Dysfunctional coping is related to impaired skin-related quality of life and psychological distress in patients with neurofibromatosis type 1 with major skin involvement.

BACKGROUND: Low skin-related quality of life (QoL) is usually associated with low levels of self-confidence and self-esteem and with high levels of anxiety and depression symptoms. The way patients cope with a physical disease impacts significantly on their psychosocial adjustment to the disorder and on their emotional functioning. OBJECTIVES: To explore how coping strategies, skin-related QoL, psychological distress and self-esteem interact in a sample of individuals with neurofibromatosis type 1 (NF1). METHODS: Seventy-two adult patients with NF1 completed the following questionnaires: Coping Orientation to Problem Experiences (COPE), Skindex-29, Padua Skin-Related QoL questionnaire (PSRQ), State-Trait Anxiety Inventory-X2 form (STAI-X2), Depression Questionnaire (DQ) and Rosenberg Self-Esteem Scale (RSES). The k-modes algorithm was used to identify clusters of patients based on four variables: sex, NF1 severity, number and distribution of cutaneous neurofibromas. Individuals in different clusters were compared with regard to their scores; correlations between scores were analysed within each cluster. RESULTS: Two main clusters were identified: individuals in Cluster 1 had a larger number and more widespread distribution of neurofibromas compared with Cluster 2. Patients in Cluster 1 scored higher only on several PSRQ and Skindex-29 scales. Among patients in Cluster 1, the COPE 'avoidance strategies' scale was significantly correlated with the PSRQ 'physical distress and impairments' scale, the Skindex-29 'physical symptoms' and 'functioning' scales, the STAI-X2, the DQ and the RSES. CONCLUSIONS: Patients with major skin involvement have reduced skin-related QoL. Among them, current findings tentatively suggest that the higher the use of dysfunctional coping, the more impaired are QoL, psychological distress and self-esteem. What's already known about this topic? Neurofibromatosis type 1 (NF1) can affect the quality of life (QoL) in adolescent and adult patients. Low skin-related QoL is usually associated with low levels of self-confidence and self-esteem and with high levels of anxiety and depression symptoms. Questionnaires evaluating skin-related QoL, anxiety, depression, self-esteem and coping are available. What does this study add? Patients with a large number and a widespread distribution of cutaneous neurofibromas have reduced skin-related QoL compared with patients with minor skin involvement. The newly developed Padua Skin-Related QoL questionnaire allows the simultaneous evaluation of discomfort and comfort skin-related QoL dimensions in patients with NF1. Among patients with major skin involvement, the higher the use of dysfunctional coping, the more impaired are skin-related QoL, psychological distress and self-esteem. Our data suggest that patients with NF1 with major skin involvement who endorse dysfunctional beliefs about their own coping abilities might benefit from psychological counselling and coping skills treatments aiming to both improve perceived self-efficacy and learn more adaptive coping strategies.

Human olfactory sensitivity for bourgeonal and male infertility: a preliminary investigation.

Olfactory receptor (OR) expression is also present in the sperm cells and could mediate sperm chemotaxis. OR1D2 was the first OR expressed in the testis demonstrated to be involved in chemotaxis and to be expressed also in the nose with a similar behavior. Bourgeonal is the OR1D2 most potent known agonist. Infertility affects ~15 % of couples in western countries and sometimes it is unexplained. This pilot study compared the bourgeonal olfactory thresholds, the ability of sperm to sense the bourgeonal and the frequency of 13 single nucleotide polymorphisms (SNPs) of OR1D2 gene in nine males suffering of unexplained infertility with a control group of 15 healthy males. The mean olfactory threshold for bourgeonal was statistically different between the study group (10.5 ± 3.7; median 12.3) and the control group (14.0 ± 2.8; median 15.5) (p = 0.006). Statistical analysis showed a significantly higher percentage of spermatozoa that migrated toward the capillaries filled with bourgeonal in the control group compared to the study group (p < 0.0001). Sperm migration was equally inhibited in both groups of subjects when, together with bourgeonal, capillaries were filled with undecanal, a strong bourgeonal inhibitor (p = 0.42). The 13 SNPs of OR1D2 revealed a statistically significant difference for allele and genotype frequency of rs769423 in study group versus control group (p = 0.02). The present preliminary study seems to confirm the important role of OR1D2 both in nose and spermatozoa and may explain the idiopathic infertility of the study group. Further studies on larger series are mandatory to confirm our preliminary evidence.

Reduced artery diameters in Klinefelter syndrome.

Various epidemiological studies in relatively large cohorts of patients with Klinefelter syndrome (KS) described the increased morbidity and mortality in these subjects. Our aim was to study the structure and function of arteries in different districts to investigate in these subjects possible alterations. A total of 92 patients having non-mosaic KS, diagnosed in Centre for Human Reproduction Pathology at the University of Padova, and 50 age-matched healthy male controls were studied. Klinefelter syndrome subjects and controls evaluation included complete medical history, physical examination, measurement of concentrations of the reproductive hormones, lipidic and glycidic metabolism, AR function and sensitivity, ultrasound examinations (diameters, carotid intima-media thickness and brachial flow-mediated dilation) of brachial, common carotid and common femoral artery and abdominal aorta. Klinefelter syndrome patients showed significantly reduced artery diameters in all districts evaluated. On the contrary no statistically significant difference was found in cIMT and brachial FMD values between KS patients and controls. Furthermore, we found no statistically significant correlation of artery diameters with reproductive hormones, metabolic parameters, anthropometric measures and weighted CAG repeats. To our knowledge, this is the first study finding a reduced artery diameter in several districts in KS patients compared with that of normal male subjects and overlapping to that of female subjects. We have not an explanation for this phenomenon, even if a possible involvement of genes controlling the development of vascular system might be hypothesized, and further research is required to verify this hypothesis.

How the human spermatozoa sense the oocyte: a new role of SDF1-CXCR4 signalling.

For fertilization to occur in mammals, ejaculated spermatozoa must reach the egg which, following ovulation has moved from the ovary into the Fallopian tube. Two active mechanisms of spermatozoa guidance have been shown in mammals: thermotaxis and chemotaxis. The identity of most of human spermatozoa chemoattractants is unknown, and herein we tested if SDF1 (chemokine stromal cell-derived factor-1) and its pathway is involved in spermatozoa chemotaxis. We found that SDF1 is expressed in the oocytes, endometrium and follicular fluid, as well as its specific receptor CXCR4 (chemokine CXC motif receptor 4) is expressed in the head of spermatozoa. By SDF1 gradient experiments, we stated that SDF1 is able to induce hyperactivation in spermatozoa leading to accumulation, to give rise to an increase in intracellular calcium concentration, and to preserve the mitochondrial status and not to induce acrosome reaction. Our findings suggest these phenomena could reflect spermatozoa chemotaxis, and that SDF1 action could represent an important event leading to egg fertilization, even if further studies regarding the link between spermatozoa accumulation and chemotaxis are mandatory. These data suggest that the SDF-1/CXCR4 signalling could be used to manipulate the human fertilization, to improve both the outcome of physiological or assisted reproduction, and to develop new contraceptive methods, by development of SDF1 or CXCR4 antagonist.

Human papilloma virus in the sperm cryobank: an emerging problem?

Human papilloma virus (HPV) infection is very common worldwide, but the actual incidence and significance of HPV infection in sperm are poorly understood. In this study, we evaluated the presence of HPV in spermatozoa from thawed semen samples previously stored in our sperm bank. We performed polymerase chain reaction and in situ hybridization for HPV detection in cryovials belonging to 98 oncology patients and in 60 semen samples from healthy controls. Statistical analysis was performed by two-tailed Student's t-test and Fisher's exact test. The frequency of HPV semen infection was 6.1% in thawed cryovials from patients and 3.3% in semen samples from controls. Among the patients, four were found positive for high-risk HPV, one for medium-risk HPV and another for low-risk HPV. Patients had a significantly higher percentage of infected sperm than controls. In conclusion, this report shows the presence of HPV in sperm cells from cryovials of a sperm bank. It is still unclear if HPV-infected sperm are able to cross-contaminate cryovials and impair the outcome of assisted reproduction techniques or to infect partners. Further studies are needed to understand whether screening for HPV should be performed in all semen samples before sperm banking or before intra-cytoplasmic sperm injection procedures.

Retraction: Expression of phosphodiesterase type 5A in human spermatozoa and influence of its inhibition on motility and functional sperm parameters.

The paper entitled "Expression of phosphodiesterase type 5A in human spermatozoa and influence of its inhibition on motility and functional sperm parameters" by C. Foresta et al, which was published online on 1 July 2010, has been withdrawn at the authors' request.

Mutations in dynein genes in patients affected by isolated non-syndromic asthenozoospermia.

BACKGROUND: Asthenozoospermia (AZS) is a common cause of male infertility characterized by reduced forward motility (WHO grade A+B sperm motility <50% or A < 25%) or absent sperm motility in fresh ejaculate. AZS may exist as an isolated disorder, in combination with other sperm anomalies or as part of a syndromic association. Up to date, only a few genes, constituting the cilia/flagella structure, have been associated with isolated AZS in humans, whereas several other genes are known to be involved in syndromic form of AZS, including primary ciliary dyskinesia (PCD) and Kartagener syndrome (KS). Axonemal ultrastructural defects, including absent or shortened arms of dyneins, can be found in >50% of PCD/KS patients. Approximately 90% of KS male patients are affected by AZS. The majority of KS patients can be ascribed to dynein genes mutations. METHODS: Mutation screening of DNAI1, DNAH5 and DNAH11 genes was performed in 90 patients with isolated non-syndromic AZS and 200 controls. RESULTS: We found three mutations (one in each gene) specifically associated with AZS in seven patients (7.8%). Mutations are inherited from the mothers and may be found in familial clusters. No ultrastructural axonemal anomaly was detected in sperm. CONCLUSIONS: We report for the first time a possible association between mutations in dynein genes and isolated AZS. Male carriers of the mutations always exhibit AZS, whereas female carriers manifest no alterations in either fertility or pulmonary clearance.

Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects.

OBJECTIVE: We tested the effect of two phosphodiesterase type-5 (PDE5) inhibitors, sildenafil and tadalafil, on ophthalmic artery (OA) blood flow velocity and investigated the presence of the PDE5 enzyme on human retinal tissue in comparison with the PDE6 enzyme localization. METHODS: Using Colour Doppler ultrasonography (CDU) we investigated, in 30 healthy young subjects (27.8 years of age; range, 24.3-33.7 years), the effects of a single oral dose of sildenafil (100 mg), tadalafil (20 mg), and placebo on OA blood flow velocity. Western blot for PDE6 and PDE5 protein expression was performed on frozen samples of human retina, testis, sperm, skin, and corpus cavernosum. Immunohistochemistry was performed on two ocular globes from dead donors. RESULTS: CDU showed a relationship between the administration of PDE5 inhibitors and OA blood flow velocity modifications in a time-dependent manner. Western blot and immunohistochemical analysis showed PDE6 and PDE5 presence in human retinal tissue and gave a map of its distribution. CONCLUSION: We demonstrated that (a) tadalafil and sildenafil are able to modify the OA flux in a time-dependent manner; (b) the PDE5 enzyme is expressed on retinal and choroid vasculature (smooth muscle and endothelial cells), on ganglion and bipolar cells; (c) human retinal tissues express the PDE6 enzyme in the rod and cone photoreceptors; (d) visual side effects after PDE5 inhibitors administration may be linked to a specific effect on the PDE5 enzyme; and (e) the PDE5 enzyme may have a physiologic role on ganglion and bipolar cells that need to be further investigated.

Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility.

CONTEXT: Mutations in the androgen receptor (AR) gene can cause the androgen insensitivity syndrome (AIS). For complete and severe partial AIS, well-characterized in vitro functional assays can be used for genotype-phenotype correlation; however, for mild forms of AIS, as associated with male infertility, experimental evidence is scarce or lacking. In particular, optimal in vitro functional tests informative about the genotype-phenotype relation have not been described. OBJECTIVE: The objective of this study was to investigate the association among genotype and phenotype for AR mutations found in infertile males by conventional functional assays and additional in-depth studies performed with several gene reporters. DESIGN: To this aim, we selected four AR missense mutations associated with isolated male infertility (L547F and two novel mutations A474V and S650G) or partial AIS (Y571H). After introduction of the specific mutations in AR expression plasmid, we performed classical in vitro studies (Western immunoblotting, electrophoretic mobility shift assay, hormone-response curves) and transactivation assays with different reporter constructs (MMTV, Sc-ARU-TK, TAT-GRE- 2X, Slp-ARU-TK and PEM). RESULTS AND CONCLUSIONS: Our results showed that standard functional tests provide sufficient information only for severe AR mutations, whereas for AR mutations found in mild AIS patients with male infertility, only an extensive analysis with different in vitro systems, and in particular with PEM promoter, can give information on the functionality of the AR and therefore on the pathogenicity of the mutations and on genotype-phenotype correlation.

Y chromosome haplogroups and susceptibility to testicular cancer.

Although in the past decades much progress in testicular cancer (TC) management has been made, little is known about the possible genetic causes and molecular mechanisms involved in its aetiopathogenesis. Some studies on possible contribution of the Y chromosome in TC development have been previously published, but data are not conclusive. In particular, ethnic influence and spermatogenic activity of patients with TC have not been adequately considered in previous studies, although they may represent important confounding factors. The objective of this study is to analyse the contribution of the Y chromosome in testicular germ cell cancer subjects who are well defined at the microgeographical, clinical and seminological level. We analysed Y chromosome classic azoospermia factor (AZF) deletions, partial AZFc deletions and Y haplogroups in 118 sporadic cases of testicular germ cell cancer and 93 microgeographically matched controls. Y chromosome screening failed to identify Y chromosome microdeletions in either cases or controls. Y chromosome haplogroup distribution and frequencies did not differ between cases and controls. Furthermore, no difference was observed when comparing patients with seminoma and non-seminoma, nor when comparing patients with TC with normozoospermia and azoo-oligozoospermia. Our findings combined with data reported so far suggest that classic AZF deletions and partial AZFc deletions are not a frequent cause or risk factor for TC and that different Y haplogroup distribution does not contribute to susceptibility to this tumour.

Paracrine and endocrine roles of insulin-like factor 3.

Insulin-like factor 3 (INSL3) is expressed in Leydig cells of the testis and theca cells of the ovary. This peptide affects testicular descent by acting on gubernaculum via its specific receptor leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8). From initial animal data showing the cryptorchid phenotype of Insl3/Lgr8 mutants, an extensive search for mutations in INSL3 and LGR8 genes was undertaken in human patients with cryptorchidism, and a frequency of mutation of 4-5% has been detected. However, definitive proofs of a causative role for some of these mutations are still lacking. More recent data suggest additional paracrine (in the testis and ovary) and endocrine actions of INSL3 in adults. INSL3 circulates at high concentrations in serum of adult males and its production is dependent on the differentiation effect of LH. Therefore, INSL3 is increasingly used as a specific marker of Leydig cell differentiation and function.

Pure trisomy 19p syndrome in an infant with an extra ring chromosome.

We report a 12-month-old infant evaluated for severe hypotonia, psychomotor retardation, and facial dysmorphisms, including round face, high prominent forehead, downward slanted palpebral fissures, hypertelorism, short nose, chubby cheeks, long philtrum, anteverted lower lip, low-set asymmetric and dysmorphic ears. Karyotype analysis disclosed an extra mosaic ring chromosome, which included the whole 19p arm. Four additional patients with supernumerary ring 19 chromosomes have been reported, but none of them had pure trisomy 19p.

High frequency of subtelomeric rearrangements in a cohort of 92 patients with severe mental retardation and dysmorphism.

About 5-10% of patients with dysmorphisms, severe mental retardation, and normal standard karyotype are affected by subtelomeric chromosome rearrangements. Sequence homology between different chromosomes and variability between homologs make these regions more susceptible to breakage and reunion. We analyzed the telomeric regions of 92 of these patients, selected with strict clinical criteria. Fifteen individuals (16.3%) had subtelomeric rearrangements. Nine had a unique anomaly, which in one case had been inherited from a balanced parent. Six subjects had double segmental imbalances, including three de novo imbalances. This study provides further evidence for the plasticity of subtelomeric regions, which often results in cryptic rearrangements, and recommends stringent criteria for selecting patient candidates to telomere analysis.

Preliminary data suggest that mutations in the CgRP pathway are not involved in human sporadic cryptorchidism.

In testicular descent to the scrotum, a multistep process, many anatomical and hormonal factors play a role. Cryptorchidism occurs in about 1-2% of males and may cause secondary degeneration of the testes. Animal models have shown that abnormalities, in the calcitonin gene-related peptide (CgRP) activity, could be relevant in the pathogenesis of cryptorchidism. We performed a mutation screening by PCR exon amplification, single-strand conformation polymorphism (SSCP) and sequencing in four candidate genes, CgRPs (alphaCgRP, betaCgRP), their receptor (CgRPR) and the receptor component protein (CgRP-RCP), in 90 selected cases of idiopathic unilateral or bilateral cryptorchidism. Mutation screening of the coding regions and intron-exon boundaries revealed some polymorphic variants but no pathogenic sequence changes. These preliminary data suggest that these genes are not major factors for cryptorchidism in humans.

A gene for familial isolated chronic nail candidiasis maps to chromosome 11p12-q12.1.

Chronic mucocutaneous candidiases (CMC) are a group of rare disorders where an altered immune response against Candida leads to persistent and/or recurrent infections of the skin, nails, and mucous membranes. We analysed a five-generation Italian family with an isolated form of CMC, affecting nails only, in the presence of low serum concentration of intercellular adhesion molecule I (ICAM-1). We excluded linkage to candidate regions on chromosomes 2p (CMC with thyroid disease), 21q22.3 (APECED), and 19q13 (ICAM-1). We then carried out a genome-wide scan and assigned the CMC locus to a 19 cM pericentromeric region on chromosome 11.

Mitochondrial 3243 BP mutation: a case report.

Mitochondrial DNA (mtDNA) gene defects may play a role in the development of maternally inherited diabetes mellitus and deafness (MIDD). Mutation in the mitochondrial gene at position 3243 was recently identified in several pedigrees of diabetes mellitus and deafness. As the mitochondria play an important role in glucose-stimulated insulin secretion in pancreatic beta-cells, we therefore searched for this mutation in a non-consanguineous family with MIDD from Southern Italy. The mitochondrial 3243 bp mutation of the tRNALEU (UUR) gene was identified in one subject with deafness and Type 1B diabetes mellitus and in his mother. The mother was affected by Type 2 diabetes mellitus, deafness and cardiomyopathy. Our study points out the variable phenotypic expression of this mitochondrial mutation. This may suggest the presence of other mitochondrial or nuclear mutations required to modulate the phenotype.

Allelic association of gene markers on chromosome 11q in Italian families with atopy.

UNLABELLED: In our study, the genetic linkage of the Fcepsilon RIbeta gene with atopy in 77 affected sibling pairs recruited from an Italian panel of 201 subjects has been examined. Atopy was defined by the presence of a positive skin prick test to one or more common aeroallergens, a positive RAST test to one or more common aeroallergens and an elevated circulating total IgE. Genotype analysis was performed by PCR amplification of Fcepsilon RIbeta CA and CI11-319 CA microsatellites. All the family members were also tested for the Ilepsilon 181 mutation with the ARMS method and for Leu181/Leu183 polymorphism. Seventy-two point five percent (72.5%) of the affected sibling pairs shared their maternal allele and 27.5% did not. Therefore, an increased maternal allele sharing was observed: chi2 = 8.10, p < 0.01. Comparing paternal versus maternal allele sharing, a significant difference was observed for the C1II-319 CA marker (chi2 = 4.32, p < 0.05). Atopy phenotype with positive skin prick test, RASTs, and high total serum IgE also showed greater sharing of maternal than paternal alleles in affected sibling pairs. Of the 201 subjects studied, 17 (8.4%) were positive for Leu181. Ten of these were children and seven (70%) had inherited the variant maternally. The seven children had maternally inherited Leu181/Leu183 and were atopic. Within this sample the maternal inheritance of Fcepsilon RIbeta Leu181/Leu183 was associated with an increased risk of IgE responses to common allergens, raised eosinophil counts and increased skin prick test reactions. Therefore, the variant identified a genetic risk factor for atopy. CONCLUSION: The central role of Fcepsilon RIbeta in atopy and the linkage data presented here point to the possibility that genetic variation in Fcepsilon RIbeta or its controlling element may cause differences in the extent of IgE responses between atopic and non-atopic subjects. A search for such mutations or polymorphisms will need to take into account some carriers of atopy among the normal population and genetic heterogeneity among atopic individuals.

Effect of variation in form on the cost of terrestrial locomotion.

The mass-specific minimum cost of terrestrial locomotion (Cmin) decreases with an increase in body mass. This generalization spans nearly eight orders of magnitude in body mass and includes two phyla. The general relationship between metabolic cost and mass is striking. However, a significant amount of unexplained interspecific variation in Cmin exists at any given body mass. To determine how variation in morphology and physiology affects metabolic energy cost, we measured the oxygen consumption of three comparably sized insects running on a miniature treadmill; the American cockroach Periplaneta americana, the caterpillar hunting beetle Calosoma affine and the Australian field cricket Teleogryllus commodus. Steady-state oxygen consumption (VO2ss) increased linearly with speed. Cmin was similar for crickets and cockroaches (8.0 and 8.5 ml O2 g-1km-1, respectively), but was substantially lower for beetles (4.6 ml O2 g-1km-1). The predicted value of Cmin for all three insects was within the 95% confidence intervals of the Cmin versus body mass function. However, the 95% confidence intervals extend approximately 2.5-fold above and 40% below the regression line, making the variation at any given body mass nearly sixfold. Normalizing for the rate of muscle force production by determining the metabolic cost per stride failed to account for the interspecific variation in the cost of locomotion observed in the three insects. Ground contact costs (i.e. VO2ss multiplied by leg contact time during a stride) in insects were similar to those measured in mammals (1.5-3.1 J kg-1) and were independent of speed, but did not explain the interspecific variation in the cost of locomotion. Muscles of the caterpillar hunting beetle may have a greater mechanical advantage than muscles of the Australian field cricket and American cockroach. Variation in musculo-skeletal arrangement, apart from variation in body mass, could translate into significant differences in the minimum cost of terrestrial locomotion.