ratio combination of insulin glargine plus lixisenatide: A simplified approach to glycemic control in type 2 diabetes mellitus.

Abstract Approximately 50% of patients with type 2 diabetes mellitus (T2DM) do not achieve glycemic targets and require treatment intensification. A fixed-ratio combination of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with basal insulin, such as lixisenatide with insulin glargine (iGlarLixi), exploits the complementary mechanisms of action of each component to address hyperglycemia while mitigating potential adverse events (AEs). The iGlarLixi dose is titrated considering the effect of basal insulin on fasting plasma glucose, and the fixed-ratio combination ensures that the lixisenatide dose never exceeds 20 μg/day. We describe the characteristics of iGlarLixi therapy, based on the LixiLan clinical program, and provide guidance on the characteristics of patients likely to benefit from such treatment in routine clinical practice. In the phase III LixiLan trials, iGlarLixi resulted in significantly greater reductions in glycated hemoglobin (HbA1c), better achievement of HbA1c targets, less glycemic variability versus insulin glargine, lixisenatide or GLP-1 RA alone, and was associated with weight control, less hypoglycemia versus insulin glargine, and fewer GI AEs versus lixisenatide. Findings were consistent regardless of age, diabetes duration, and baseline HbA1c. The efficacy, safety, and convenient once-daily administration schedule of iGlarLixi make it a valuable treatment option for patients with T2DM requiring treatment intensification

Evidence for human diabetic cardiomyopathy.

Growing interest has been accumulated in the definition of worsening effects of diabetes in the cardiovascular system. This is associated with epidemiological data regarding the high incidence of heart failure (HF) in diabetic patients. To investigate the detrimental effects both of hyperglycemia and insulin resistance, a lot of preclinical models were developed. However, the evidence of pathogenic and histological alterations of the so-called diabetic cardiomyopathy (DCM) is still poorly understood in humans. Here, we provide a stringent literature analysis to investigate unique data regarding human DCM. This approach established that lipotoxic-related events might play a central role in the initiation and progression of human DCM. The major limitation in the acquisition of human data is due to the fact of heart specimen availability. Postmortem analysis revealed the end stage of the disease; thus, we need to gain knowledge on the pathogenic events from the early stages until cardiac fibrosis underlying the end-stage HF

Bone fragility in patients with diabetes mellitus: A consensus statement from the working group of the Italian Diabetes Society (SID), Italian Society of Endocrinology (SIE), Italian Society of Gerontology and Geriatrics (SIGG), Italian Society of Orthopaedics and Traumatology (SIOT)

Bone fragility is one of the possible complications of diabetes, either type 1 (T1D) or type 2 (T2D). Bone fragility can affect patients of different age and with different disease severity depending on type of diabetes, disease duration and the presence of other complications. Fracture risk assessment should be started at different stages in the natural history of the disease depending on the type of diabetes and other risk factors. The risk of fracture in T1D is higher than in T2D, imposing a much earlier screening and therapeutic intervention that should also take into account a patient's life expectancy, diabetes complications etc. The therapeutic armamentarium for T2D has been enriched with drugs that may influence bone metabolism, and clinicians should be aware of these effects.Considering the complexity of diabetes and osteoporosis and the range of variables that influ-ence treatment choices in a given individual, the Working Group on bone fragility in patients with diabetes mellitus has identified and issued recommendations based on the variables that should guide screening of bone fragility and management of diabetes and bone fragility: (A) ge, (B)MD, (C)omplications, (D)uration of disease, & (F)ractures (ABCD&F). Consideration of these parameters may help clinicians identify the best time for screening, the appropriate glycaemic target and anti-osteoporosis drug for patients with diabetes at risk of or with bone fragility.(c)& nbsp;2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved

Sensory Processing, Gastrointestinal Symptoms and Parental Feeding Practices in The Explanation of Food Selectivity: Clustering Children with and Without Autism

Children with Autism Spectrum Disorders are a group of neurodevelopmental disorders (ASD) and compared to Typically Developing Children (TDC), experience significantly more feeding problems. Food selectivity is a complex phenomenon that involves individual and contextual factors (sensory abnormalities, severity of behavioral problems, gastrointestinal disorders, parenting styles and so on). The clarification of these key factors is the aim of the current study, comparing a group of children with ASD with a group of TDC on different variables such as food selectivity, anthropometric measures, gastrointestinal symptoms, diet, sensory processing and caregiver feeding practices. Moreover, the same variables described above are studied using a classification model for both groups. Results display that parenting style, sensory anomalies and gastrointestinal symptoms were associated with food refusal of children. Moreover, it is possible to observe similar profiles in children with feeding problems in both groups. Autism Spectrum Disorders (ASD) are a group of neurodevelopmental disorders characterized by social communication deficit and a tendency to engage in a pattern of restricted and repetitive behaviors, in which sensory issues are included (American Psychiatric Association [APA], [1]). Children with ASD, compared to Typically Developing Children (TDC), experience significantly more feeding problems [2], with food selectivity being the most frequently reported. Food selectivity could be operationally defined on the basis of the occurrence of the following behaviours: food refusal, limited repertoires of food, high frequency single food intake [3]. Several research studies observed a prevalence between 70% and 80% of food selectivity among children with ASD [4-6], despite parents never having described their children as in appetent [7]. Klein and Nowak (1999) [8] found that 53% of children were reluctant to try new foods. Whiteley, Rodgers, and Shattok (2000) [9] indicated a prevalence of 83% of children with a restricted repertoire of foods eaten. Similarly, Schreck and Williams (2006) [6] found that 57% of children refused food, while 72% accepted limited variety. A more consistent prevalence was found by Lockner, Crowe, and Skipper (2008), [10] who thought that new foods refusal in children with ASD was higher compared to TDC (95% vs. 47%). Furthermore, children with ASD were characterized also by a limited variety of food intake (16% vs. 58%). However, Bandini et al. (2010) [3] found lower rates of refusal in both groups compared to previous studies (41.7% vs. 18.9%). Methodological differences in research studies such as different approach mechanisms may have accounted for conflicting results. Food selectivity in ASD is really important because it is linked to health risks for children, and it may require some medical intervention [11]. In fact, in a recent review by the same authors, BMI and other anthropometric values in children with autism seem to differ from that of TDC, along with nutritional insufficiency [12]. However, in this survey as well as other recent studies [13,14] this difference was not always confirmed, with the literature still seeming incomplete. At the same time several studies tried to identify some of the causes for food selectivity in children with ASD. Some researchers investigated the role of motor coordination disorders and/or gastrointestinal problems. Children with praxis difficulties may lack the necessary motor skills to adequately handle food, leading to negative emotions avoidance [15]. Also, researchers have found contrasting results in Gastrointestinal Disorders (GID). According to a recent survey, a higher frequency of GID may be associated with a more severe food selectivity in children with ASD [16], while for others, the two phenomena seem largely independent in children with autism [17]. Indeed, children with and without autism experiencing frequently bowel problems and/or gastroesophageal reflux could display more feeding-related problems, since they could try to avoid foods associated with adverse circumstances. On the other hand, many children with autism commonly well-defined as picky or choosy eaters do not show gastrointestinal issues. In fact, other authors explained food selectivity in children with ASD as a consequence of repetitive behaviour and restricted interests [18,19]. However, the most accepted etiological hypothesis would seem to postulate a relationship between sensory perception abnormalities and rejection of food [20] both from children with typical and atypical development. As shown by Nadon, Feldman, Dunn, and Gisel (2011) [21], almost 90% of children with ASD show impairment in sensory processing information, including a hypo and or hypersensitivity to environmental stimuli. The differences in sensory processing in children with ASD have been well documented [22]. These abnormalities have been associated with both behavioural and emotional problems [23,24] and the severity of symptoms [25]. Since foods have several properties which can stimulate sense organs, it is possible that children who have sensory perception alteration might refuse them to a greater extent as they are more or less stimulating. From interviews with parents and behavioural observations it has been proven that children with ASD are adverse towards food characteristics such as texture, smell, taste and temperature [10,14,23,26-28], yet other food properties seem to be more important to them such as brand, packaging (patterns/colours), food presentation and even cutlery [4,6,9]. Finally, eating behaviours not only have a biological matrix but are also influenced by social and cultural variables [29], therefore it’s possible that in addition to the individual dimensions, parental feeding practices can also play a significant role in food selectivity. Currently, a research study [13] evaluated the parental feeding style and the food selectivity in children with ASD, indicating strategies as prompting/encouragement as the most used among parents. This direction of research is of particular interest not only scientifically but also in the way of application. If a relationship between parental feeding practices and food selectivity is found, it will be possible to devise intervention programs aimed at promoting functional parenting styles in order to achieve healthy eating behaviors. Hence, the aim of the current study is to compare a group of children with ASD with a group of TDC on different variables such as food selectivity, weight, gastrointestinal disorders, diet, sensory process and caregiver feeding practices. To sum up, we want to explore the following research questions: a) if the group of children with ASD shows more levels of food selectivity than controls; b) if the children with ASD report lower scores of BMI than controls; c) if the clinical group shows more sensory abnormalities than controls; d) if an association between food selectivity, BMI, GID, sensory dimensions and parental feeding styles can be established in both groups of children, e) if it is possible to discover similar profiles of children in both groups

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients

Scaling behaviour of braided active channels: a Taylor’s power law approach

none9At a channel (reach) scale, braided channels are fluvial, geomorphological, complex systems that are characterized by a shift of bars during flood events. In such events water flows are channeled in multiple and mobile channels across a gravel floodplain that remain in unmodified conditions. From a geometrical point of view, braided patterns of the active hydraulic channels are characterized by multicursal nature with structures that are spatially developed by either simple- and multi-scaling behavior. Since current studies do not take into account a general procedure concerning scale measurements, the latter behavior is still not well understood. The aim of our investigation is to analyze directly, through a general procedure, the scaling behavior of hydraulically active channels per transect and per reach analyzed. Our generalized stochastic approach is based on Taylor’s law, and the theory of exponential dispersion distributions. In particular, we make use of a power law, based on the variance and mean of the active channel fluctuations. In this way we demonstrate that the number of such fluctuations with respect to the unicursal behavior of the braided rivers, follows a jump-process of Poisson and compound Poisson–Gamma distributions. Furthermore, a correlation is also provided between the scaling fractal exponents obtained by Taylor’s law and the Hurst exponents.Samuele De Bartolo, Stefano Rizzello, Ennio Ferrari, Ferdinando Frega, Gaetano Napoli, Raffaele Vitolo, Michele Scaraggi, Carmine Fallico, Gerardo SeverinoDE BARTOLO, Samuele; Rizzello, Stefano; Ferrari, Ennio; Frega, Ferdinando; Napoli, Gaetano; Vitolo, Raffaele; Scaraggi, Michele; Fallico, Carmine; Severino, Gerard

Integration of HVSR measures and stratigraphic constraints for seismic microzonation studies: the case of Oliveri (ME)

Because of its high seismic hazard the urban area of Oliveri has been subject of first level seismic microzonation. The town develops on a large coastal plain made of mixed fluvial/marine sediments, overlapping a complexly deformed substrate. In order to identify points on the area probably suffering relevant site effects and define a preliminary Vs subsurface model for the first level of microzonation, we performed 23 HVSR measurements. A clustering technique of continuous signals has been used to optimize the calculation of the HVSR curves. 42 reliable peaks of the H/V spectra in the frequency range 0.6–10 Hz have been identified. A second clustering technique has been applied to the set of 42 vectors, containing Cartesian coordinates, central frequency and amplitude of each peak to identify subsets which can be attributed to continuous spatial phenomena. The algorithm has identified three main clusters that cover significant parts of the territory of Oliveri. The HVSR data inversion has been constrained by stratigraphic data of a borehole. To map the trend of the roof of the seismic bedrock, from the complete set of model parameters only the depth of the seismic interface that generates peaks fitting those belonging to two clusters characterized by lower frequency has been extracted

Pretreatment with verapamil in patients with persistent or chronic atrial fibrillation who underwent electrical cardioversion

AbstractOBJECTIVESTo evaluate, in a prospective and randomized fashion, the efficacy of a pretreatment with verapamil (V) in reducing recurrences of atrial fibrillation (AF) after electrical cardioversion (C).BACKGROUNDThe increased vulnerability for AF recurrence is probably due to AF-induced changes in the electrophysiologic properties of the atria. This electrical remodeling seems to be due to intracellular calcium overload.METHODSOne hundred seven patients with persistent or chronic AF underwent external and/or internal C. All patients received oral propafenone (P) (900 mg/day) three days before and during the entire period of follow-up (three months). In the first group, patients received only the P. In the second group, in adjunct to P, oral V (240 mg/day) was initiated three days before C and continued during the follow-up. Finally, in the third group, oral V was administered three days before and continued only for three days after electrical C.RESULTSDuring the three months of follow-up, 23 patients (23.7%) had AF recurrence. Mantel-Haenszel cumulative chi-square reached a significant level only when comparing AF free survival curves of group I versus group II and group III (chi-square = 5.2 and 4, respectively; p < 0.05). Significantly, 15 (65.2%) AF relapses occurred during the first week after cardioversion with a higher incidence in group I (10/33 patients, 30.3%) than group II (2/34 patients, 5.9%; p = 0.01) and group III (3/30 patients, 10%; p = 0.04).CONCLUSIONSSix days of oral V administration centered on the C day, combined with P, significantly reduce the incidence of early recurrences of AF compared with P alone

Evidence of key role of Cdk2 overexpression in pemphigus vulgaris

The pathogenesis of pemphigus vulgaris (PV) is still poorly understood. Autoantibodies present in PV patients can promote detrimental effects by triggering altered transduction of signals, which results in a final acantholysis. To investigate mechanisms involved in PV, cultured keratinocytes were treated with PV serum. PV sera were able to promote the cell cycle progression, inducing the accumulation of cyclin-dependent kinase 2 (Cdk2). Microarray analysis on keratinocytes detected that PV serum induced important changes in genes coding for one and the same proteins with known biological functions involved in PV disease (560 differentially expressed genes were identified). Then, we used two different approaches to investigate the role of Cdk2. First, small interfering RNA depletion of Cdk2 prevented cell-cell detachment induced by PV sera. Second, pharmacological inhibition of Cdk2 activity through roscovitine prevented blister formation and acantholysis in the mouse model of the disease. In vivo PV serum was found to alter multiple different pathways by microarray analysis (1463 differentially expressed genes were identified). Major changes in gene expression induced by roscovitine were studied through comparison of effects of PV serum alone and in association with roscovitine. The most significantly enriched pathways were cell communication, gap junction, focal adhesion, adherens junction, and tight junction. Our data indicate that major Cdk2-dependent multiple gene regulatory events are present in PV. This alteration may influence the evolution of PV and its therapy. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc