The proximity between styloid process and internal carotid artery as a possible risk factor for dissection: a case-control study.

PURPOSE: The anatomical proximity of the styloid process (SP) to the ipsilateral internal carotid artery (ICA) has been recently recognized as a possible risk factor for carotid artery dissection (CAD). We aimed to verify this hypothesis by comparing the minimum distance between SP and ICA in young adult patients (< 55 years) with and without CAD. METHODS: Thirty-one CAD patients (cases) were compared with 41 sex-matched patients without dissection, group one of control (G1), and with 16 sex-matched patients with vertebral artery dissection (VAD), group two of control (G2). Two independent observers measured, on CT angiography images, the minimum distance on the axial plane between the SP and ICA in cases and controls. They evaluated both the intercentric and the marginal distance. Differences between groups were estimated by Student t-test. RESULTS: SP-ICA intercentric distance ipsilateral to dissection was significantly shorter compared to that of the contralateral side of cases (p < 0.001), to those of left and right side of G1 patients (p < 0.001 for both), and to those of left and right side of G2 patients (p < 0.001 for both). SP-ICA marginal distance of cases was significantly shorter compared to those of left and right side of G1 patients (p < 0.001 for both) and to those of left and right side of G2 patients (p < 0.001 for both). CONCLUSION: A short SP-ICA distance appears to be a risk factor for CAD as it likely induces a continuous microtraumatism of the vessel wall during normal head and neck movements.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience.

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

Clinical and prognostic implications of the genetic diagnosis of hereditary NET syndromes in asymptomatic patients.

Neuroendocrine tumors (NETs) can be sporadic or they can arise in complex hereditary syndromes. Patients with hereditary NETs can be identified before the development of tumors by performing genetic screenings. The aim of the study was to evaluate the clinical and prognostic impact of a preclinical genetic screening in subjects with hereditary NET syndromes. 46 subjects referred for hereditary NET syndrome [22 MEN1, 12 MEN2, 12 Familial Paragangliomatosis (FPGL)] were enrolled and divided in 2 groups (group A, 20 subjects with clinical appearance of NET before the genetic diagnosis; group B, 26 subjects with genetic diagnosis of hereditary NET syndromes before the clinical appearance of NETs). The main outcome measures were severity of disease, prognosis, and survival. The rate of surgery for MEN1-, MEN2-, FPGL4-related tumors was 90% in group A and 35% in group B (p<0.01). Both symptoms related to tumors and symptoms related to therapies were significantly less frequent in group B than in group A (p<0.05). Tumor stage was locally advanced or metastatic in 50% of group A and in no one of group B (p<0.01). The mortality rate was 25% in group A and 0% in group B (p<0.05). An early genetic screening for hereditary NET syndromes results in an improvement in clinical presentation and morbidity. A potential impact of the genetic screening on the mortality rate of these subjects is suggested and needs to be investigated in further and more appropriate studies.

Thyroid function in Fabry disease before and after enzyme replacement therapy.

UNLABELLED: AM: Patients with Fabry disease (FD), a genetic disorder caused by lysosomal a-galactosidase-A enzyme deficiency and characterized by a systemic accumulation of globotriaosylceramides, present high prevalence of subclinical hypothyroidism. The pathogenic mechanism is thought not to be related to anti-thyroid autoimmunity and may be dependent by intra-thyroid lipid accumulation. In this study, it was investigated whether thyroid function recovers in FD after long-term enzyme replacement therapy (ERT). METHODS: Study population included 14 FD patients (7 females, 7 males, aged 21-62 years) and 14 sex- and age-matched normal subjects. Thyroid function was evaluated in each patient at baseline and after the beginning of ERT with rh-a-galactosidase-A (1 mg/kg/BW every 2 weeks) for three years. RESULTS: TSH levels were higher in FD patients than in controls (P<0.05). In FD patients, TSH levels were higher before than after ERT (1.9±0.2 vs 1.2±0.2 mU/L, P<0.01) while fT3 and fT4 levels were normal at baseline and unchanged after ERT. At baseline, TSH levels were >3 mU/L in three patients and normalize after ERT. Anti-Tg and/or anti-TPO titres were positive in 14% of patients and 21% of controls. After ERT, the rate of autoimmunity was unchanged. At the thyroid ultrasonography, a slight hypoechoic pattern was found in 71% of patients at baseline and decreased to 43% after ERT. CONCLUSION: Primary hypothyroidism in FD patients is reverted after long-term ERT. A screening of thyroid function and periodical re-evaluation during ERT is mandatory in all FD patients.

The roles of parathyroid hormone in bone remodeling: prospects for novel therapeutics.

The aim of this review is to focus on the roles of PTH in bone remodeling. PTH plays a central role in regulating calcium-phosphate metabolism and its production increases in response to low serum calcium levels. A continue hypersecretion of PTH, as occurs in primary hyperparathyroidism, leads to bone resorption. On the other hand, there is clear evidence of the anabolic properties of PTH.When administered at a low dose and intermittently, this hormone seems to be able to exert positive effects on bone volume and microarchitecture. The effects of PTH are mediated by PTH/PTH-related protein receptor, a G protein that can activate the cAMP-dependent protein kinase (PK)A and calcium-dependent PKC; the activation of PKA account for most of the PTH anabolic action. The anabolic actions of PTH involve direct effects on osteoblasts and indirect effects mediated by activation of skeletal growth factors (IGF-I) and inhibition of growth factor antagonists, such as sclerostin. PTH enhances the number and the activation of osteoblast through 4 pathways: increasing osteoblast proliferation and differentiation, decreasing osteoblast apoptosis and reducing the negative effects of peroxisome proliferator activator (PPAR)γ receptor on osteoblast differentiation. Moreover PTH enhances the Wnt-ß catenin pathway, that is central to osteogenesis and bone formation, inhibiting sclerostin. Finally, PTH induces the synthesis of IGF-I and, due to its prodifferentiating and pro-survival effects on osteoblasts, this could be a key mediator of PTH effect on osteoblasts. In conclusion, the intermittent administration of PTH has a pleiotropic anabolic effect on bone; further studies about mechanisms of action of PTH could be a starting point to new osteoporosis treatments.

Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks.

Autologous haematopoietic stem-cell transplantation has been evaluated over the last years as a possible new therapeutic strategy in severe forms of multiple sclerosis unresponsive to the approved therapies. Up to now, more than 400 patients have been treated and numerous are the phase I and phase II studies which addressed the feasibility of this treatment, the efficacy, side effects and transplant-related mortality. The clinical response is strongly related to the intensity of the conditioning regimen utilized as well as to the phase of the disease course in which the therapy is carried out. Rapidly evolving multiple sclerosis with a relapsing-remitting clinical course and MRI signs of activity are the cases that can take more advantage. The risk of mortality, which dropped in the last years to 2-3%, is still the main problem of this powerful therapy.

An Approach to Prevent Frailty in Community Dwelling Older Adults: a pilot study performed in Campania region in the framework of the PERSSILAA project.

We developed and tested an innovative physical training method in older adults that embeds the gym program into everyday life in the most conservative way possible. Physical training was included in the activities of local parishes where older women from Southern Italy spend most of their free time and was delivered by trained physical therapists with the support of an ICT tool known as CoCo. 113 older women (aged 72.0 [69.0-75.0] years) noncompliant to conventional exercise programs participated to the study. 57 of them underwent the final anthropometric assessment and 50 the final physical tests. In study completers handgrip strength and physical performance evaluated with the chair-stand, the two minutes step and the chair-sit and -reach tests significantly improved. Quality of life as evaluated with the EuroQol-5dimension (EQ-5D) questionnaire improved as well. In conclusion, a training program designed to minimally impact on life habits of older people is effective in improving fitness in patients noncompliant to other to physical exercise programs.

Metabolic and cardiovascular consequences of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting 5-10% of reproductive aged women, about 1 out of 15 women worldwide. Traditionally it was considered as a reproductive disorder showing hyperandrogenism, chronic anovulation and infertility; it is now well accepted that PCOS represents a ''multifaceted'' syndrome with substantial metabolic and cardiovascular long term consequences. Several PCOS women present abdominal adiposity (visceral fat) with a level of peripheral insulin resistance (IR), similar to that present in women with type 2 diabetes, in association with an increased incidence of impaired glucose tolerance. Several cardiovascular risk factors are often related to metabolic alterations, such as dyslipidemia, hypertension, endothelial dysfunction, low grade chronic inflammation, that are present even at early age in PCOS women. Pathogenetic mechanisms of these impairments are not completely clarified yet, but IR appears to play a critical role, such as the key factor linking hypertension, glucose intolerance, obesity, lipid abnormalities and coronary artery disease. In conclusion, although increased incidence of metabolic abnormalities and metabolic disease like type 2 diabetes, and several cardiovascular abnormalities have been widely demonstrated in PCOS women, larger and multicenter trials of long term cardiovascular outcomes are required to better define the incidence of cardiovascular risk and cardiovascular disease in PCOS.

Spectroscopic, diffusion and perfusion magnetic resonance imaging at 3.0 Tesla in the delineation of glioblastomas: preliminary results.

Recent advances in magnetic resonance imaging (MRI) have allowed the evaluation of metabolic, diffusion and hemodynamic features of malignant gliomas. The aim of this study was to evaluate whether such information provided useful, complementary information to conventional MRI for improving the evaluation of glioblastoma extent. Ten patients with glioblastoma multiforme underwent conventional MRI, proton MR spectroscopic imaging (1H-MRSI), perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI). Metabolite signals, including normalized choline, N-acetylaspartate, creatine and lactate/lipids, were obtained by 1H-MRSI; apparent diffusion coefficient (ADC) by DWI; and relative cerebral blood volume (rCBV) by PWI. In edematous-appearing areas, 3 multiparametric patterns were identified: infiltrating tumor, with abnormal metabolite ratios, lower ADC and higher rCBV; pure edema, with normal metabolite ratios, higher ADC and lower rCBV; and tumor-infiltrated edema, with abnormal metabolite ratios and intermediate ADC and rCBV. In normal-appearing areas, 2 multiparametric patterns were identified: tumor-infiltrated tissue, with abnormal metabolite ratios and higher rCBV; and normal tissue, with normal MR parameters. The combination of 1H-MRSI, DWI and PWI features contributed to delineation of glioblastomas, offering information not available with conventional MRI. This approach may enhance the assessment of brain gliomas, providing useful information for guiding stereotactic biopsies, surgical resection and radiation treatment.

Nutrition and Osteoporosis: Preliminary data of Campania Region of European PERsonalised ICT Supported Service for Independent Living and Active Ageing.

BACKGROUND: Bone impairment and malnutrition are associated with significant disability and mortality. PERSSILAA is an European project developing health services to detect and prevent frailty in older adults by addressing cognitive, physical and nutritional. METHODS: Subjects underwent anthropometric measurements, calcaneal quantitative ultrasound (QUS) scan and PREDIMED (PREvención con DIeta MEDiterránea) questionnaire. AIM: To investigate the association between adherence to the Mediterranean Diet (MD) and bone health. RESULTS: 87 subjects (4 males and 83 females) 70.1±4.9 aged, were examined. Mean Body Mass Index (BMI) was 28.7±4.7(kg/m(2)): in particular 28 subjects (32.2%) resulted obese, 42 (48.3%) overweight, and only 17 (19.5%) with normal weight. Mean T score was -1.2±1.2: in particular 13 subjects (14.9%) resulted osteoporotic; 43 (49.5%) osteopenic; and 31 (35.6%) with normal bone mineral density. Regarding adherence to MD, 9 subjects (10.3%) were poorly adherent; 41 (47.2%) average adherent; 37 (42.5%) highly adherent. T-score was associated with PREDIMED score and osteoporotic subjects presented the lowest PREDIMED score (5.8±2.2). CONCLUSIONS: These preliminary data show a significant correlation between the adherence to the MD and bone health parameters. The association between MD and bone health highlights the potential beneficial effects of nutritional interventions promoting a Mediterranean food pattern, as safe adjuvant treatment in ageing.

Formation of mutagens in cooked foods. V. The mutagen reducing effect of soy protein concentrates and antioxidants during frying of beef.

Cooking beef patties results in the formation of mutagens detectable by Salmonella typhimurium TA98 with metabolic activation. Decreased mutagenic activity results when frying beef with added soy protein concentrates (SPC). The reduction in mutagenicity takes place during the cooking process. Whereas fried beef hamburgers show high mutagenic activity, by comparison, similarly fried soy-hamburgers have much less mutagenic activity. Volumetric effects are responsible partly for the reduction on mutagenicity by SPC. Naturally occurring antioxidants in SPC, such as chlorogenic acid, also play a role. Also, a commonly used antioxidant, butylated hydroxyanisole (BHA), has been found effective in reducing the mutagenicity of fried beef. Thus, the addition of SPC or BHA in beef patties may provide a practical way of reducing mutagen formation during frying of beef.

Formation of mutagens in cooked foods. IV. Effect of fat content in fried beef patties.

Cooking beef patties results in the formation of mutagens detectable by Salmonella typhimurium TA98 with metabolic activation. We now show that the amount of fat in beef affects the quantity of mutagens formed. While char increases with increasing fat, over the range of 5-309% of added fat content, mutagenicity reaches a peak at 10% added fat and subsequently decreases. Thus, char formation is not an accurate measure of mutagenicity. These results suggest that fat plays an important role in mutagen formation in fried beef.

Formation of mutagens in cooked foods. III. Isolation of a potent mutagen from beef.

The major mutagenic component of fried beef has been isolated using a series of chromatographic steps. The pure compound has been analyzed by low and high resolution mass spectroscopy and nuclear magnetic resonance spectroscopy. The results indicate that the molecular weight of this extremely mutagenic compound is 198, with an elemental composition of C11H10N4. The compound is different from the known mutagenic pyrolysis products of amino acids or proteins.

Spinal deformity index in patients with type 2 diabetes.

The objective of this study is to investigate bone metabolism, density, and quality in patients with diabetes type 2 using DEXA and spinal deformity index (SDI), a surrogate index of bone quality. Fifty-six patients with type 2 diabetes were studied; exclusion criteria were diseases and medications that affect bone and mineral metabolism. Mean age was 65 ± 7 years. Mean diabetes duration was 10 ± 7 years and mean HbA1C was 6.6 ± 0.5 %. BMI was 30 ± 4. Fifty-six sex, age, and BMI matched served as controls. All subjects underwent a clinical and biochemical examination. Spinal and femoral neck BMD were measured by DEXA, and a spine radiography was performed to assess vertebral fractures and to calculate SDI. Mean serum 25-OH vitamin D levels were 19.6 ± 3.7 ng/ml in patients and 30 ± 14 ng/ml in controls (p < 0.01). PTH serum levels were 47.9 ± 40 pg/ml in patients versus 37 ± 5.3 pg/ml in controls (p < 0.01). At lumbar spine there was a significant difference between patients and controls only for T-score (p = <0.01), while at femoral neck there was a difference in BMD (p < 0.01) and in T-score (p < 0.01). Radiological vertebral fractures were found in 46 % of patients and 17 % of controls (p < 0.05). SDI was higher in patients than in controls (p < 0.05). The percentage of fractures with T-score BMD greater than -2.5 was 69 % in patients and 10 % in controls (p < 0.05). As a conclusion, BMD was similar in patients and in controls, while SDI value was higher in patients; therefore, SDI was more specific than BMD for the diagnosis of osteoporosis due to metabolic diseases.

Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism.

Cinacalcet is effective in controlling the biochemical abnormalities in patients with primary hyperparathyroidism (PHPT) but it seems to be less effective on bone mineral density (BMD). In the same patients, bisphosphonates are reported to be effective on bone resorption but less effective on calcium and PTH excess. In this study, the efficacy of cinacalcet in combination with alendronate has been retrospectively evaluated in patients with PHPT. Twenty-three patients with PHPT who had not been operated were retrospectively investigated. Cinacalcet was evaluated in combination with alendronate in 10 of the 23 patients, and in monotherapy in 13 other patients. Serum calcium, phosphorus and PTH, 24 h urine calcium and phosphorus as well as BMD, evaluated by DXA and expressed as T-score, were measured before and after treatment. In all patients serum calcium and phosphorus and urinary calcium excretion were effectively and stably controlled and PTH was significantly decreased after treatment. There was no difference in the rate of serum calcium and PTH decrease between subjects treated with cinacalcet plus alendronate and those treated with cinacalcet alone. T-score increased by 9.6% at lumbar spine and 3.9% at femur level in the cinacalcet plus alendronate subgroup and was unchanged in the cinacalcet subgroup (P < 0.01). In patients with PHPT, the biochemical abnormalities are rapidly improved by cinacalcet regardless from the administration in monotherapy or in combination with alendronate. BMD is significantly improved in patients receiving cinacalcet plus alendronate and stable in those receiving cinacalcet in monotherapy.

Role of IGF-I on PTH effects on bone.

IGF-I and PTH have synergistic actions on bone and some effects of the anabolic actions of PTH are mediated by local production of IGF-I, as has been shown in vitro and in vivo studies both in animals and humans. PTH can induce skeletal IGF-I expression both in vitro and in vivo. In chondrocytes, IGF-I synthesis is under GH control, whereas in osteoblasts its synthesis is fundamentally under the control of PTH. PTH stimulates the synthesis of IGF-I via a cAMP-dependent mechanism, and this factor has pro-differentiating and prosurvival effects on osteoblasts. In in vitro studies, IGF-I and PTH have shown a synergistic action on the osteoblasts of bone marrow. Human clinical data confirm the interactions between PTH and GH-IGF-I axis on bone. PTH is involved in the development of osteoporosis in adult patients with GH deficiency (GHD). In fact, patients with GHD show renal, skeletal, and intestinal cell insensitivity to PTH, leading to a mild state of PTH resistance and increased serum PTH levels. In addition, GH replacement in these patients restores PTH secretory rhythm, increases bone turnover markers, 1,25-dihydroxy vitamin D concentration, and Ca absorption/reabsorption, thus contributing to the positive effects of GH on bone. On the other hand, in post-menopausal women with primary hyperparathyroidism a reduced secretion of GH is observed, in association with a greater impairment of bone mass. GH administration resulted in increased IGF-I concentration, decreased PTH concentration, and increased nephrogenous cAMP. In conclusion, the anabolic action of PTH requires paracrine and autocrine effects of IGF-I.

Protein pyrolysate products.

Diet and nutrition may be responsible for 60% of the total cancer incidence for women and greater than 40% for men. Fat, animal protein, and meat consumption are highly correlated with colon cancer incidence. The charcoal broiling of meat and fish yield mutagenic substances. Many findings support the hypothesis that the predominant mutagens are formed by the Maillard reaction. A number of mutagenic compounds have been identified both from cooked foods and from protein pyrolysates. The identified compounds are N-heterocyclic primary amine derivatives of either carbolines, imidazoquinolines, or imidazoquinoxalines. The carboline-type mutagens are structurally related to the known carcinogens 2-acetylaminofluorene (AAF) and 2-aminofluorene (AF), while the imidazoquinoline and imidazoquinoxaline types are believed to resemble 3,2'-dimethyl-4-aminobiphenyl (DMAB). Studies support the theory that these compounds require metabolic activation and are carcinogenic. The major metabolites of several compounds have been identified as the N-hydroxy derivatives. DNA binding was found to be a necessary but not a sufficient condition for mutagenesis. The modified base products have been identified as C-8-guanyl derivatives, resembling adducts formed by the carcinogenic aromatic amines.

Induction of human HL-60 leukemic cell differentiation by immune interferon is accompanied by an increase in NADase activity and by a decrease in DNA-binding proteins.

The effects of highly purified human immune interferon (IFN-gamma) on the differentiation of human promyelocytic HL-60 leukemic cells have been studied. The addition of 100 units/ml interferon to HL-60 cells for 5 days results in morphological changes characteristic of macrophages. At the biochemical level, there is a 3-fold increase in the specific activity of the enzyme NADase. Kinetic analysis shows that IFN-gamma causes an increase in the Vmax of NADase without affecting the apparent Km. Pulse labeling experiments with [35S] methionine show a marked change in the de novo synthesis of several proteins in the course of interferon treatment. Chromatography on DNA-agarose show that after treatment with interferon for 24 or 48 h, there is a 60-70% decrease in newly synthesized proteins which bind DNA-agarose and can be subsequently displaced from the column with 2% SDS containing buffer (from 7.7-8.7% bound in control cell extracts to 2.6-3.1% bound in interferon treated cell extract).