Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Physical Activity and Type 2 Diabetes: In Search of a Personalized Approach to Improving ß-Cell Function.

Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual ß-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and ß-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on ß-cell function.

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Patterns in ano-rectal dose maps and the risk of late toxicity after prostate IMRT.

Purpose: The aim of this work was to determine how the spatial pattern of dose in the ano-rectal wall is related to late gastro-intestinal toxicity for prostate cancer patients treated with mainly IMRT.Patients and methods: Patients from the DUE-01 multicentre study with patient-reported (prospective) follow-up and available dosimetric data were included. Conventionally fractionated patients received 74-80 Gy and hypofractionated patients received 65-75.2 Gy. A large majority of the patients were treated with intensity-modulated radiotherapy (IMRT). Dose-surface maps (DSMs) for the anal canal and rectum as a single structure, and for the anal canal and the rectum separately, were co-registered rigidly in two dimensions and, for the patients with and without toxicity, respectively, the mean value of the dose in each pixel was calculated. A pixel-wise t-test was used to highlight the anatomical areas where there was a significant difference between the 'mean dose maps' of each group. Univariate models were also fitted to a range of spatial parameters. The endpoints considered were a mean grade ≥1 late fecal incontinence and a maximum grade ≥2 late rectal bleeding.Results: Twenty-six out of 213 patients had fecal incontinence, while 21/225 patients had rectal bleeding. Incontinence was associated with a higher dose in the caudal region of the anal canal; the most relevant spatial parameter was the lateral extent of the low and medium isodoses (5-49 Gy in EQD2). Bleeding was associated with high isodoses reaching the posterior rectal wall. The spatial dose parameters with the highest AUC value (.69) were the lateral extent of the 60-70 Gy isodoses.Conclusions: To avoid fecal incontinence it is important to limit the portion of the anal canal irradiated. Our analysis confirms that rectal bleeding is a function of similar spatial dose parameters for patients treated with IMRT, compared to previous studies on patients treated with three-dimensional conformal radiotherapy.

Potential cause-effect relationship between insulin autoimmune syndrome and alpha lipoic acid: Two case reports.

OBJECTIVES: Insulin autoimmune syndrome (IAS) or Hirata disease is a rare cause of autoimmune hypoglycemia with apparent high insulin levels and anti-insulin autoantibodies and was first described by Hirata in Japan in 1970. IAS cases are usually related to exposure to sulfhydryl-containing drugs, which stimulate the production of insulin autoantibodies. Among sulfhydryl-containing compounds, alpha lipoic acid (ALA) has recently emerged as a cause of IAS. After the first observations of ALA-induced IAS were reported in Japan in 2006, an increasing number of cases related to ALA administration have been described. An Italian group recently reported on six cases of IAS of which one was associated with HLA-DRB1*04:06 and the remaining five with HLA-DRB1*04:03. This suggests that the latter is potentially involved in the genetic susceptibility of people of European descent to IAS. METHODS: Here, we describe two new cases of IAS in women that were triggered by ALA. RESULTS: Both cases are associated with HLA-DRB1*04:03 and confirm the evidence that HLA-DRB1*04:03 rather than HLA-DRB1*04:06 is specifically related to IAS susceptibility in Europeans. CONCLUSIONS: Case reports of ALA-induced hypoglycemic episodes highlight the need for greater care in prescribing ALA supplementation as well as the identification of specific and personalized therapeutic targets.

Characterization of a New Dry Drill-Milling Process of Carbon Fibre Reinforced Polymer Laminates.

Carbon Fibre Reinforced Polymer (CFRP) composites are widely used in aerospace applications that require severe quality parameters. To simplify the assembly operations and reduce the associated costs, the current trend in industry is to optimize the drilling processes. However, the machining of CFRP composites is very challenging compared with metals, and several defect types can be generated by drilling. The emerging process of orbital drilling can greatly reduce the defects associated with the traditional drilling of CFRP, but it is a more complex process requiring careful process parameters selection and it does not allow for the complete elimination of the thrust force responsible for delamination damage. As an alternative to traditional and orbital drilling, this work presents a new hole making process, where the hole is realized by a combination of drilling and peripheral milling performed using the same cutting tool following a novel tool path strategy. An original tool design principle is proposed to realize a new drill-milling tool, made of a first drilling and a subsequent milling portion. Two different tool configurations are experimentally tested to evaluate the performance of the newly-conceived combined drill-milling process. This process is quick and easy, and the experimental results show an improvement in the drilled hole quality.

Cognitive dysfunctions in occipital lobe epilepsy compared to temporal lobe epilepsy.

OBJECTIVE: To compare cognitive profiles of occipital lobe epilepsy (OLE) and temporal lobe epilepsy (TLE) and to investigate whether impairment of visuospatial functions is a specific deficit of OLE. METHOD: Eighteen patients with OLE, 18 patients with TLE, and 18 controls underwent a neuropsychological battery assessing memory, visuospatial functions, and frontal/executive functions. RESULTS: Multivariate analysis evidenced poorer performance of patients with TLE and patients with OLE relative to controls on tasks assessing verbal and non-verbal long-term memory, frontal functions, and visuospatial functions. Patients with OLE had poorer performance than patients with TLE on visuospatial tasks, whereas patients with TLE performed worse than patients with OLE on verbal long-term memory test. Discriminant analysis identified two canonical discriminant functions: The first explained 53.3% of the variance, and the second explained 46.7% of the variance. The first function included verbal and non-verbal memory tests distinguishing controls from both OLE and TLE, whereas the second factor including a visuoconstructional test distinguished OLE from TLE and controls. CONCLUSIONS: The results demonstrate that visuoconstructional dysfunction is related to OLE and support the idea that alterations of occipito-parietal stream may be specific to patients with OLE.

Baseline status and dose to the penile bulb predict impotence 1 year after radiotherapy for prostate cancer.

AIM: To assess the predictors of the onset of impotence 1 year after radiotherapy for prostate cancer. PATIENTS AND METHODS: In a multi-centric prospective study, the International Index of Erectile Function (IIEF) questionnaire-based potency of 91 hormone-naïve and potent patients (IIEF1-5 > 11 before radiotherapy) was assessed. At the time of this analysis, information on potency 1 year after treatment was available for 62 of 91 patients (42 treated with hypofractionation: 2.35-2.65 Gy/fr, 70-74.2 Gy; 20 with conventional fractionation: 74-78 Gy). Prospectively collected individual information and Dmax/Dmean to the penile bulb were available; the corresponding 2 Gy-equivalent values (EQD2_max/EQD2_mean) were also considered. Predictors of 1­year impotency were assessed through uni- and multi-variable backward logistic regression: The best cut-off values discriminating between potent and impotent patients were assessed by ROC analyses. The discriminative power of the models and goodness-of-fit were measured by AUC analysis and the Hosmer-Lemeshow (H&L) test. RESULTS: At 1­year follow-up, 26 of 62 patients (42 %) became impotent. The only predictive variables were baseline IIEF1-5 values (best cut-off baseline IIEF1-5 ≥ 19), Dmax ≥ 68.5 Gy and EQD2_max ≥ 74.2 Gy. The risk of 1­year impotence may be predicted by a two-variable model including baseline IIEF1-5 (OR: 0.80, p = 0.003) and EQD2_max ≥ 74.2 Gy (OR: 4.1, p = 0.022). The AUC of the model was 0.77 (95% CI: 0.64-0.87, p = 0.0007, H&L: p = 0.62). The 1­year risk of impotency after high-dose radiotherapy in potent men depends on the EQD2_max to the penile bulb and on baseline IIEF1-5 values. CONCLUSION: A significant reduction in the risk may be expected mainly when sparing the bulb in patients with no/mild baseline impotency (IIEF1-5 > 17).

Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy.

PURPOSE/OBJECTIVE: Prospectively assessing clinical/dosimetry factors affecting the acute worsening of urinary functionality after radiotherapy for prostate cancer. MATERIAL/METHODS: DUE01 population was considered, including patients treated with conventional or moderate hypo-fractionation (2.2-2.7 Gy/fr). Relevant clinical factors were collected, urinary symptoms were self-reported through the International Prostate Symptom Score (IPSS) before and at the end of radiotherapy; while absolute weekly dose-surface histograms (DSHw) were chosen as dosimetry descriptors. An IPSS increase of at least 10 and 15 points (ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15) were chosen as endpoints. Patients with baseline IPSS>20 were excluded. Relevant factors were chosen through a bootstrap-based in silico methodology. RESULTS: Complete information was available for 380 patients: 77/380 (20%) and 28/380 (7%) with ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15, respectively. Neoadjuvant hormone was protective (OR=0.49 and 0.69). DSHw at 8.5 Gy/week and 12 Gy/week were risk factors, with additional risk for patients who use cardiovascular drugs and anti-hypercholesterolemia drugs. In the hypo-fractionated subgroup (n=209) the role of cardiovascular drugs (OR=2.16) for ΔIPSS ⩾ 10 and anti-hypercholesterolemia drugs (OR=2.80) for ΔIPSS⩾15, together with DSHw (10 Gy/week and 12.5 Gy/week, respectively), was confirmed. CONCLUSION: Current study shows a dose-surface/volume effect for acute large worsening of urinary functionality; several clinical variables largely impact the risk and especially all the factors related with vascular diseases.

Body Constraints on Motor Simulation in Autism Spectrum Disorders.

Developmental data suggested that mental simulation skills become progressively dissociated from overt motor activity across development. Thus, efficient simulation is rather independent from current sensorimotor information. Here, we tested the impact of bodily (sensorimotor) information on simulation skills of adolescents with Autism Spectrum Disorders (ASD). Typically-developing (TD) and ASD participants judged laterality of hand images while keeping one arm flexed on chest or while holding both arms extended. Both groups were able to mentally simulate actions, but this ability was constrained by body posture more in ASD than in TD adolescents. The strong impact of actual body information on motor simulation implies that simulative skills are not fully effective in ASD individuals.

Cognitive and affective theory of mind in patients with essential tremor.

The theory of mind (ToM) is the ability to attribute mental states to oneself and others and to understand that others have beliefs, desires and intentions different from one's own. The aim of the present study was to explore the neuropsychological correlates of cognitive and affective ToM in patients affected by essential tremor (ET). Thirty consecutive ET outpatients and 30 healthy age-, sex- and education-matched control subjects underwent tasks assessing short-term memory, verbal learning and executive functions, as well as tasks assessing "cognitive" and "affective" ToM; questionnaires evaluating behavioral disorders and quality of life were also administered. Although the two groups did not differ on demographic variables, ET patients scored worse on memory tasks, and showed more apathy and worse quality of life than controls. After covarying for mnestic, behavioral and quality of life scores, ET patients achieved significantly lower scores than controls on task assessing cognitive ToM, whereas no difference was found between the two groups on task assessing affective ToM. In ET, "Cognitive" ToM was significantly associated with frontal tasks, whereas "Affective" ToM was not correlated with cognitive, behavioral or quality of life scales. Our results indicate that cognitive aspects of ToM may be selectively impaired in ET. Possible underlying neural mechanisms of the deficits are discussed.

Neuropsychological profile of adult patients with nonsymptomatic occipital lobe epilepsies.

To explore the neuropsychological and neurobehavioral profile in adult patients affected by nonsymptomatic (cryptogenic and idiopathic) occipital lobe epilepsy (OLE), with normal intelligence, we enrolled 20 adult patients with nonsymptomatic OLE and 20 age-, sex-, and education-matched healthy subjects. All participants underwent neuropsychiatric assessment scales, and standardized neuropsychological tests tapping memory, executive functions, constructional, visuospatial and visuoperceptual skills. After Bonferroni correction for multiple comparisons, patients performed significantly worse than controls on several tests tapping complex visuospatial skills and frontal lobe functions. The analysis of single patients' performance revealed that a significantly higher number of OLE patients achieved age- and education-adjusted pathological scores on three tests (Benton Judgment of Line Orientation Test, Freehand Copying of Drawings Test, color-word interference task of Stroop test) with respect to controls. Patients did not differ from control subjects on neuropsychiatric aspects. The direct comparison between OLE subtypes showed that cryptogenetic OLE patients tended to achieve lower scores than idiopathic OLE patients on most tests, but no difference between the two groups was fully significant. In summary, patients with nonsymptomatic OLE can be affected by clinically relevant impairments in selected neuropsychological domains: complex visuospatial skills and executive functions. It could be speculated that frontal and visuospatial cognitive deficits might be the result of epileptic activity spreading within a neural network that includes structures far beyond the occipital lobe.