Abnormalities of insulin-like growth factor-I signaling and impaired cell proliferation in osteoblasts from subjects with osteoporosis

IGF-I regulates bone acquisition and maintenance, even though the cellular targets and signaling pathways responsible for its action in human bone cells are poorly understood. Whether abnormalities in IGF-I action and signaling occur in human osteoblasts under conditions of net bone loss has not been determined. Herein we carried out a comparative analysis of IGF-I signaling in primary cultures of human osteoblasts from osteoporotic and control donors. In comparison with control cells, osteoporotic osteoblasts showed increased tyrosine phosphorylation of the IGF-I receptor in the basal state and blunted stimulation of receptor phosphorylation by IGF-I. Augmentation of basal IGF-I receptor phosphorylation was associated with coordinate increases in basal tyrosine phosphorylation of insulin receptor substrate (IRS)-2 and activation of Erk, which were also minimally responsive to IGF-I stimulation. By contrast, phosphorylation levels of IRS-1, Akt, and glycogen synthase kinase-3 were similar in the basal state in control and osteoporotic osteoblasts and showed marked increases after IGF-I stimulation in both cell populations, even though these responses were significantly lower in the osteoporotic osteoblasts. The IGF-I signaling abnormalities in osteoporotic osteoblasts were associated with reduced DNA synthesis both under basal conditions and after stimulation with IGF-I. Interestingly, treatment of the osteoporotic osteoblasts with the MAPK kinase inhibitor PD098059 reduced the elevated levels of Erk phosphorylation and increased basal DNA synthesis. Collectively, our data show that altered osteoblast proliferation in human osteoporosis may result from dysregulation of IGF-I receptor signaling, including constitutive activation of the IRS-2/Erk signaling pathway, which becomes unresponsive to IGF-I, and defective induction of the IRS-1/Akt signaling pathway.     

Fabry disease in Italy: first epidemiologic and collaborative study

The authors sought to define the prevalence of Fabry disease and to establish the incidence and its natural history in Italy. The aim of this study was to point out the first clinical signs and symptoms to perform an early diagnosis and hence to start a specific therapeutic treatment. Fabry disease is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. Fabry disease is a severe X-linked disorder presenting with a higher morbidity between the third and the fourth decade of life. Fabry disease may be confused with other diseases or completely misdiagnosed: its frequency is estimated worldwide to be 1:117000. In Italy, 65 patients have been identified by several specialized institutions; age, sex, onset of first clinical signs and symptoms were analyzed and reported. In conclusion, this is the first Italian collaborative study that allows to delineate and point out the clinical signs of Fabry disease to perform a correct and early diagnosis. Enzyme replacement therapy is now available and its early beginning can prevent renal and cardiac failure, improve the quality of life and life expectancy in these patients.     

A cohort study of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis> infection dynamics in Western Kenya Highlands

Background  

The Kenyan highlands were malaria-free before the 1910s, but a series of malaria epidemics have occurred in the highlands of western Kenya since the 1980s. Longitudinal studies of the genetic structure, complexity, infection dynamics, and duration of naturally acquired Plasmodium falciparum infections are needed to facilitate a comprehensive understanding of malaria epidemiology in the complex Kenyan highland eco-epidemiological systems where malaria recently expanded, as well as the evaluation of control measures.     

Cardiovascular safety of aripiprazole and pimozide in young patients with Tourette syndrome

The pharmacotherapy for tic management in Tourette syndrome (TS) relies on neuroleptics, which have been associated with electrocardiographic abnormalities, including QTc interval prolongation. This study assessed the cardiovascular safety of the newer antipsychotic aripiprazole in comparison with the neuroleptic pimozide among young patients affected by TS. Fifty patients aged 6–18 years were assigned to either pimozide (n = 25; mean daily dose 4.4 mg/die) or aripiprazole (n = 25; 5.3 mg/die) treatment for up to 24 months. All patients underwent five serial cardiovascular assessments (baseline, 6, 12, 18 and 24 months). The group treated with pimozide showed significant changes in blood pressure (decreased), QT and QTc (both prolonged). The aripiprazole group showed changes from baseline to peak values in blood pressure (increased), whilst modifications in QT and QTc were not statistically significant. At equivalent doses, aripiprazole is characterised by a safer cardiovascular profile than pimozide, being associated with a lower frequency of QTc prolongation.     

Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance,Dyslipidemia, Atherosclerosis and Coronary Heart Disease

Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease.     

D1 receptors play a major role in the dopamine modulation of mouse ileum contractility

Since the role of dopamine in the bowel motility is far from being clear, our aim was to analyse pharmacologically the effects of dopamine on mouse ileum contractility. Contractile activity of mouse ileum was examined in vitro as changes in isometric tension. Dopamine caused a concentration-dependent reduction of the spontaneous contraction amplitude of ileal muscle up to their complete disappearance. SCH-23390, D1 receptor antagonist, which per se increased basal tone and amplitude of spontaneous contractions, antagonized the responses to dopamine, whilst sulpiride or domperidone, D2 receptor antagonists, were without effects. The application of both D1 and D2 antagonists had additive effects. SKF-38393, D1 receptor agonist, mimicked dopamine-induced effects. Dopamine responses were insensitive to tetrodotoxin, atropine, nitric oxide synthase inhibitor or adenosine receptor antagonists, but they were reduced by adenylyl cyclase inhibition or apamin. Dopamine at a concentration which did not cause a significant reduction of phasic contractions inhibited the cholinergic contractions in response to field stimulation. SCH-23390 per se induced an increase of the neural cholinergic contraction and antagonized the dopamine effects, whilst sulpiride or domperidone did not. The application of D1 and D2 antagonists had additive effects. In conclusion, mouse ileum is under basal inhibitory control by dopamine, through D1 receptor activation, linked to adenylyl cyclase and activation of apamin-sensitive potassium channels. An agonistic interaction of the dopamine receptor subtypes in the regulation intestinal contractility has being also highlighted. This study would provide new insight on the pharmacology of the modulation of the gastrointestinal contractility by dopamine.     

Neuroendocrine–immune interactions in healthy aging

Aim: The nervous, endocrine and immune systems are connected by shared neurotransmitters, hormones and cytokines. The function of these systems shows patterns of circadian rhythmicity and a number of age‐related changes in the 24‐h hormonal and non‐hormonal rhythms have been found in older human beings. The aim of this study was to evaluate integration among the nervous, endocrine and immune systems in the elderly. Methods: Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every 4 h for 24 h from 15 healthy young‐middle‐aged subjects (range 36–55 years, mean age ± standard error [SE] 44.08 ± 1.76) and 15 healthy old‐aged subjects (range 67–79 years, mean age ± SE 68.52 ± 1.27). Results: There was a statistically significant difference between the groups in the observed values of CD20 (total B cells higher in young‐middle‐aged subjects, P = 0.02), CD25 (activated T cells with expression of the α‐chain of interleukin‐2 receptor, higher in elderly subjects, P = 0.04) and DR⁺ T cells (activated T cells higher in elderly subjects, P = 0.01). There were different correlations among lymphocyte subpopulations and hormone serum levels in young and middle‐aged subjects in compared to old‐aged subjects. In the group of young‐middle‐aged subjects, a clear circadian rhythm was validated for the time‐qualified changes of all the factors studied. In the group of elderly subjects, a clear circadian rhythm was validated for the nyctohemeral changes of CD3 (with a phase delay of 3 h), CD8, CD4/CD8 ratio, CD16, CD25 (in opposite phase), cortisol (with a phase delay of 1 h) and melatonin. Conclusion: The results of the current study show that aging is associated with enhanced responsiveness of the T‐cell compartment, impairment of B‐cell compartment and alterations in temporal architecture and correlations of neuroendocrine–immune parameters. Geriatr Gerontol Int 2011; 11: 98–106.     

Recognition and naming of famous buildings: Italian normative data

Semantically unique items are concrete entities characterized by a unique cluster of semantic information. In this field, neuropsychology has always given more attention to faces than to other kind of stimuli. An important category that has been largely neglected so far is famous buildings. A total of 200 healthy Italian adults with age, sex and education homogenously distributed across subgroups were administered a famous buildings naming and recognition test, which assessed both visual and verbal modalities. The test was divided in seven sections; norms were calculated taking into account demographic variables such as age, sex and education. Multiple regression analyses showed that education influenced significantly the performance on all subtests; age had a significant effect for five subtests; sex for three subtests. Adjusted scores were used to determine inferential cutoff scores and to compute equivalent scores.