No association between body mass index and sperm DNA integrity.

STUDY QUESTION: Is overweight associated with impaired sperm DNA integrity? SUMMARY ANSWER: High body mass index (BMI) is not associated with impaired sperm DNA integrity as assessed by the DNA Fragmentation Index (DFI). WHAT IS KNOWN ALREADY: Previous studies, based on fewer subjects and including mainly subfertile men, have shown conflicting results regarding the influence of overweight and obesity on sperm DNA integrity. STUDY DESIGN, SIZE, DURATION: This cross-sectional study was based on semen samples from 1503 men from the general population. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included two cohorts (cohort A and B) of military recruits (n = 275, n = 304, respectively), one group (cohort C) of fertile men and men without known fertility problems (n = 724), and one group (cohort D) of men between 19 and 40 years without known fertility problems (n = 200). In all cohorts, data were available on BMI, DFI as measured by the sperm chromatin structure assay (SCSA), standard semen characteristics, and potential confounders (age, abstinence time, smoking habits). The subjects were categorized according to BMI into four groups: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)) and obese (≥30.0 kg/m(2)). Using a linear regression model, the inter-group differences in DFI were calculated. Furthermore with the normal-weight group as the reference, the odds ratios (ORs) for DFI > 20% and DFI > 30%, were calculated for the other groups. Calculations were made for the material as a whole and after exclusion of cohort C which included proven fertile men. MAIN RESULTS AND THE ROLE OF CHANCE: We found that normal-weight men had significantly higher DFI than overweight men, with a mean difference of 1.13% (95% CI: 1.05-1.22%); P = 0.001). Overweight men had a reduced risk of having DFI ≥ 20% and DFI ≥ 30%, compared with normal-weight men; adjusted odds ratio (OR) = 0.61 (95% CI: 0.42-0.88; P < 0.01) and adjusted OR = 0.48 (95% CI: 0.28-0.84; P < 0.01), respectively. When excluding cohort C, the statistical significance was lost. Regarding standard semen parameters, we found that obese men had a higher percentage of progressive motile spermatozoa than normal-weight men; mean difference 1.15% (95% CI: 1.02-1.30%, P < 0.05) but the significance was lost when excluding cohort C. All other standard semen parameters were unaffected by BMI. LIMITATIONS, REASONS FOR CAUTION: A main limitation might be the cross-sectional nature of the data. Furthermore our study included a significant proportion of men with proven fertility (75% of cohort C, n = 550), and could therefore be biased toward fertility. WIDER IMPLICATIONS OF THE FINDINGS: Our study indicates that overweight per se is not associated with a higher level of sperm DNA damage. STUDY FUNDING/COMPETING INTERESTS: This research has been given grants from the following: EU 5th and 7th framework program (Inuendo and Clear projects, [Contracts no. QLK4-CT-2001-00202 and FP7-ENV-2008-1-226217)]), the Swedish Research Council (Grants No. 2007-2590, 521-2004-6072 and 521-2002-3907); the Swedish Governmental Funding for Clinical Research, Skåne county council's research and development foundation, MAS Funds, University Hospital MAS Foundation in Malmö, Crafoordska Fund, Ove Tulefjords Fund, Foundation for Urological Research, Fundacion Federico SA, and Gunnar Nilssons Cancer Fund. The authors declare that there are no conflicts of interest.

Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children.

Congenital cytomegalovirus (CMV) infection is the most common congenital infection causing childhood morbidity. The pathogenetic mechanisms behind long-term sequelae are unclear, but long-standing viremia as a consequence of the inability to convert the virus to a latent state has been suggested to be involved. Whereas primary CMV infection in adults is typically rapidly controlled by the immune system, children have been shown to excrete virus for years. Here, we compare T cell responses in children with congenital CMV infection, children with postnatal CMV infection and adults with symptomatic primary CMV infection. The study groups included 24 children with congenital CMV infection, 19 children with postnatal CMV infection and eight adults with primary CMV infection. Among the infants with congenital CMV infection, 13 were symptomatic. T cell responses were determined by analysis of interferon gamma production after stimulation with CMV antigen. Our results show that whereas adults display high CMV-specific CD4 T cell responses in the initial phase of the infection, children younger than 2 years have low or undetectable responses that appear to increase with time. There were no differences between groups with regard to CD8 T cell function. In conclusion, inadequate CD 4 T cell function seems to be involved in the failure to get immune control of the CMV infection in children younger than 2 years of age with congenital as well as postnatal CMV infection.

Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: clinical presentation of 22 children diagnosed during a 30-year period.

AIM: The aim of this study was to present the natural clinical course in children and adolescents with MPS III diagnosed during a 30-year period in Sweden. METHODS: The patients were identified from metabolic laboratory records between 1975 and 2004. Patient data were assessed from interviews of parents and by clinical examination and records from the patients. RESULTS: A total of 15 children, 68%, with MPS IIIA were diagnosed at a median age of 6.8 years (range 1.2-18.9 years). One boy had MPS IIIB and five children MPS IIIC, diagnosed at ages between 1.9 and 11.6 years. In one child the type was not determined. The median age of children with type IIIA who had deceased was 16.2 years (range 10.4-31.2 years). Ten individuals with MPS III are alive at ages between 5 and 29 years. In four families, two children were affected. CONCLUSION: In 22 Swedish children with Sanfilippo disease an early normal development followed by a delay in speech and an appearance of behaviour problems was found in most children during the early preschool period. Mental retardation was diagnosed in almost all individuals before starting school. Early diagnosis is important in this devastating, progressive disorder, not only for genetic counselling but also for participation in future treatments.

Congenital cytomegalovirus infection: the impact of cerebral cortical malformations.

AIM: Cytomegalovirus has been suggested to have a teratogenous influence during the migration of neural cells from the ventricular zones to the cortex during the gestational period. The aim of this study was to investigate the prevalence of congenital cytomegalovirus infections in a cohort of children with neurological disability and cerebral cortical malformations recognized by neuroimaging. METHODS: Twenty-six children with neurological disability and cerebral cortical malformations were investigated retrospectively for congenital cytomegalovirus infection by analysing the dried blood spot samples for cytomegalovirus deoxynucleic acid using qualitative polymerase chain reaction. RESULTS: CMV DNA in the dried blood spot samples was found in four out of 26 children. Two of these four had severe disabilities with mental retardation, autism, spastic cerebral palsy, epilepsy and deafness. A third child had epilepsy and unilateral cerebral palsy, while the fourth had a mild motor coordination dysfunction and hearing deficit. CONCLUSION: In our study, the number of congenital cytomegalovirus infections in children with cerebral cortical malformations was higher (4/26) than expected with reference to the birth prevalence (0.2-0.5%) of congenital cytomegalovirus infection in Sweden. We thus conclude that congenital cytomegalovirus infection should be considered in children with cortical malformations of unknown origin.

Mortality and cause of death in mucopolysaccharidosis type II-a historical review based on data from the Hunter Outcome Survey (HOS).

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Association between semen parameters and chance of fatherhood - a long-term follow-up study.

BACKGROUND: Evaluation of male fertility includes standard semen analysis; however, there is uncertainty about the value of sperm parameters in predicting fertility. OBJECTIVE: To evaluate the association between semen parameters and fatherhood during a long-time period. MATERIALS AND METHODS: Semen parameters (total sperm count, concentration, motility, and morphology) and sperm DNA fragmentation Index (DFI) assessed on samples collected from 195 Norwegian men from the general population in 2001/2002 were matched with information about fatherhood until 2015, obtained from the Medical Birth Register. The parameters were dichotomized as normal vs. abnormal according to the WHO reference values from 1999 and 2010. Cut-offs at 20% and 30% were used for DFI. RESULTS: Among men who had no children before 2003, those with normal progressive sperm motility had more often become fathers (WHO 1999, cut-off ≥50%, adjusted OR 2.8, 95% CI 1.3-6.1 and WHO 2010, cut-off ≥32%; aOR 4.2, 95% CI 1.1-15). Based on the WHO 1999 reference value, men with normal sperm concentration (≥20 × 106 /mL) had more often become fathers (aOR 3.1, 95% CI 1.1-8.6). Men with progressive sperm motility ≥50% and concentration ≥20 × 106 /mL did more often achieve fatherhood (aOR 8.4, 95% CI 2.1-34). For DFI, there was a borderline significance at cut-off 20% in the group of men who had ever been fathers (OR 2.7, 95% CI 1.0-7.0 p < 0.05). DISCUSSION: The results indicate that sperm progressive motility, sperm concentration, and DFI are associated with fatherhood during a longer time period, with sperm motility being most consistent. Although the sample size is relatively small and our results should be replicated in larger studies, they may be of clinical relevance. CONCLUSION: Semen parameters may have a diagnostic value not only in a short time frame but also for predicting future fertility potential.

Independent measures of insulin secretion and insulin sensitivity during the same test: the glucagon-insulin tolerance test.

BACKGROUND: To validate a test for independent assessment of insulin secretion and insulin sensitivity during the same occasion for metabolic studies in clinical practice, i.e. combined glucagon-stimulated C-peptide test and insulin tolerance test (GITT). SUBJECTS AND METHODS: We measured C-peptide response to 0.5 mg of intravenous glucagon followed 30 min later by administration of 0.05 U kg(-1) insulin (insulin tolerance test, ITT). Ten subjects with normal glucose tolerance participated on different days in an ITT, glucagon-C-peptide test, ITT followed by glucagon-C-peptide test and glucagon-C-peptide test followed by ITT to establish whether and how the tests could be combined. The test was then repeated in nine patients with type 2 diabetes to investigate its reproducibility. In 20 subjects with varying degrees of glucose tolerance, the test was compared with the Botnia clamp (an intravenous glucose tolerance test combined with a euglycaemic hyperinsulinemic clamp). RESULTS: When ITT preceded the glucagon test, C-peptide response was blunted. Therefore, we first administered glucagon and then insulin (GITT). The K(ITT) from the GITT was reproducible (CV = 13 %) and correlated strongly with the glucose disposal rate from the Botnia clamp (r = 0.87, r(2) = 0.75, P < 0.001). The C-peptide response to glucagon was reproducible (CV = 13 %). The disposition index, providing a measure of beta-cell function adjusted for insulin sensitivity, calculated from the GITT showed good discrimination between individuals with varying degrees of glucose tolerance. CONCLUSIONS: The GITT provides simple, reproducible and independent estimates of insulin sensitivity and secretion on the same occasion for metabolic studies in individuals with normal and abnormal glucose tolerance.

Determinants of response to a parent questionnaire about development and behaviour in 3 year olds: European multicentre study of congenital toxoplasmosis.

BACKGROUND: We aimed to determine how response to a parent-completed postal questionnaire measuring development, behaviour, impairment, and parental concerns and anxiety, varies in different European centres. METHODS: Prospective cohort study of 3 year old children, with and without congenital toxoplasmosis, who were identified by prenatal or neonatal screening for toxoplasmosis in 11 centres in 7 countries. Parents were mailed a questionnaire that comprised all or part of existing validated tools. We determined the effect of characteristics of the centre and child on response, age at questionnaire completion, and response to child drawing tasks. RESULTS: The questionnaire took 21 minutes to complete on average. 67% (714/1058) of parents responded. Few parents (60/1058) refused to participate. The strongest determinants of response were the score for organisational attributes of the study centre (such as direct involvement in follow up and access to an address register), and infection with congenital toxoplasmosis. Age at completion was associated with study centre, presence of neurological abnormalities in early infancy, and duration of prenatal treatment. Completion rates for individual questions exceeded 92% except for child completed drawings of a man (70%), which were completed more by girls, older children, and in certain centres. CONCLUSION: Differences in response across European centres were predominantly related to the organisation of follow up and access to correct addresses. The questionnaire was acceptable in all six countries and offers a low cost tool for assessing development, behaviour, and parental concerns and anxiety, in multinational studies.

Direct observation and imaging of a spin-wave soliton with p-like symmetry.

Spin waves, the collective excitations of spins, can emerge as nonlinear solitons at the nanoscale when excited by an electrical current from a nanocontact. These solitons are expected to have essentially cylindrical symmetry (that is, s-like), but no direct experimental observation exists to confirm this picture. Using a high-sensitivity time-resolved magnetic X-ray microscopy with 50 ps temporal resolution and 35 nm spatial resolution, we are able to create a real-space spin-wave movie and observe the emergence of a localized soliton with a nodal line, that is, with p-like symmetry. Micromagnetic simulations explain the measurements and reveal that the symmetry of the soliton can be controlled by magnetic fields. Our results broaden the understanding of spin-wave dynamics at the nanoscale, with implications for the design of magnetic nanodevices.

Mumps virus infection of the developing mouse brain--appearance of structural virus proteins demonstrated with monoclonal antibodies.

Newborn mice and hamsters were inoculated intracerebrally with mumps virus strains of high and low neurovirulence, Kilham and RW, respectively and with an egg-adapted patient isolate. The presence of viral antigen in brain tissue was analyzed with the immunofluorescence technique employing monoclonal antibodies against nucleoprotein (NP), polymerase (P), matrix (M), hemagglutinin-neuraminidase (HN) and fusion (F) mumps virus components. As expected, hamsters developed a fatal encephalitis eight to nine days after infection with the Kilham strain and synthesis of all five structural viral antigens was identified. In contrast, mice infected with any of the virus strains did not develop signs of disease, but in brain material collected on days nine and 12 after infection viral antigen was present in many neurons. However, only NP and P antigens were demonstrable and no infectious virus was present. The antibody response in mice developed later than in hamsters. Neurons in the mouse brain may exert a host cell restriction on the virus maturation, and mice offer a suitable host for the establishment of defective, persistent mumps virus infections.

Clinical outcome in four children with metachromatic leukodystrophy treated by bone marrow transplantation.

Four children with metachromatic leukodystrophy (MLD) underwent allogeneic bone marrow transplantation between 1988 and 1993. No effect on the natural course of the disease was observed in two children with late infantile and juvenile MLD. They had moderate neurological symptoms at the time of BMT and were followed for 7 and 6 years, respectively. The third child with the juvenile form of MLD was mildly to moderately affected when transplanted. She had lost some gross motor functions as well as speech and mental abilities at follow-up 3 years later. The fourth case, diagnosed biochemically and presymptomatically as late infantile MLD, had a subtle gait disturbance when grafted at 18 months of age. Demyelination, not observed before BMT, was visualized 1 year later on MRI. This boy's condition has continued to deteriorate 2 years after transplantation. We have adopted recent recommendations that BMT should be considered only in presymptomatic children with late infantile MLD or early in the course of juvenile MLD. In such children, still longer follow-up periods are necessary to evaluate the benefit of BMT.

Late ophthalmologic manifestations of neonatal herpes simplex virus infection.

We examined 32 children one to 15 years after virologically verified neonatal herpes simplex virus infection. Sixteen of 17 (94%) neurologically impaired children had ocular abnormalities compared to three of 15 (20%) neurologically healthy children. Disturbed oculomotor control occurred in 14 children (44%), most of whom were among those with severe handicap. Ocular morbidity was present in 13 (40%) of 32 children: one had cataracts, two had corneal scars, seven had optic atrophy, and nine had chorioretinal scars. The clinically silent chorioretinal lesions were manifest as coarse hyperpigmented areas between the equator and ora serrata. One child had suffered from acute fulminant retinitis. Twelve of 13 (93%) severely handicapped children had impaired vision, mainly because of cortical blindness. Less affected children had normal vision unless corneal scars were present. Long-term observation of patients with neonatal herpes infections is essential because ocular manifestations are not rare, and recurrences may be more common than previously reported.

Type distribution of muscle fibres and their ultrastructure related to intracellular elemental composition as revealed by energy dispersive X-ray microanalysis. A study of multicore myopathy.

Four cases of congenital myopathy, two children and two adults, are described whose light-microscopical and ultrastructural findings are consistent with a multicore myopathy. In all cases a hereditary etiology to the disorders is obvious presumably by an autosomal recessive trait. Fibres with central nuclei and multiple minicores was a prominent finding in all cases. Energy dispersive X-ray microanalysis of single muscle fibres revealed a normal intracellular content of elements (sodium, potassium and chlorine). This is in contrast to the findings in some cases of s.c. myotubular myopathy earlier described from our group where content of sodium and chlorine is markedly increased while that of potassium is decreased. It is suggested that in myotubular myopathy membrane dysfunction causing decreased ionic gradients is an important feature of the pathophysiology while in multicore myopathy other mechanisms, as a suggestion related to mitochondrial and myofibrillar function play a more prominent part. From a diagnostic point of view it seems that X-ray microanalysis can be used to differentiate the two conditions.

Neonatal herpes simplex virus infections: HSV DNA in cerebrospinal fluid and serum.

AIM: To investigate the diagnostic potential of herpes simplex virus (HSV) DNA in cerebrospinal fluid and serum; to correlate the findings with outcome in the child and with type of maternal infection. METHODS: Cerebrospinal fluid and serum specimens from 36 children with verified neonatal HSV infections, diagnosed between 1973 and 1996, were examined using the polymerase chain reaction technique (PCR). RESULTS: In 21 children for whom both cerebrospinal fluid and sera were available, HSV DNA was found in one or both specimens in 19 (90%). Overall, HSV DNA was found in the cerebrospinal fluid of 74% of 27 children, and in the sera of 20 out of 30 children (67%). In two children HSV DNA was not demonstrable in either serum or cerebrospinal fluid. In sequential specimens from four children, the persistence of HSV DNA after the end of intravenous treatment was associated with a poor prognosis. CONCLUSIONS: These findings indicate that HSV DNA detection in CSF and serum is highly sensitive for the diagnosis of neonatal HSV infections but does not replace the detection of virus in other locations using virus isolation and antigen detection.

Congenital cytomegalovirus infection: a retrospective diagnosis in a child with pachygyria.

A 2-year, 6-month-old child with pachygyria demonstrated on magnetic resonance imaging at 12 months of age, psychomotor delay, and deafness who was diagnosed with congenital cytomegalovirus infection by the demonstration of cytomegalovirus DNA in blood from the stored neonatal filter paper is reported. The use of this technique provides an opportunity for the retrospective viral diagnosis in children with neurodevelopmental impairments and abnormalities, such as migration disturbances, in the brain.

Mutually synchronized bottom-up multi-nanocontact spin-torque oscillators.

Spin-torque oscillators offer a unique combination of nanosize, ultrafast modulation rates and ultrawide band signal generation from 100 MHz to close to 100 GHz. However, their low output power and large phase noise still limit their applicability to fundamental studies of spin-transfer torque and magnetodynamic phenomena. A possible solution to both problems is the spin-wave-mediated mutual synchronization of multiple spin-torque oscillators through a shared excited ferromagnetic layer. To date, synchronization of high-frequency spin-torque oscillators has only been achieved for two nanocontacts. As fabrication using expensive top-down lithography processes is not readily available to many groups, attempts to synchronize a large number of nanocontacts have been all but abandoned. Here we present an alternative, simple and cost-effective bottom-up method to realize large ensembles of synchronized nanocontact spin-torque oscillators. We demonstrate mutual synchronization of three high-frequency nanocontact spin-torque oscillators and pairwise synchronization in devices with four and five nanocontacts.

Molecular cytogenetic characterization of an insertional translocation, ins(6;7)(p25;q33q34): deletion/duplication of 7q33-34 and clinical correlations.

A balanced insertional translocation between chromosomes 6 and 7, ins(6;7)(p25;q33q34) has been extensively investigated. The insertional translocation was found in several members of a three-generation family, where some were healthy balanced carriers while others had clinical symptoms due to deletion or duplication of 7q33-34. The deleted/duplicated segment could only be detected using high resolution banding and fluorescent in situ hybridization. A number of BAC/PAC clones located on chromosome 6 and 7 were used to characterize the breakpoint regions in detail and to determine the size of the deletion, which was 7.6 Mb, containing up to 68 genes. However, the insert on chromosome 6 was only 7.4 Mb, due to a deletion of 227 kb at the distal breakpoint on 7q. This small deletion was also found in the "balanced" carriers, and although the chromosome segment contains at least eight genes, none of the carriers seem to be affected by haploinsufficiency, since the phenotype is apparently normal. This is the first detailed characterization and phenotype correlation of such a deletion/duplication of distal 7q.