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Background Several observational studies have shown that exercise reduces the risk of cognitive decline; however, evidences from long-term, well-conducted, randomized controlled trials are scanty. The principal aim of this study is to verify whether a long-term program of multimodal supervised exercise improves the cognitive function and/or reduces the rate of cognitive decline in older adults at different degrees of risk for dementia. Methods/design EPD is a parallel group, double-blind, randomized controlled trial. Community-dwelling volunteers aged 50 years or more are being recruited from different community centers and screened for eligibility. Enrolled subjects are being divided in 3 groups: a) without subjective or objective cognitive impairment, b) with subjective memory complaints, and c) with mild cognitive impairments. Participants in each group (at least 180) are being randomly assigned (1:1) to an experimental group, performing a supervised training including aerobic and resistance exercises of moderate/high intensity, or to a control group. Primary outcome will be 48-months changes in Mini Mental State Examinations. Secondary outcomes will be changes in several cognitive tests including a composite cognitive score. Time points will be at baseline, and at 6, 12, 24, 36 and 48 months. Statistical analysis will be done as intention to treat, complete case and mixed model analysis. Discussion EPD is the first trial to examine the effects of a long exercise program (48 months) on cognitive performances. If successful, this trial may provide evidence for using long-term and multimodal exercise interventions for dementia prevention programs in the aging population. Trial registration The study is registered at ClinicalTrials.gov with the code NCT02236416.

This study aimed at comparing the effects of intermittent and repeated sprint ability training on physiological variables.Sixteen young female basketball players were randomly allocated to intermittent training (IT=8) or repeated sprint ability training (RST=8) groups. The following outcomes were measured at baseline and after 6 weeks of training: Yo-Yo intermittent recovery (Yo-Yo) and repeated sprint ability (RSA) tests.For all the variables investigated the effect of training type showed a different trend respect at current knowledge. In the RSA, best time (BT) was a significant main effect of training time (pre- vs. post-) (P0.0001), and of the interaction training type/time (P=0.03). The RST showed a decrease in BT of 3.1% (P=0.005) while the IT showed a decrease of 6.2% (P0.0001). In the IT there was a significant main effect of time for the total distance with an increment of 26.9%, and a significant main effect of time in the final speed with an increment of 1.23%.These findings suggest that the two training methods used in this study can be an effective training strategy for inducing anaerobic and basketball-specific training schedules. Besides, even when IT training is not done at very high speed, it can increase the maximum speed of the RSA.

Background: Several studies have shown an elevated prevalence of coeliac disease (CD) in sibs of coeliac patients (risk 8-12%). Aim and method: This study seeks to evaluate the risk that sibs of children with CD will also develop CD. This cohort of 188 Italian families was composed of probands with CD, at least one sib, and both parents. CD status was determined and HLA-DQ genotyping performed for all family members. The study also used a data set of Italian triads (127 probands and both their parents) also genotyped for HLA-DQ. Results: The overall risk that a sib of a CD patient will develop the disease is estimated at 10% in this sample. The risk estimate ranges from 0,1 to 29% when HLA-DQ information of the proband, parents and sib is considered. We found a negligible risk (lower than 1%) for 40% of the sibs of probands, a risk greater than 1% but less than 10% for 30%, and finally a high or very high risk (above 25%) in one third of families. Conclusion: These results make it possible to provide more accurate information to parents with child with CD about the real risk for another child. An antenatal estimate of the order of risk of CD is now possible. Specific follow-up can thus be offered for babies at high risk.

The aim of this study was to identify the influence of training workloads and dietary habits on the menstrual status of elite rhythmic gymnasts. In many sports disciplines, it has long been assumed that menstrual disorders among elite female athletes are related to intense physical effort and insufficient energy intake. Potential consequences of this condition include reduced fertility and decreased bone density.Eighty-one female gymnasts (age 15.9±3.1) completed two self-administered questionnaires: the Menstrual History Questionnaire (MHQ), and the Semiquantitative Food Frequency Questionnaire (FFQ). Eighty female athletes (age 16.3±3.7), who participated in basketball, volleyball, tae kwon do and fitness activity served as a control group. Physical characteristics, menstrual cycles, training workloads and dietary habits were compared and the relationship between physical training and menstrual cycle characteristics was assessed for the two groups.Fifty percent of the gymnasts declared themselves amenorrheic. Age was significantly and positively correlated (P0.01) with menarche and menstrual irregularities, and negatively correlated with amenorrhea. The percentage of variance for age at menarche, explained by training hours/week and body mass, was 43%, (P0.01).The present study, which examined and compared different age groups of gymnasts, showed that young rhythmic gymnasts who trained intensively, had a delayed onset of menarche of more than two years, thus favouring secondary amenorrhea. Nonetheless, almost all athletes, even though with significant delay, reached cycle regularity, thus minimizing the effect of menstrual disorders on fertility and bone density.

The forkhead, Fox, gene family comprises a diverse group of 'winged-helix' transcription factors that play important roles in development, metabolism, cancer and aging. Recently, several forkhead genes have been demonstrated to play critical roles in lymphocyte development and effector functions. Alterations of the FOXN1 gene in both mice and humans result in a severe combined immunodeficiency caused by an intrinsic defect of the thymus associated with congenital alopecia (Nude/severe combined immunodeficiency phenotype). FOXN1 is a member of the class of proteins involved in the development and differentiation of the central nervous system. We identified a human fetus homozygous for a mutation in FOXN1 gene who lacked the thymus and also had abnormal skin, anencephaly and spina bifida. Moreover, we found that FOXN1 gene is expressed in mouse developing choroid plexus. These observations suggest that FOXN1 may be involved in neurulation in humans.

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

OBJECTIVES: Polymorphisms in the major histocompatibility complex class I chain-related gene A may influence its binding to the Natural Killer Cell Receptor G2D (NKG2D). We looked for polymorphisms in major histocompatibility complex class I chain-related gene A exon 5 and in Human Leukocyte Antigen (HLA)-DQ/DR in adult coeliac disease patients to determine whether they affected coeliac disease phenotypes. METHODS: Adult coeliac disease patients with (n=98) and without (n=93) gastrointestinal symptoms (gastrointestinal symptoms+/gastrointestinal symptoms-) and 108 control subjects from Campania (Italy) were characterized by Polymerase Chain Reaction (PCR) sequence specific oligonucleotide followed by PCR sequence specific primer assays for HLA DQ/DR, and by PCR followed by capillary electrophoresis for major histocompatibility complex class I chain-related gene A exon 5 polymorphisms. Immunoglobulin A (IgA) anti-transglutaminase antibodies were also evaluated by immunosorbent assay. RESULTS: Five different major histocompatibility complex class I chain-related gene A alleles were detected in both coeliac disease patients and control subjects. The major histocompatibility complex class I chain-related gene A 5.1 allele occurred more frequently in patients than in controls (p

Background: Chronic liver diseases can progress to cirrhosis and to hepatocellular carcinoma. Timely and unequivocal recognition of the neoplastic evolution of cirrhosis is critical. To this aim, we used a noncompetitive reverse transcription-PCR procedure to analyze aldolase A mRNA in liver tissue from patients with chronic liver diseases at different stages. Methods: We studied 12 patients with hepatocellular carcinoma, 19 patients affected by chronic hepatitis C or cirrhosis, and 7 healthy controls. Aldolase A mRNA was reverse-transcribed to cDNA, which was then amplified by PCR. The amplified segments were “read” with a novel dot-blot procedure. A calibrator with the same sequence, synthesized in vitro using a T7 phage promoter, was processed at scalar dilutions in parallel to the target samples to generate a calibration curve and so quantify the target mRNA (detection limit, 0.03 amol; linearity spanning five orders of magnitude). Results: Aldolase A mRNA was ∼10-fold higher in liver biopsies from patients with hepatocellular carcinoma vs patients with chronic hepatitis C or cirrhosis, and healthy individuals. Furthermore, aldolase A mRNA concentrations were 1.2- to 21.3-fold higher in 12 liver biopsies compared with the paired surrounding cirrhotic tissue. Conclusions: The quantitative analysis of liver tissue aldolase A mRNA differentiates between nonneoplastic chronic liver diseases and hepatocellular carcinoma, which suggests that it has diagnostic potential.

Objective To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever. Methods 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients. Results Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of ‘familial Mediterranean fever (FMF)-like symptoms’ decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms’. Conclusions This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an autosomal-dominant disease caused by mutations of the type I tumor necrosis factor receptor (TNFRI) gene (TNFRSF1A) (1,2). The TNFRSF1A mutations reported in TRAPS patients include missense substitutions, mainly affecting the highly conserved cysteine residues of the extracellular cysteine-rich domains involved in disulfide bond formation and in the folding of the extracellular portion of TNFRI (3,4). These genetic variants (also defined as structural mutations) have a high penetrance, and the corresponding phenotype is characterized by a severe disease course. Patients display long-lasting fever episodes (duration of 1–3 weeks) associated with rash, arthralgia, myalgia, and abdominal pain. Progression toward a more chronic disease course and renal amyloidosis is a possible long-term complication in adulthood (5). Patients may require prolonged treatment with steroids and use of second-line drugs (3–5). Among Caucasian populations, the R92Q mutation is the most frequently observed variant of the TNFRSF1A gene in children with periodic fever (6,7). R92Q is a missense and low-penetrance mutation with no relevant impact on the structure and function of the mutated protein and is usually associated with a milder disease course, characterized by episodes of fever lasting only a few days, lower intensity of disease-associated symptoms, and a much lower prevalence of amyloidosis (3,4). Notably, according to different studies, the allele frequency of the R92Q variant in the general population ranges from 1.2% to 4% (3,4,6,8). Apart from the description of very few anecdotal cases of renal amyloidosis in adults (9), no information is available on the long-term clinical profile of patients affected with TRAPS who are carriers of the R92Q mutation. Indeed, only 10–20% of children with a clinical picture consistent with a periodic fever turn out to be carriers of at least one mutation of the genes known to be associated with monogenic periodic fevers such as familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS (10). The clinical spectrum of the large group of mutation-negative children with periodic fever is extremely variable. In the pediatric population, the most common cause of periodic fever is a clinical entity characterized by recurrent episodes of fever, known under the acronym PFAPA (periodic fever, aphthosis, pharyngitis, and adenitis syndrome) (6,11,12). The genetic basis of this syndrome is not yet documented, and usually spontaneous resolution of the fever episodes will occur a few years after symptom onset. In the present study, we chose to analyze mutation-negative patients who fulfilled the PFAPA criteria, in order to have a more homogeneous disease control group. The aim of the present study was to analyze the long-term clinical course in children with periodic fever carrying the R92Q mutation, as compared with that in TRAPS patients carrying structural mutations of TNFRSF1A and patients with periodic fever of unknown origin fulfilling the criteria for PFAPA.

Background The transcription factor FOXN1 is implicated in the differentiation of thymic and skin epithelial cells, and alterations in it are responsible for the Nude/SCID phenotype. During a genetic counselling programme offered to couples at risk in a community where a high frequency of mutated FOXN1 had been documented, the identification of a human FOXN1(-/-) fetus gave the unique opportunity to study T cell development in utero. Results Total blockage of CD4(+) T cell maturation and severe impairment of CD8(+) cells were documented. Evaluation of the variable-domain beta-chain (V beta) families' usage among T lymphocytes revealed that the generation of T cell receptor (TCR) diversity occurred to some extent in the FOXN1(-/-) fetus, although it was impaired compared with the control. A few non-functional CD8(+) cells, mostly bearing TCR gamma delta in the absence of CD3, were found. Discussion FOXN1 is crucial for in utero T cell development in humans. The identification of a limited number of CD8(+) cells suggests an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.

Background: Severe obesity is a major worldwide public health concern affecting 0.5–5% of the adult population. Adiponectin (Acpr30), an adipokine secreted from adipocytes, shows pleiotropic beneficial effects on obesity and related disorders. In this study, sequence analysis of Acpr30 gene (ACDC) was performed in a highly selected population of severely obese young adult patients from Southern Italy to investigate the associations between polymorphisms in the ACDC gene and the development of severe obesity concomitantly with other features of the metabolic syndrome. Methods: The ACDC gene was analyzed by direct sequencing in the severely obese patients (n = 220) and compared to healthy controls (n = 116). The associations between the ACDC gene single-nucleotide polymorphisms (SNPs) and the levels of serum Acpr30 as well as the correlation with the presence of severe obesity jointly associated with other features of the metabolic syndrome were also investigated. Total serum Acpr30 concentrations were measured by the ELISA method. Results: ACDC gene molecular screening revealed the presence of previously described SNPs and a new nucleotide alteration, c.355T>G, leading to a protein variant, p.L119V. Measurement of serum concentration of Acpr30 demonstrated lower levels of Acpr30 in the obese population compared to controls (30.5 ± 28.3 vs. 43.9 ± 35.7 μg/ml, p < 0.01); in particular, significantly lower Acpr30 concentrations were observed in obese patients bearing c.–11377C>G SNP CG+GG genotypes than in those with CC genotype (22.9 ± 20.5 vs. 33.1 ± 29.4 μg/ml, p < 0.05). Conclusions: Our results confirmed that low serum levels of Acpr30 are related to severe obesity and a difference in protein expression is associated with variants in ACDC gene promoter region.

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked allelic neuromuscular disorders that have a prevalence of 1 in 3500 live-born males. The genetic defect is the result of mutations of the dystrophin gene, which encodes a 427-kDa rod-shaped cytoskeletal protein (1). The locus is very unstable: one-third of all DMD/BMD cases represent new mutations without a family history of the disease (1). Approximately 50–70% of DMD/BMD cases are the result of macrodeletions, and partial gene duplications have been reported in ∼6% of patients (2). Both macrodeletions and macroduplications are preferentially clustered in two areas, the amino-terminal (exons 3–7) and the central (exons 44–55) regions (1). The remaining cases are presumably attributable to point mutations or small insertions/deletions (2) scattered along the entire gene. PCR detection of macrodeletions is very useful in the analysis of affected males (3)(4), but it provides no information about the carrier status of at-risk women. Carrier status within families is usually assessed by haplotype analysis (5), fluorescence in situ hybridization (6), amplification of ectopic transcripts (7)(8), dosage analysis on Southern blots (9), or separation of quantitative PCR products by gel electrophoresis (10). Semiquantitative methods, based on the separation of fluorescently labeled amplified exons by gel or capillary electrophoresis, are also available (11)(12)(13)(14)(15). Here we report a quantitative PCR method, followed by separation by capillary gel electrophoresis of the fluorescently labeled amplified exons of hot spot regions of the dystrophin gene, which allowed us to detect ∼99% patients (affected males and female carriers) with macrodeletions and 89% with macroduplications, and to identify small insertions or deletions in those regions. This method is rapid, and unlike other procedures, it includes an internal standard to normalize amplification efficiency and to calculate a diagnostic index. We validated …