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Background: Although well-defined in the general population, correlates of total homocysteine (tHcy) plasma concentration have not been sufficiently evaluated in diabetes. We investigated factors potentially associated with tHcy concentration in a cohort of type 2 diabetic subjects., Materials and Methods: The common methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism, fasting tHcy, vitamin B12 and folate plasma levels were assessed in 312 diabetic subjects, whose clinical, metabolic and lifestyle information was also available., Results: The MTHFR genotype distribution was comparable to the Hardy-Weinberg equilibrium, with an overall TT homozygous frequency of 22%. Fasting tHcy concentration was significantly higher in men than in women (P < 0.001). Multivariate-adjusted tHcy concentration was significantly different across the quartiles of age (P < 0.001), folate (P = 0.01), vitamin B12 (P = 0.03), creatinine concentrations (P = 0.001) and smoking (P = 0.02). Overall, significant trends were noted for creatinine clearance (P for trend = 0.02) and systolic blood pressure (BP) (unadjusted P for trend = 0.01), whereas no differences were noted according to BMI, diastolic BP, presence of hypertension, and diabetes-related variables, such as diabetes duration, fasting glucose and glycated haemoglobin concentrations, current treatment and diabetes long-term complications. Total homocysteine levels significantly correlated with age, systolic BP, vitamin B12, creatinine and creatinine clearance, but only age, creatinine, folate and vitamin B12 levels were independently associated with tHcy concentration in stepwise regression analysis., Conclusions: Age, creatinine, folate, vitamin B12, and to a minor extent, sex, smoking, TT genotype and systolic BP were significantly associated with Hcy plasma concentration in type 2 diabetes, whereas no significant associations were noted with diabetes-related variables.

Hyperhomocysteinemia can result from decreased methylenetetrahydrofolate reductase (MTHFR) enzyme activity, owing to genetic polymorphisms andor inadequate folate intake. This study was aimed at investigating the prevalence of C677T and A1298C MTHFR polymorphisms, and their impact on hyperhomocysteinemia in 95 epileptic patients and 98 controls. Double gradient-denaturing gradient gel electrophoresis screening revealed that the frequency of T677 polymorphic allele was similar between cases and controls (46.3% vs 42.3%), whereas that of C1298 allele was significantly higher in patients (30.5% vs 19.4%, p < 0.05). Significant differences between the two groups were also found for the frequencies of genotypes AA1298 (46.3% in cases vs 67.3% in controls, p < 0.01) and AC1298 (46.3% in cases vs 26.6% in controls, p < 0.01). Other genotype frequencies did not show any statistically significant differences. Haplotype frequencies significantly differed between the two groups. The CT677/AC1298 diplotype was significantly more frequent in epileptic patients than in controls (32.6% vs 18.4%, p < 0.05). Patients treated with enzyme-inducing antiepileptic drugs, having this diplotype and concomitant low folate concentration (i.e., < 3.4 nmol/L), exhibited plasma homocysteine levels significantly higher than normal values (27.1 +/- 2.44 micromol/L, p < 0.001). This increase, however, was lower than that observed in folate-deficient patients with diplotype TT677/AA1298 (41.3 +/- 3.41 micromol/L, p < 0.001). Indeed, these two diplotypes could be regarded as risk factors for hyperhomocysteinemia. Conversely, we found that the CC677/AA1298 diplotype was significantly more frequent in controls (p < 0.01), suggesting a protective role. Our study suggests that both C677T and A1298C MTHFR polymorphisms should be examined when assessing genetic risk factors of hyperhomocysteinemia in epilepsy.

The Short Form 36 Health Survey (SF-36) is a self-administered scoring system that has been widely used and validated as a quality of life (QOL) assessment tool. In our study, a cluster analysis of SF-36 scores was performed in 50 healthy volunteers (controls) and 50 neurobiologically asymptomatic patients on maintenance hemodialysis (MHD). Firstly, we assayed the tendency to form clusters from each of the investigated dimensions. Statistic analysis was performed using the Student's t-test for independent measurements and multiple regression analysis. Secondly, we attempted to evaluate if the MHD to apply to both groups a general psychobiological personality model developed by Cloninger in 1987. Cloninger describes three independent personality dimensions: novelty seeking (NS), harm avoidance (HA)and reward dependence (RD). Each personality dimension would be the expression of hereditary variations integrating the three main brain systems, respectively: dopaminergic, serotoninergic and noradrenergic. Finally, we then aimed to investigate possible interferences among the seric concentrations of the neuromodulators and SF-36 scores, in the attempt to identify, using a simple approach, the complex personality structure of MHD patients. QOL self-assessment and seric neuromodulators were measured in both groups, choosing an interdialytic day for MHD patients. We found that MHD patients perceived a significant worsening in their QOL in all investigated dimensions with respect to the controls. In addition, they showed significantly lower dopamine and serotonine concentrations and significantly higher noradrenaline concentrations. Therefore, our study, confirmed data reported previously in the literature, that cluster analysis of SF-36 scores provides different results in the MHD population in comparison to normal subjects. In fact, comparing the hierarchical trees of both groups, it appeared evident that in MHD patients, cluster dimensions were greater than in the controls. In cluster compositions showed differences between the two groups. In fact, in MHD patients there were only a few of the clusters that were observed in the controls (mental health and social functioning, vitality and general health), while role-physical and role-emotional dimensions aligned outside the hierarchical tree, with a considerable linkage distance. In our opinion, it is fascinating that the three Cloninger neuromodulators could suggest that HD patient personalities are potentially cyclothymiac, altering the disposition of the two role functions inside the hierarchical tree.

Recent evidence indicates that longevity may be achieved when efficient defence mechanisms against oxidative stress, infections, neoplasia, and cardiovascular events are preserved. Centenarians represent an example of "successful aging," and the aim of this study was to evaluate serum levels of vitamins A and E, which represent two important nonenzymatic antioxidant defence systems, and their correlation in 16 healthy centenarians and two groups of control subjects. Centenarians showed normal values of retinol (450.9 +/- 240.3 ng/mL) and alpha-tocopherol (9220.2 +/- 3410.9 ng/mL). Moreover, a significant direct correlation between the two vitamins was observed in centenarians (Rho = 0.715, p = 0.0056), such as in younger control subjects (Rho = 0.618, p = 0.0168), but not in older control subjects. We assume that the preservation of normal values and the correlation between vitamin A and E concentrations protects centenarians against oxidative stress and contributes to their extreme longevity.

All currently available and approved therapies for osteoporosis inhibit bone resorption. But, despite their great value, antiresorptive agents are generally not associated with dramatic increases in bone mass. In light of these data, the aim of our prospective, placebo-controlled, randomized clinical trial, with a 3-year follow up, was to examine the effects of cyclic intravenous pamidronate and fluoride in combination, versus pamidronate alone, on bone mineral density (BMD) at vertebral and femoral levels, biochemical markers of bone turnover, IGF-1 serum levels, and safety and tolerability in 40 postmenopausal women with osteoporosis. During the treatment period, pamidronate alone reduced both markers of bone formation and bone resorption, resulting in an increase of BMD, after 3 years, of 7.07% at the lumbar level and of 6.76% at the femoral level. In the group treated with pamidronate and fluoride, markers of bone turnover had a different trend: after 3 years, there was a lower reduction of bone resorption and an increase of bone formation markers, with a concomitant increase in IGF-1 levels. This resulted, after 3 years of treatment, in a marked variation of BMD at the lumbar level (+12.74%) and a reduced, but still significant, increase at the femoral level (3.89%). Spine radiography and clinical evaluation did not reveal any vertebral fractures in either treatment group. In conclusion, the combined use of pamidronate and fluoride produced somewhat larger, continuous increases in BMD, at the lumbar level, than pamidronate alone.

Objective: The loss of pancreatic beta-cells is thought to be one of the principal causes of diabetes mellitus (DM) in cystic fibrosis (CF), but the role of peripheral insulin resistance (IR) in the pathogenesis of DM in CF remains unclear. The aim of this study was to evaluate whether eventual changes of glucose tolerance (GT) over time were associated with modifications of insulin secretion or sensitivity., Methods: Plasma glucose and insulin responses to an oral GT test (OGTT) were investigated and reinvestigated 13 Years later in 14 CF patients with initial and persistent fasting euglycemia and no history of insulin treatment. Insulin sensitivity (IS) at both tests was assessed on the basis of insulin and glucose levels both in the fasting state and during OGTTs., Results: From the 1st to the 2nd OGTT: (a) the prevalence of DM responses significantly increased; (b) the areas beneath the respective glucose and insulin curves significantly increased and decreased respectively; (c) IR and IS indices decreased and increased respectively, even in the patients who developed DM; (d) pulmonary function significantly worsened in the entire series, especially in the patients who developed DM., Conclusions: (i) the natural history of glyco-metabolic status in CF is characterized by deteriorating GT over time; (ii) insulinopenia plays a prominent role in the pathogenesis of GT worsening; (iii) IR does not play any significant part in the pathogenesis of DM development; (iv) deterioration of lung function tests is more severe in the subjects who develop DM over time.

Data reported in this study have been recently published elsewhere. The authors retrospectively analyzed the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP), who had been treated with the same therapy protocol (Decapeptyl Depot at the dose of 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0 +/- 1.3 yr) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: A) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, p<0.01); B) a striking deceleration of BA, revealed by the subnormal deltaBA:deltaCA ratio (0.2 +/- 0.1); C) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, p<0.0005). Treatment interruption was followed by notable catchdown growth, with FH (158.4 +/- 5.8 cm) lower (p < 0.025) with respect to that predicted at the end of therapy. However FH fell within the population norm and the target range in 87.3% and 90% of patients, respectively. The tallest FH was recorded in the patients who discontinued treatment at a BA of 12.0-12.5 years. We conclude that: 1) Most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; 2) The height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; 3) The most favorable height prognosis with respect to target height (TH) is generally observed in the patients with the tallest H2 and the lowest BA2:CA2 ratio, due to the notable deterioration of height prognosis which frequently follows therapy interruption; 4) In order to strengthen the weak therapeutic effect of GnRH agonists in CTPP, this treatment should be discontinued at a BA of 12-12.5 years.

The aim of this retrospective study was to analyze the factors which affected the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP) who had been treated with the same therapy protocol (Decapeptyl Depot, 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0+/-1. 3 (S.D.) years of age) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: (a) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, P<0.01); (b) a striking deceleration of bone age (BA), revealed by the subnormal DeltaBA:Deltachronological age (CA) ratio (0.2+/-0.1); (c) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, P<0.0005). Treatment interruption was followed by an important catch-down growth, with an FH (158.4+/-5.8 cm) lower (P<0.025) than that predicted at the end of therapy. However, FH fell within the population norm and the target range in respectively 87.3 and 90% of the patients. The tallest FH was recorded in the patients who started therapy at less than 6 years of age and in those who discontinued treatment at a BA of 12.0--12.5 years. At stepwise regression analysis, FH in the whole study population was positively affected by the following independent factors: (a) height at the end of therapy (F=45.45, P<0.0001); (b) pretreatment height (F=13.91, P<0.0005); (c) treatment duration (F=8. 51, P<0.005); (d) target height (TH) (F=7.70, P<0.01). We conclude that: (i) most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; (ii) the height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; (iii) the most favorable height prognosis with respect to TH is generally observed in the subjects with the tallest height at the end of treatment and the lowest BA2:CA2 ratio, due to the important deterioration of height prognosis which frequently follows therapy interruption; (iv) FH is also significantly conditioned by both TH and treatment duration; (v) in order to strengthen the weak therapeutic effect of GnRH agonists in CTPP this treatment should be started as early as possible and discontinued at a BA of 12.0--12.5 years.

Literature data on statural growth effect of growth hormone (GH) treatment of children with GH deficiency (GHD) appears disappointing when treatment had late onset. It seems therefore that GH treatment should be started as early as possible, thus requiring early diagnosis. This study was undertaken: 1) to define the main characteristics of early onset GHD which may help the clinician for early diagnosis; 2) to evaluate the effect of a GH treatment on the statural growth of early onset GHD, when treatment is started before 1 year of age. Sixteen children with GHD diagnosed before 1 year of age were included in the study; all of them received a GH treatment before 1 year of age and for a minimal duration of 5 years; four had isolated GHD secondary to a GH gene deletion (type 1A GHD). Based on this series, the main anamnestic and clinical characteristics of early onset GHD are: frequent perinatal pathology, short birth height in more than half of the cases, relatively elevated birth weight in all cases, poor statural growth with neonatal onset, associated signs (hypoglycemia, special facies, micropenis, cryptorchidism, liver dysfunction). The effect of GH treatment (> or = 5 years) on statural growth was limited and transient in children with type 1A GHD, and resulted in an incomplete catch-up growth in children with sporadic GHD, their mean height remaining significantly below their target height.

Glyco-metabolic status was evaluated in 29 pubertal homozygous thalassaemics aged from 17 to 42 years and in 12 age-matched healthy subjects. Diagnosis of diabetes mellitus was assessed in 4 patients (13.8%), who became diabetic after the age of 18 years. With respect to controls non-diabetic patients exhibited significantly higher fasting plasma glucose levels and more sustained glycemic responses to oral glucose tolerance test, whereas their overall insulin output was significantly lower. Moreover non-diabetic thalassaemic patients showed a clear reduction of both beta-cell function and insulin resistance indices (HOMA model). In conclusion our data show a high prevalence of diabetes but do not support the existence of an insulin resistant status in thalassaemia major, at least in adulthood.

The aim of this retrospective study was to ascertain, whether an early growth hormone (GH) treatment can normalize height prognosis of children with congenital GH deficiency (GHD). The study covers 23 children with early onset GHD who received GH 0.1 U/kg/day from the beginning of therapy (0.4-4.9 years). This dose was corrected for weight every 3 months during the whole duration of treatment (mean 7.9 +/- 2.4 years). As a consequence of the significant growth acceleration induced by GH treatment, the patients' height deficiency at the last check had changed from a range of between -8.0 and -1.8 SDS to between +0.5 and -4.3 SDS; on the average, it was significantly less severe than before treatment. Satisfactory growth acceleration was achieved in most patients concomitantly with accelerated bone maturation, as was shown by the stable height age/bone age ratio observed during the follow-up period. The predicted ultimate height was significantly greater than the pretreatment height and it did not differ from the target height. It is concluded that catch-up growth to the target percentile in GHD patients is possible, provided that substitutive treatment is begun during the first years of life and that GH doses are adjusted periodically for weight changes.

Plasma glucose and insulin responses to oral glucose load were investigated and reinvestigated approximately 4 years later in 29 cystic fibrosis children and adolescents with initially normal fasting blood glucose levels. Patients' clinical status was evaluated at the time of both oral glucose tolerance tests. With respect to the basal test, the second one elicited blunted insulin responses and enhanced glycemic levels. Moreover, the prevalence of patients with diabetic glucose tolerance was significantly increased at the second evaluation and insulin secretion was markedly reduced in these patients. Deterioration of glucose tolerance and/or of insulin secretion over time was never accompanied by a significant worsening of clinical and/or nutritional status. In conclusion, in cystic fibrosis subjects with fasting euglycemia (a) both insulin secretion and glucose tolerance deteriorate during a 4-year follow-up, (b) an insulin secretion decrease is more evident in patients who develop diabetic glucose tolerance and (c) these metabolic changes are not significantly linked to a worsening of either nutritional or clinical parameters, even in the patients who develop diabetic glucose tolerance.

This case report concerns a prepubertal patient (height 148.7 cm) with congenital anterior panhypopituitarism diagnosed at the chronological age of 25.2 years (bone age 12.5). In spite of his advanced age on initiation of hormonal replacement therapy this patient achieved an adult height (172.8 cm), exceeding those of his father and brothers, because of his markedly delayed bone age. This satisfactory height outcome confirms that final height in hypopituitarism depends on both height at onset of puberty and height with respect to bone age but not chronological age at initiation of growth hormone treatment.

Putrescine, spermidine and spermine levels were detected in the retina, visual cortex, cerebellum and parietal cortex of CD1 mice exposed to 36h continuous light or darkness. Retinal putrescine and polyamine concentrations were found to be highest in dark-adapted mice, and the stimulation of dark-adapted retina with flicker illumination was also accompanied by a significant decrease in putrescine, spermidine and spermine levels. In visual cortex as well as in cerebellum spermidine and spermine contents were higher in dark-adapted mice in comparison to light-exposed animals, while in parietal cortex no significant change was found neither in spermidine nor spermine levels. In the brain areas studied flicker illumination produced no significant decreases in putrescine and polyamine contents. The total polyamines expressed as putrescine equivalents were noticeably decreased in retina, visual cortex and cerebellum of light-adapted mice. In the retina spermine/spermidine molar ratio was significantly higher than in dark-adapted mice. The administration of N1, N2-bis-(2,3-butadienyl)-1,4-butanediamine (MDL 72527) produced a strong decrease of retinal putrescine and spermidine concentrations in both dark-adapted and light-exposed mice, and in the retina of mice exposed to continuous light a significant decrease in the spermine level was also observed. According to the influence on polyamine reutilization, after the irreversible inhibition of polyamine oxidase by MDL 72527, in the retina N1-acetylspermidine and N1-acetylspermine accumulation was highest in light-adapted mice. On the contrary in visual cortex, cerebellum and parietal cortex the MDL 72527 administration produced a more marked decrease of putrescine and spermidine contents in mice kept in continuous darkness.