The primary role of radiological imaging in the diagnosis of rare musculoskeletal diseases. Emphasis on ultrasound.

Objective: In July 2017 a multidisciplinary clinical Center specialized in rare diseases was activated. A rare disease can involve the musculoskeletal system. A multimodality musculoskeletal imaging approach allows for a rapid diagnosis. The purpose of this study was to assess when musculoskeletal radiology, ultrasound in particular, plays a primary role in the diagnostic path of a rare disease. Methods and materials: The Center included a list of 621 main rare diseases. Pathologies in which radiology has a primary diagnostic role were extracted from the list. From September 2017 to January 2018 all conditions involving the musculoskeletal system, including the peripheral nervous system, were systematically evaluated by one radiologist. The second radiologist, an official consultant of the Center, verified the list for consistency. Descriptive analysis was performed. Results: A total of 101/621 (16%) rare diseases can be diagnosed for the first time in the diagnostic path of the patient with medical imaging. A total of 36/101 (36%) rare diseases involve the musculoskeletal system. A total of 14/36 (39%) are pediatric diseases, 10/36 (28%) are adult age diseases, while 12/36 (33%) diseases affect all ages. A total of 23/36 (64%) of the selected rare diseases could be diagnosed with MRI, 19/36 (53%) with CT, 23/36 (64%) with X-ray, 9/36 (25%) with an US, and 1/36 (3%) with PET. Conclusions: Musculoskeletal imaging could be important for a non-invasive diagnosis in up to 36/101 (36%) rare diseases, as well as for outcome prediction, especially in pediatrics. Musculoskeletal imaging plays a crucial role in the diagnosis of rare diseases and could strongly influence the clinical pathway. Ultrasound is crucial in up to 25% of patients with rare diseases affecting the musculoskeletal system.

Conscientious Objection to Animal Testing: A Preliminary Survey Among Italian Medical and Veterinary Students.

The use of animals for educational and research purposes is common in both veterinary and human medicine degree courses, and one that involves important ethical considerations. The aim of this study was to assess the extent of differences between the knowledge and attitudes of veterinary students and medical students on animal bioethics, on alternative strategies and on their right to conscientiously object to animal experimentation. To this end, a questionnaire was completed by 733 students (384 human medicine students (HMS) and 349 veterinary medicine students (VMS)). VMS were more aware than HMS (72.2% and 59.6%, respectively) of the existence of an Italian law on the right to conscientiously object to animal experimentation. However, very few of them had exercised this right. Many VMS (43.3%) felt that animal bioethics courses should be mandatory (only 17.4% of HMS felt the same way). More VMS than HMS (81.7% and 59.1%, respectively) expressed an interest in attending a course on alternatives to animal experimentation. The data suggest the need for appropriate educational interventions, in order to allow students to make choices based on ethical principles. Fostering close collaborations between departments of human medicine and veterinary medicine, for example, through shared study modules, could promote the development of ethical competence as a basic skill of students of both veterinary and human medicine courses.

Bioethics in Italian Medical and Healthcare Education. A Pilot Study.

BACKGROUND AND AIM OF THE WORK: Bioethics is relevant in healthcare and medical schools. However, unlike other foreign countries, its teaching in Italy has only been recently introduced, it is less extensively offered and no academic standards for bioethics education have been established. This research aims at understanding whether university bioethics courses attendees appreciate and consider teaching strategies to be effective with the objective of validating a coherent didactic approach to the discipline and stimulate further discussion on ways to improve it. METHODS: A standardized survey was administered to 1590 students attending undergraduate degree programs in medicine and healthcare at four Italian universities. RESULTS: The majority of interviewees (92.5%) had an interest in bioethics, considered it to be important for any life-sciences-related program (73.5%) and most healthcare (77.2%) and medical students (69.2%) suggested its teaching should be included in their curricula and made mandatory (66.3%) and continuous (57.7%), given its usefulness in clinical practice. Students consider bioethics as a care-integrated practice and appreciate teaching methods where it is integrated into clinical cases. Conceptual specificity and interdisciplinarity may affect the learning process and contribute to enhance students' analytical skills. CONCLUSIONS: Italian bioethics education should be revised to meet students' expectations and preferences. Its complex, multi-disciplinary and transversal nature suggests bioethical education to be flexible and integrated among different disciplines, thus stimulating a broader critical capacity through cases studies and other interactive teaching methods for helping students better deal with bioethics-inherent difficulties and improve the learning process.

Chronic Intake of Micrograms of Abscisic Acid Improves Glycemia and Lipidemia in a Human Study and in High-Glucose Fed Mice.

We tested the effect of chronic low-dose abscisic acid (ABA), a phytohormone-regulating human glucose tolerance, on the metabolic parameters that are dysregulated in prediabetes and metabolic syndrome (MS).Ten healthy subjects received 1 µg ABA/Kg body weight (BW)/day as an ABA-rich food supplement: (i) the glycemia profile after a carbohydrate-rich meal, with or without supplement, was compared; (ii) fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), and body mass index (BMI) after 75 days of daily supplementation of a habitual Mediterranean diet were compared with starting values.CD1 mice were fed a high-glucose diet with or without synthetic ABA (1 µg/Kg BW) for 4 months and the same parameters investigated in the human study were compared. The food supplement significantly reduced the area under the curve of glycemia after a carbohydrate-rich meal and FBG, HbA1c, TC, and BMI after chronic treatment. ABA-treated mice showed a significant reduction of HbA1c, TC, and body weight gain compared with untreated controls. The combined results from the human and murine studies allow us to conclude that the observed improvement of the metabolic parameters can be attributed to ABA and to advocate the use of ABA-containing food supplements in prediabetes and/or MS.

Oculo-auriculo-vertebral spectrum with myopathy and velopharyngeal insufficiency. A case report with a non-branchiomeric muscle biopsy.

In the present paper we report on a case of oculo-auriculo-vertebral spectrum presenting fluorescence in situ hybridization and comparative genomic hybridization tests negative, hypotonia of some branchiomeric muscles (with velo-pharyngeal insufficiency, dysphagia and nasal voice) and non-branchiomeric muscles (with strabismus and limb hypotrophy). On the basis of the left quadriceps muscle biopsy, showing anisometry and prevalence of type 1 fibers, and on literature data, we underline the relevance of TBX1 gene (regulator of neural crest cells and activator of myogenic factors in branchiomeric muscles development) and of PAX3 gene (present in neural crest, inducing migration of these cells and reported in non-branchiomeric muscles). We conclude that the case of OAVS presented a generalized myopathy and we hypothesize that a cluster of genes strictly neural crest cells related, including TBX1 and PAX3, may be responsible of the branchiomeric and non-branchiomeric myopathy; alternatively, a regulatory mechanism abnormally common to OAVS and velo-cardio-facial syndrome could be present.

Lower limb ischemia due to long-term abuse of cocaine.

: Cocaine is the most commonly used recreational drug among young adults with levels reaching epidemics proportions. This accelerated rate of use is due mainly to easy access and administration, reduced cost, and, importantly, underestimation of the drug risks. Cocaine, instead, is responsible of endothelial dysfunction and accelerated atherosclerosis with consequent organ damage. Cocaine abuse is not only associated with central necrotizing vasculitis, but it is also appeared to play a role in the development of peripheral vasoconstriction with symptoms similar to Buerger's disease. The current study reports a middle-aged man addicted to cocaine for 20 years. The patient presents several cardiovascular disease risk factors and manifestations, including diabetes mellitus and hypertension. Additionally, arteriography showed complete left posterior tibial artery obstruction with distal collateral vessels and severe leftfoot ischemia. For clinical worsening 1 month later, the patient underwent another arteriography. Although angioplasty of posterior tibial artery showed recovery of blood flow, immediately after treatment (selective percutaneous transluminal angioplasty of posterior tibial artery, dilation with balloon without stenting), a return to pretreatment blood flow 2 min later was observed. This transient change was mediated by severe vasospasm resulting in a complete re-obstruction of the vessel. The poor vascular manifestations are most probably due to cocaine-necrotizing vasculitis subsequent to endothelial dysfunction and accelerated atherosclerosis usually associated with cardiovascular risk factors. Therefore, treatments of young cocaine addicts presenting many cardiovascular risk factors and manifestations should always be carefully investigated and cautiously approached, especially in those with poor outcomes.

Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans.

2-Cis,4-trans-abscisic acid (ABA) is a plant hormone that is present also in animals. Several lines of evidence suggest that ABA contributes to the regulation of glycemia in mammals: nanomolar ABA stimulates insulin release from ß-pancreatic cells and glucose transporter-4-mediated glucose uptake by myoblasts and adipocytes in vitro; plasma ABA increases in normal human subjects, but not in diabetic patients, after a glucose load for an oral glucose tolerance test (OGTT). The presence of ABA in fruits prompted an exploration of the bioavailability of dietary ABA and the effect of ABA-rich fruit extracts on glucose tolerance. Rats underwent an OGTT, with or without 1 µg/kg ABA, either synthetic or present in a fruit extract. Human volunteers underwent an OGTT or a standard breakfast and lunch, with or without a fruit extract, yielding an ABA dose of 0.85 or 0.5 µg/kg, respectively. Plasma glucose, insulin, and ABA were measured at different time points. Oral ABA at 0.5-1 µg/kg significantly lowered glycemia and insulinemia in rats and in humans. Thus, the glycemia-lowering effect of low-dose ABA in vivo does not depend on an increased insulin release. Low-dose ABA intake may be proposed as an aid to improving glucose tolerance in patients with diabetes who are deficient in or resistant to insulin.

Impaired increase of plasma abscisic Acid in response to oral glucose load in type 2 diabetes and in gestational diabetes.

The plant hormone abscisic acid (ABA) is present and active in humans, regulating glucose homeostasis. In normal glucose tolerant (NGT) human subjects, plasma ABA (ABAp) increases 5-fold after an oral glucose load. The aim of this study was to assess the effect of an oral glucose load on ABAp in type 2 diabetes (T2D) subjects. We chose two sub-groups of patients who underwent an oral glucose load for diagnostic purposes: i) 9 treatment-naive T2D subjects, and ii) 9 pregnant women with gestational diabetes (GDM), who underwent the glucose load before and 8-12 weeks after childbirth. Each group was compared with matched NGT controls. The increase of ABAp in response to glucose was found to be abrogated in T2D patients compared to NGT controls. A similar result was observed in the women with GDM compared to pregnant NGT controls; 8-12 weeks after childbirth, however, fasting ABAp and ABAp response to glucose were restored to normal in the GDM subjects, along with glucose tolerance. We also retrospectively compared fasting ABAp before and after bilio-pancreatic diversion (BPD) in obese, but not diabetic subjects, and in obese T2D patients, in which BPD resulted in the resolution of diabetes. Compared to pre-BPD values, basal ABAp significantly increased 1 month after BPD in T2D as well as in NGT subjects, in parallel with a reduction of fasting plasma glucose. These results indicate an impaired hyperglycemia-induced ABAp increase in T2D and in GDM and suggest a beneficial effect of elevated ABAp on glycemic control.

Autonomic nervous system and cardiovascular risk assessment during one year of growth hormone replacement therapy in adults with growth hormone deficiency.

OBJECTIVE: This prospective study aimed to evaluate the impact of growth hormone deficiency (GHD) on cardiac autonomic tone and on cardiovascular risk and the changes after 12 months of GH replacement therapy (GHRT). GHD is associated with increased cardiovascular morbidity and mortality. This has been attributed to increased markers of cardiovascular risk and to abnormalities of both the cardiac and peripheral autonomic nervous systems. The autonomic cardiac nervous system (ACNS) can be indirectly evaluated by analysis of heart rate variability (HRV) in clinostatism and orthostatism. DESIGN: We compared 14 GHD patients at baseline and after 12 months of GHRT and 17 healthy controls. We analyzed a number of cardiovascular risk factors and we used analysis of HRV during the Tilt Test that identified high frequency (HF) and low frequency (LF), representing parasympathetic and sympathetic activity, respectively. RESULTS: Compared with the control group, in either clinostatism or in orthostatism our patients showed a significantly lower value of LF (P=0.047; P=0.004, respectively), whereas HF was significantly reduced in orthostatism (P=0.037), and indicatively in clinostatism (P=0.065). These values remained unchanged after 12 months of GHRT. No statistically significant differences were found between the LF/HF ratio in untreated and treated patients. In GHD patients, there was a significant reduction of cardiovascular risk in 12 months of replacement therapy (P=0.002). CONCLUSIONS: Our study highlights the absence of sympathovagal imbalance in GHD patients; GHRT does not change ACNS during the first year of GH treatment but it reduces the absolute cardiovascular risk in these patients.

Vitamin D modulates the association of circulating insulin-like growth factor-1 with carotid artery intima-media thickness.

OBJECTIVE: Experimental evidence indicates that circulating insulin-like growth factor-1 (IGF-1) counteracts vascular aging and atherosclerosis, for which increased carotid artery intima-media thickness (IMT) is a marker. Yet, IGF-1 concentrations have been inconsistently associated with carotid IMT in epidemiological studies. Since vitamin D is also implicated in vascular protection and affects IGF-1 biology, we hypothesized that it would influence the effect of IGF-1 on IMT. METHODS: The relationship between carotid IMT and fasting serum IGF-1 was examined across strata of 25-hydroxyvitamin D [25(OH)D] in 472 participants in the Baltimore Longitudinal Study of Aging (BLSA) with well-controlled blood pressure and in 165 treatment-naive patients with essential hypertension from the Microalbuminuria: A Genoa Investigation on Complications (MAGIC) study. Moreover, the interplay between vitamin D and IGF-1 was preliminarily explored in EA.hy926 endothelial cells. RESULTS: After adjusting for age, sex, BMI, renal function, smoking, systolic blood pressure, LDL-cholesterol, glycemia, antihypertensive or lipid-lowering therapy, season, parathyroid hormone, and vitamin D supplementation, IGF-1 was significantly and negatively associated with carotid IMT only within the lowest 25(OH)D quartile (range 6.8-26 ng/mL) of the BLSA (ß -0.095, p = 0.03). Similarly, a significant negative correlation between IGF-1 and carotid IMT was found after full adjustment only in MAGIC patients with 25(OH)D concentrations below either the deficiency cut-off of 20 ng/mL (ß -0.214, p = 0.02) or 26 ng/mL (ß -0.174, p = 0.03). Vitamin D dose-dependently decreased hydrogen peroxide-induced endothelial cell oxidative stress and apoptosis, which were further inhibited by IGF in the presence of low, but not high vitamin D concentration. CONCLUSIONS: Circulating IGF-1 is vasoprotective primarily when vitamin D levels are low. Future studies should address the mechanisms of vitamin D/IGF-1 interaction.

Inferior vena cava parameters predict re-admission in ischaemic heart failure.

BACKGROUND: The clinical history of heart failure (HF) is usually characterized by frequent hospitalizations for decompensation. Therefore, several markers of subclinical hemodynamic congestion are under investigation for predicting early rehospitalization. In this field, the potential of ultrasound inferior vena cava (IVC) assessment has been recently investigated in HF but not yet assessed in the different aetiological categories. MATERIAL AND METHODS: Forty-eight patients admitted for decompensated HF (n = 25 with ischaemic heart disease [IHD] and n = 23 non-IHD) underwent biochemical examination (including NT-proBNP), echocardiography and IVC assessment by hand-carried ultrasound (HCU). During 60-day follow-up after discharge, the re-hospitalization rate for HF was recorded to investigate the predictive power of NT-proBNP and IVC assessment among the two study groups. RESULTS: IHD and non-IHD patients with HF were similar except for gender distribution. During follow-up, 16·7% of patients were rehospitalized for decompensated HF, with higher prevalence in IHD group (28% vs. 4·3% P = 0·031). IVC assessment at discharge significantly predicted re-admission in the overall population and in IHD group, whereas NT-proBNP failed to predict rehospitalization in IHD group. In adjusted hazard ratio, only IVC min and the changes of IVC from admission significantly predicted re-admission. ROC analysis confirmed the change in IVC min as the best predictor of rehospitalization in patients with IHD. CONCLUSION: This pilot study showed a higher early re-admission rate in patients with HF due to IHD. In addition, the change in IVC min diameter from admission to discharge was the best predictor of re-admission in patients with IHD.

Vitamin D increases circulating IGF1 in adults: potential implication for the treatment of GH deficiency.

OBJECTIVES: Previous studies suggested that vitamin D modulates circulating IGF1. We investigated this effect in adults and its clinical relevance in the management of GH deficiency (GHD). DESIGN AND METHODS: IGF1 levels were prospectively measured before and after 12 weeks of treatment with oral vitamin D3 (5000 or 7000 IU/week) vs no intervention in 39 subjects 61.9±7.9 years old. The frequency of IGF1 values ≥50th age- and sex-specific percentile in relation to vitamin D status, as determined by the concentration of 25-hydroxyvitamin D (25(OH)D), was retrospectively assessed in 69 GHD patients (57.4±16.6 years) on stable hormone replacement and with 25(OH)D and IGF1 concurrently measured. RESULTS: Treatment with 5000 and 7000 IU vitamin D3/week significantly raised 25(OH)D by 12.7±8.4 and 13.1±6.5 ng/ml respectively (both P<0.001 vs baseline). In the 7000 IU group, IGF1 levels also significantly increased by 31.3±36.7 ng/ml (P=0.01). Neither 25(OH)D nor IGF1 significantly varied in controls. IGF1 was ≥50th percentile more frequently in GHD patients with 25(OH)D levels ≥15 than <15 ng/ml (65.9 vs 40.0%, P<0.05). Logistic regression with adjustment for recombinant human GH (rhGH) dose, vitamin D supplements, gender, use of thyroid hormones, corticosteroids or estrogen/testosterone, and season revealed a significant positive association between ≥15 ng/ml 25(OH)D and IGF1 ≥50th percentile (OR 4.4, 95% CI 1.0-18.8, P<0.05). A significant negative correlation between 25(OH)D concentrations and rhGH dose was found after correcting for age and IGF1 (ß -0.042, P<0.01), but not after further adjusting for sex, thyroid, adrenal or gonadal replacement, and season (ß -0.037, P=0.06). CONCLUSIONS: Vitamin D increases circulating IGF1 in adults. As a result, a better vitamin D status may ease the achievement of normal IGF1 values in GHD.

Interactions between vitamin D and IGF-I: from physiology to clinical practice.

The interplay between vitamin D and IGF-I is complex and occurs at both endocrine and paracrine/autocrine levels. Vitamin D has been shown to increase circulating IGF-I and IGFBP-3, with the consistent finding of a positive correlation between vitamin D and IGF-I serum values in population-based cohorts of healthy subjects. The modulation of IGF-I and IGFBP-3 concentrations by vitamin D may impact recombinant human (rh) GH dosing for the treatment of GHD. It might also underlie some of the extra-skeletal beneficial effects ascribed to vitamin D. On the other hand, IGF-I stimulates renal production of 1,25-dihydroxyvitamin D, which increases calcium and phosphate availability in the body and suppresses PTH secretion. This effect is responsible for an altered calcium-phosphate balance in uncontrolled acromegaly and might also account for the improvement in bone metabolism associated with rhGH treatment in patients with GHD. Data on the paracrine/autocrine vitamin D-IGF-I interactions are abundant, but mostly not linked to one another. As a result, it is not possible to draw a comprehensive picture of the physiological and/or pathological interrelations between vitamin D, IGF-I and IGF-binding proteins (IGFBP) in different tissues. A potential role of vitamin D action is related to its association with carcinogenesis, a paradigm being breast cancer. Current evidence indicates that, in breast tumours, vitamin D modulates the IGF-I/IGFBP ratio to decrease proliferation and increase apoptosis.