Analysis of the main risk factors for gestational diabetes diagnosed with International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria in multiple pregnancies.

INTRODUCTION: The aim is to investigate the proportion of multiple pregnancies with gestational diabetes mellitus (GDM) diagnosed using the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria and to identify the impact of age, body mass index (BMI), and mode of conception on incidence of GDM. MATERIALS AND METHODS: This is a single center, retrospective cohort study on 656 multiple pregnancies screened for GDM with 75-g, 2-h oral glucose tolerance test at 24-28 weeks of gestation, between January 2010 and January 2016. The diagnosis of gestational diabetes mellitus (GDM) was reached through the IADPSG. RESULTS: The incidence of GDM in our population was 15.1%. When patients who conceived through heterologous assisted reproduction technology were compared with those who conceived spontaneously, there was a significant difference for GDM (31.1 vs 13.6%, p < 0.001, OR 2.86). A similar finding was also observed comparing egg donation IVF/ICSI patients with homologous IVF/ICSI patients (31.1 vs 14.8%, p = 0.006, OR 2.59). Incidence of GDM was significantly higher in obese than in non-obese patients (42.5 vs 14.8%, p < 0.001, OR 4.88) and in women over 35 compared to younger patients (18.4 vs 11.1%, p = 0.01, OR 1.81). Logistic regression comparing the diabetes onset with conception mode gave a p = 0.07. The calculation of the Chi-square and odds ratio for single mode of conception showed that homologous vs conceived spontaneously p = 0.90, OR 0.97, heterologous vs homologous p = 0.01 with OR 2.46, and heterologous vs conceived spontaneously p = 0.01 with OR 2.39. Logistic regression showed that age and BMI are risk factors for developing GDM, respectively, p = 0.03 with OR 1.4 and p < 0.01 and OR 1.09. DISCUSSION: The contribution our study can make is improved counseling about GDM risks for couples with multiple pregnancies. Our data support the role of age, BMI, and mode of conception as risk factors for GDM in multiple pregnancies.

Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells.

TDP-43 is aggregated in patients with ALS and FLTD through mechanisms still incompletely understood. Since aggregation in the cytosol is most probably responsible for the delocalization and loss of proper RNA-binding function of TDP-43 in the nucleus, interception of the formation of aggregates may represent a useful therapeutic option. In this study, we investigated the relative importance of the N-terminal and C-terminal moieties of TDP-43 in the aggregation process and the weight of each of the six cysteine residues in determining unfolding and aggregation of the different domains. We report that cytoplasmic inclusions formed by WT and mutant TDP-43 in motor neuron-like NSC34 cells are redox-sensitive only in part, and contain at least two components, i.e. oligomers and large aggregates, that are made of different molecular species. The two N-terminal cysteine residues contribute to the seeding for the first step in oligomerization, which is then accomplished by mechanisms depending on the four cysteines in the RNA-recognition motifs. Cysteine-independent large aggregates contain unfolded isoforms of the protein, held together by unspecific hydrophobic interactions. Interestingly, truncated isoforms are entrapped exclusively in oligomers. Ab initio modeling of TDP-43 structure, molecular dynamics and molecular docking analysis indicate a differential accessibility of cysteine residues that contributes to aggregation propensity. We propose a model of TDP-43 aggregation involving cysteine-dependent and cysteine-independent stages that may constitute a starting point to devise strategies counteracting the formation of inclusions in TDP-43 proteinopathies.

Semen quality impairment is associated with sexual dysfunction according to its severity.

STUDY QUESTION: Is sexual dysfunction associated with severity of semen quality impairment in men with couple infertility? SUMMARY ANSWER: In males of infertile couples the prevalence of erectile dysfunction (ED) increases as a function of semen quality impairment severity. WHAT IS KNOWN ALREADY: Infertile men are at a higher risk for sexual dysfunction, psychopathological and general health disorders. However, it has never been systematically investigated if these problems are associated with severity of semen quality impairment. STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of a first-time evaluation of 448 males of infertile couples attending an outpatient clinic from September 2010 to November 2015. In addition, 74 age-matched healthy, fertile men from an ultrasound study on male fertility were studied for comparison. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent a complete physical, biochemical, scrotal and flaccid penile colour-Doppler ultrasound evaluation and semen analysis. Patients had already undergone at least one semen analysis; therefore, the majority were aware of their sperm quality before taking part in the study. Validated tools, such as the International Index of Sexual Function-15 (IIEF-15), Premature Ejaculation Diagnostic Tool (PEDT), Middlesex Hospital Questionnaire (MHQ), National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Chronic Disease Score (CDS), were used to evaluate, respectively, sexual dysfunction, premature ejaculation (PE), psychopathological traits, prostatitis-like symptoms, lower urinary tract symptoms and general health status. MAIN RESULTS AND THE ROLE OF CHANCE: Among men with couple infertility, 96 showed azoospermia (Group #1), 245 at least one sperm abnormality (Group #2) and 107 normozoospermia (Group #3). Fertile men were considered as a control group (Group #4). After adjusting for age, we observed a higher prevalence of ED (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men. The ED prevalence increases as a function of semen quality impairment severity (P < 0.0001), even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health: in this group, erectile function was negatively associated not only with psychopathological disturbances (MHQ total and MHQ-S scores; P < 0.0001) but also with a less healthy phenotype (higher CDS; P = 0.015). In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptoms. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional nature of the study represents its main limitation. A possible selection bias concerning the control group of healthy, fertile men recruited into an ultrasound study might have occurred. Finally, causality cannot be inferred in this type of study design and hence there should be some caution in interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: Investigation of male sexual function, general health and psychological status in infertile couples, especially if azoospermic, is advisable, in order to improve not only reproductive but also general and sexual health. STUDY FUNDING/COMPETING INTERESTS: Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: None.

Clinically relevant quality assurance for intensity modulated radiotherapy plans: gamma maps and DVH-based evaluation.

PURPOSE: To explore a novel patient-dose DVH-based method for pretreatment dose quality assurance tests. METHODS: 20 IMRT plans for head-and-neck cancer patients were used. A comparison was performed between the planned dose distributions, the computed, and the reconstructed ones using the gamma-index (GI) method. The GI analysis was performed using both the 3%/3 mm and the 2%/2 mm criteria. RESULTS: No significant DVH-deviation was observed. Considering the 3%/3 mm criteria the mean GI% < 1 for the body and structures was significantly higher compared to 2%/2 mm criteria. CONCLUSIONS: Our results underline the importance of QA-methods based on DVH-metrics to predict the impact of delivered dose.

Reprint of: Vitamin D receptor activation and prevention of arterial ageing.

In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

[Adjuvant radiochemotherapy in the elderly affected by glioblastoma: single-institution experience and literature review]. / Radiochemioterapia adiuvante nei pazienti anziani affetti da glioblastoma: esperienza di un singolo istituto e revisione della letteratura.

PURPOSE: Radiochemotherapy (RCT) is the standard adjuvant treatment for patients affected by glioblastoma (GBM). As there is no evidence in elderly patients with GBM, combined, single modality or best supportive care is used. The aim of this retrospective study was to evaluate acute toxicity and outcome of elderly patients with GBM treated with RCT with temozolomide (TMZ). MATERIALS AND METHODS: Patients >65 years with newly diagnosed GBM who underwent surgery or biopsy and RCT were evaluated. Recursive Partitioning Analysis (RPA) class and National Cancer Institute--Common Toxicity Criteria (NCI-CTC) version 3 were used to classify patients and evaluate acute toxicity, respectively. RESULTS: From April 2005 to January 2011, 35 patients (18 women and 17 men) with GBM were treated at our institution. Only 31.43% of cases underwent complete resection. Median progression-free survival (PFS) was 8 months and median overall survival (OS) 13 months. At univariate and multivariate analysis, only RPA class correlated with OS (p=0.01, p=0.03, respectively). During RCT, toxicity was mild (thrombocytopaenia G3-4, 11.43%; neurological toxicity, G3-4, 8.57%). CONCLUSIONS: Our data suggest that RCT with TMZ seems to produce a better outcome with a mild toxicity profile in elderly patients affected by GBM.

Third whole-brain radiation therapy for multiple brain metastases. Should it be considered in selected patients?

Whole brain reirradiation for the treatment of multiple brain metastases has shown promising results. However, concerns remain over the possible neurotoxic effects of the cumulative dose as well as the questionable radiosensitivity of recurrent metastases. A second reirradiation of the whole brain is ordinarily performed in our department for palliative purposes in patients presenting with multiple metastatic brain progression. For this study, an investigational third whole brain reirradiation has been administered to highly selected patients to obtain disease control and delay progression. Clinical outcomes and neurological toxicity were also evaluated.

Vitamin D receptor activation and prevention of arterial ageing.

In chronic kidney disease (CKD) patients, cardiovascular (CV) morbidity and mortality rate is higher than in the general population, because of frequently concomitant hypertension, peripheral vascular disease, heart failure, vascular calcification (VC), diabetes and mineral bone disease. Recently, another important factor associated to CV risk in CKD has been deeply investigated: vitamin D deficiency. Vitamin D Receptors (VDRs) are present in several systems and tissues and VDR activation is associated to positive effects, resulting in better blood pressure control and prevention of diabetic nephropathy. Unfortunately, the natural, non-selective vitamin D receptor activator (VDRA), calcitriol, is associated to higher serum calcium and phosphate levels, thus worsening CV risk in CKD. Recent data showed that the selective VDRA paricalcitol might have ameliorative CV effects. The potential positive impact of the use of paricalcitol on diabetic nephropathy, cardiac disease, hypertension, and VC may open new paths in the fight against CV disease in CKD patients.

Facial approximation for identification purposes: soft tissue thickness in a Caucasian population. Sex and age-related variations.

The aim of this study was to collect soft tissue thickness (STT) values of an Italian population from 12 bone landmarks, to improve the facial approximation process for identification purposes. 100 Italian adults (50 males and 50 females), who had undergone head CT for clinical purposes, were analysed in order to expand the database of the Italian population. Average values, standard deviation and range were collected according to gender and age and the obtained values were statistically analysed in order to evaluate any possible significant difference. Only one landmark was statistically significant associated with sex, females showed significantly higher values for para-zygomaxillary. Two landmarks were statistically significant associated with age, upper incisor and pogonion. The obtained results were compared with the existing literature. Such information can be useful in the forensic craniofacial reconstruction process and can facilitate choosing the most suitable STT values according to osteological analysis of the human remains.

Unsuccessful application of taurolidine in the treatment of fungal peritonitis in peritoneal dialysis.

Fungal peritonitis (FP) is a serious complication for peritoneal dialysis (PD) patients, determining hospitalization, technique failure, catheter loss and death. In the 2005 update, treatment recommendations for FP from the International Society of Peritoneal Dialysis (ISPD) advocate catheter removal immediately after fungi are identified by microscopy or culture. The availability of more effective medical treatments could therefore be of great importance. The aim of this report is to describe a case of a 43-year-old, diabetic, HIV positive PD patient with fluconazole resistant Candida peritonitis, who was treated with an i.p. taurolidine solution. Taurolidine is a non-antibiotic antimicrobial, with broad bactericidal and fungicidal properties. It has been used during surgery for lavage of the peritoneum in cases of peritonitis. Its mechanism of action is related to direct toxic action on micro-organisms, through a chemical reaction between active taurolidine derivatives and structures on the cell wall. Treatment failed because the patient had severe burning pain during i.p. administration of the drug, limiting its dose. PD catheter removal allowed complete recovery. It remains undetermined if, with different doses and methodology, taurolidine could be more effective in treating bacterial and/or fungal peritonitis. Currently, catheter removal remains the most effective therapy of fungal peritonitis.

Clinical significance of FGF-23 measurement in dialysis patients.

AIMS: Considering the growing relevance of fibroblast growth factor-23 (FGF-23) in the pathogenesis of chronic kidney disease bone and mineral disorder (CKD-MBD), an analysis was performed to determine the relative importance of C-terminal (cFGF-23) and intact (iFGF-23) assays in assessing CKD-MBD status in the first place and the relationship between FGF-23 and mortality as a secondary aim. METHODS: In 77 patients (15 peritoneal dialysis and 62 hemodialysis), levels of calcium, phosphate, parathyroid hormone (PTH), 25-hydroxyvitamin- D (25D), 1,25D, FGF-23 (C-terminal and intact molecule) were measured and their correlations were analyzed. The relationship between FGF-23 levels and patient survival was also analyzed. RESULTS: A significant correlation was found between cFGF-23 and 1,25D, PTH and 25D while iFGF-23 was significantly correlated with phosphate, 25D and PTH. PTH and 1,25D were independent predictors of cFGF-23, while for iFGF-23 independent predictors were phosphate and 25D. No significant relationship was found between FGF-23 and mortality. CONCLUSIONS: C-terminal or intact FGF-23 levels are weakly correlated and thus not clearly indicative of FGF-23 effects on PTH, P and vitamin D metabolism in dialysis patients. Assays for cFGF-23 and iFGF-23 showed a good correlation, but the intact molecule was not superior in defining interactions with CKD-MBD molecules. Measuring FGF-23 on a regular basis with the current assays in CKD and dialysis patients does not yet seem clinically useful.

Paricalcitol and outcome: a manual on how a vitamin D receptor activator (VDRA) can help us to get down the "U".

Modern strategies to prevent secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients give great relevance to vitamin D replacement therapy. However, a sound approach to treatment requires taking into account many factors, including stage of CKD, underlying renal disorder, levels of circulating PTH, bone status, vitamin D deposits, and serum calcium (Ca) and phosphate (P) levels. The aim of vitamin D replacement therapy should be to prevent SHPT from the early stages of CKD, because once parathyroid hyperplasia and osteodystrophy develop, they cannot be completely reverted. The therapeutic strategies for SHPT are now changing. The availability of VDRAs allows inhibition of parathyroid glands with less effect on calcium and phosphate levels, and perhaps reduces the mortality of dialysis patients. Actual objectives for treating CKD patients with new generation VDRAs are to retain or amplify the effects of calcitriol on PTH suppression, with no effects on serum Ca and P levels. Paricalcitol is such a new VDRA with minimal impact on serum Ca and P levels. Since cardiovascular disease is the leading cause of morbidity and mortality in dialysis patients, these data suggest that the beneficial effect associated with paricalcitol injection on patient survival is at least partially related to its effect on the cardiovascular system.

[Cardiovascular effects of VDR and CaSR activation]. / Effetti cardiovascolari dell'attivazione dei VDR e dei CaSR.

Cardiovascular complications are the most common cause of death in uremic patients, especially those on chronic dialysis. One of the major findings is massive calcium deposition in the vessel walls. There is general consensus about the correlation between the distribution of vascular calcification and increased risk of death due to cardiovascular disease. An emerging issue is the possible beneficial role of vitamin D receptor (VDR) activation in reducing the morbidity and mortality rates in patients on chronic dialysis, as shown in large, although retrospective, studies. Still open is the possible role of CaSR activators in ameliorating the clinical course of patients on dialysis, although calcimimetics are able to improve the Ca-P-PTH serum profile and increase the number of patients within the international guidelines parameters. This review has been structured to give the readers an updated opinion on the possible positive impact of VDR and CaSR activators in terms of all-cause and cardiovascular morbidity and mortality in dialysis patients.

[Prevention and treatment of secondary hyperparathyroidism in non-dialyzed patients with stage 3-5 chronic kidney diease]. / Prevenzione e trattamento dell'iperparatiroidismo secondario nel paziente con malattia renale cronica allo stadio 3-5 non in dialisi.

Deficiencies in vitamin D and vitamin D receptor (VDR) activation adversely affect cardiovascular health in the general population and in people at high risk of cardiovascular disease, as well as contributing to secondary hyperparathyroidism in patients with chronic kidney disease (CKD). Furthermore, epidemiological and observational data indicate that there is a close interrelationship between progressive renal dysfunction in CKD, cardiovascular disease, and mortality. The causes of death in patients even with only moderate kidney dysfunction are commonly associated with cardiovascular events. Modulation of vitamin D levels results in correlative regulatory effects on mineral homeostasis, hypertension, vascular disease, and calcification, as well as a number of other endpoints in cardiac and renal disease. The use of VDR activators to treat these and other parameters outside of cardiovascular and renal disease not only results in enhanced patient health but significantly lowers the risk of mortality in CKD and non-CKD patients with low systemic activity of vitamin D. The cardiovascular and renal systems continue to demonstrate their interrelated effects on each other, particularly when vitamin D and VDR signaling are considered.

[Pathogenesis and treatment of vascular calcification in CKD]. / Invecchiamento cardiovascolare nel soggetto uremico: nuove acquisizioni.

Increased vascular calcification is a major cause of cardiovascular events in patients with chronic kidney disease (CKD). It is the result of an active ossification process counteracted by ''bone'' proteins such as osteopontin, alkaline phosphatase, osteoprotegerin, and osteocalcin. Chronic kidney disease - mineral and bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in CKD. In addition to abnormalities in the serum calcium and phosphate profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification. Considering that the presence and extent of vascular calcification in CKD portend a poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent vascular calcium deposition and its progression. Indeed, careful control of calcium load, serum phosphate and parathyroid hormone along with the use of calcium-free phosphate binders and vitamin D receptor activators represent a new therapeutic armamentarium to improve quality of life and reduce mortality in CKD.

The mechanisms of hyperphosphatemia-induced vascular calcification.

Extensive calcification of the arterial wall and soft tissues is a frequent feature of patients with end-stage chronic kidney disease (CKD stage 5). Hyperphosphatemia and secondary hyperparathyroidism have been extensively investigated as inducing factors in cardiovascular calcification. In fact, cardiovascular disease in renal failure is associated with bone metabolism alterations. Together with passive deposition of calcium-phosphate in extraskeletal tissues, it has recently been demonstrated that inorganic phosphate induces arterial calcification directly through a real "ossification" of the tunica media in the vasculature of CKD patients. Therefore, control of serum phosphate in CKD patients becomes crucial in preventing increases in calcium x phosphate product, secondary hyperparathyroidism, and ultimately vascular calcification.

The management of viral hepatitis in CKD patients: an unresolved problem.

Chronic kidney disease (CKD) patients in dialysis (HD) show peculiar, atypical features of clinical presentation and diseases (cardiovascular, metabolic, hematologic). This is also true for viral hepatitis infections, for which CKD patients represent an important risk group. In the past, hepatitis B virus (HBV) was the major cause of viral hepatitis in end-stage renal disease (ESRD). However, the introduction of a rigorous infection-control strategy, routine screening of patients and staff for hepatitis B serologic markers, vaccination of susceptible patients and staff, use of separate rooms and dedicated machines for HD of HbsAg-positive patients have all led to a decline in the spread of HBV infection in dialysis. Despite the prevalence of the antibody-hepatitis C virus (HCV), there has been a marked decrease in HD patients; after the introduction of routine screening for HCV and the use of erythropoietin, its occurrence ranges from 5% to 25% in the United States, with a prevalence of 6.8% in Europe. In CKD and in HD patients, the presence of HBV and HCV is an independent and significant risk factor for death and this risk may be at least partially attributed to chronic liver disease with its attendant complications. Liver disease can progress with modest hepatic inflammation and prominent fibrosis; the natural history of viral hepatitis in these patients is dependent on the immune dysfunction typical of kidney disease. Despite recent advances in antiviral therapy, there are still many uncertainties in regards to the efficacy and long-term outcomes of treatment with antiviral agents.

Impaired brachial artery endothelial flow-mediated dilation and orthostatic stress in hemodialysis patients.

PURPOSE: Chronic kidney disease (CKD) is associated with an impaired endothelial function, which may contribute to cardiovascular events. Whether impairment in endothelial function is involved in the circulatory response to orthostatic stress is unknown. We assessed endothelial function via brachial artery flow-mediated dilation (BAFMD), an index of endothelial-dependent vasodilation. METHODS: We measured changes in brachial artery diameter (BAD) and blood flow by Doppler ultrasound in 35 CKD patients on hemodialysis, 37 young healthy controls (HC) and 50 non-uremic matched controls (MC), in the supine position and after 60 degrees head-up tilting (HUT). RESULTS: In the supine position, endothelial flow-mediated BAD was significantly increased in HC (p<0.001) and MC (p<0.01) while no significant changes were detected in CKD. Mean percent blood flow changes were HC+323.5%, MC+195.1% and CKD+158.8% (HC vs. CKD p<0.001; HC vs. MC p<0.001; MC vs. CKD p=0.04). Similarly, during HUT mean BAD and blood flow increases were significantly impaired in CKD patients. CONCLUSION: In CKD patients, an impaired response in the physiologic vascular reactivity, suggesting endothelial dysfunction, was found in the supine position and after orthostasis by BAFMD. Our results are in favor of a possible adjunctive role of uremia in the abnormal brachial artery response.

[Therapeutic options for mineral metabolism disorders in dialysis patients: a case report]. / Opzioni terapeutiche per la gestione clinica delle alterazioni del metabolismo minerale in dialisi: un caso clinico.

Mineral metabolism disorders are well-recognized complications in patients with chronic kidney disease (CKD). Furthermore, hyperphosphatemia and secondary hyperparathyroidism are associated with both renal osteodystrophy and cardiovascular disease. During the last 5 years, new therapeutic options have become available to treat these conditions in CKD. We describe the case of a 70-year-old lady with a dialysis history of 5 years and a number of cardiovascular risk factors (hypertension, hypercholesterolemia and obesity). Unfortunately, the patient was poorly compliant with any pharmaceutical treatment. After 2 years, a pharmacological approach with a low dosage of calcium salts and sevelamer HCl, subsequently changed to lanthanum carbonate, intravenous paricalcitol, and cinacalcet HCl reached the goals suggested by the current guidelines. Every nephrologist should look at the pathogenesis and treatment of hyperphosphatemia and secondary hyperparathyroidism. New options are now available and may help the clinician to obtain satisfactory short- and long-term outcomes in the treatment of this disease.