Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders

Background Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Methods Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Results A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. Conclusions This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts

Negative phenotypic and genetic associations between copulation duration and longevity in male seed beetles

Reproduction can be costly and is predicted to trade-off against other characters. However, while these trade-offs are well documented for females, there has been less focus on aspects of male reproduction. Furthermore, those studies that have looked at males typically only investigate phenotypic associations, with the underlying genetics often ignored. Here, we report on phenotypic and genetic trade-offs in male reproductive effort in the seed beetle, Callosobruchus maculatus. We find that the duration of a male's first copulation is negatively associated with subsequent male survival, phenotypically and genetically. Our results are consistent with life-history theory and suggest that like females, males trade-off reproductive effort against longevity

Human papillomavirus (HPV) screening and cervical cancer burden. A Brazilian perspective

This review tackles the issues related to disease burden caused by cervical cancer (CC) and its precursor (CIN) lesions in Brazil. A special focus is given to new technologies with potential to interfere with the development of CC by reducing the high-risk human papillomavirus (hr-HPV)-induced lesions that remain a major public health burden in all developing countries where organized screening programs do not exist. Globally, 85 % of all incident CC and 50 % of CC deaths occur in the developing countries. Unfortunately, most regions of Brazil still demonstrate high mortality rates, ranking CC as the second most common cancer among Brazilian women. Recently, CC screening programs have been tailored in the country to enable early detection of CC precursor lesions and thereby reduce cancer mortality. A combination of HPV testing with liquid-based cytology (LBC) seems to be a promising new approach in CC screening, with high expectation to offer an adequate control of CC burden in this country

Risk Factors for Cervical Precancer and Cancer in HIV-Infected, HPV-Positive Rwandan Women

Although cervical cancer is an AIDS-defining condition, infection with human immunodeficiency virus (HIV) may only modestly increase the risk of cervical cancer. There is a paucity of information regarding factors that influence the natural history of human papillomavirus (HPV) in HIV-infected women. We examined factors associated with cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in Rwandan women infected with both HIV and HPV (HIV+/HPV+).In 2005, 710 HIV+ Rwandan women ≥25 years enrolled in an observational cohort study; 476 (67%) tested HPV+. Each woman provided sociodemographic data, CD4 count, a cervical cytology specimen and cervicovaginal lavage (CVL), which was tested for >40 HPV genotypes by MY09/MY11 PCR assay. Logistic regression models calculated odds ratios (OR) and 95% confidence intervals (CI) of associations of potential risk factors for CIN3+ among HIV+/HPV+ women.Of the 476 HIV+/HPV+ women 42 (8.8%) were diagnosed with CIN3+. Factors associated with CIN3+ included ≥7 (vs. 0-2) pregnancies, malarial infection in the previous six months (vs. never), and ≥7 (vs. 0-2) lifetime sexual partners. Compared to women infected by non-HPV16 carcinogenic HPV genotypes, HPV16 infection was positively associated and non-carcinogenic HPV infection was inversely associated with CIN3+. CD4 count was significantly associated with CIN3+ only in analyses of women with non-HPV16 carcinogenic HPV (OR = 0.62 per 100 cells/mm(3), CI = 0.40-0.97).In this HIV+/HPV+ population, lower CD4 was significantly associated with CIN3+ only in women infected with carcinogenic non-HPV16. We found a trend for higher risk of CIN3+ in HIV+ women reporting recent malarial infection; this association should be investigated in a larger group of HIV+/HPV+ women

Altered aortic 3D hemodynamics and geometry in pediatric Marfan syndrome patients

BACKGROUND: Blood flow dynamics make it possible to better understand the development of aortopathy and cardiovascular events in patients with Marfan syndrome (MFS). Aortic 3D blood flow characteristics were investigated in relation to aortic geometry in children and adolescents with MFS. METHODS: Twenty-five MFS patients (age 15.6 ± 4.0 years; 11 females) and 21 healthy controls (age 16.0 ± 2.6 years; 12 females) underwent magnetic resonance angiography and 4D flow CMR for assessment of thoracic aortic size and 3D blood flow velocities. Data analysis included calculation of aortic diameter and BSA-indexed aortic dimensions (Z-score) along the thoracic aorta, 3D mean systolic wall shear stress (WSS(mean)) in ten aortic segments and assessment of aortic blood flow patterns. RESULTS: Aortic root (root), ascending (AAo) and descending (DAo) aortic size was significantly larger in MFS patients than healthy controls (Root Z-score: 3.56 ± 1.45 vs 0.49 ± 0.78, p < 0.001; AAo Z-score 0.21 ± 0.95 vs −0.54 ± 0.64, p = 0.004; proximal DAo Z-score 2.02 ± 1.60 vs 0.56 ± 0.66, p < 0.001). A regional variation in prevalence and severity of flow patterns (vortex and helix flow patterns) was observed, with the aortic root and the proximal DAo (pDAo) being more frequently affected in MFS. MFS patients had significantly reduced WSS(mean) in the proximal AAo (pAAo) outer segment (0.65 ± 0.12 vs. 0.73 ± 0.14 Pa, p = 0.029) and pDAo inner segment (0.74 ± 0.17 vs. 0.87 ± 0.21 Pa, p = 0.021), as well as higher WSS(mean) in the inner segment of the distal AAo (0.94 ± 0.14 vs. 0.84 ± 0.15 Pa, p = 0.036) compared to healthy subjects. An inverse relationship existed between pDAo WSS(mean) and both pDAo diameter (R = −0.53, p < 0.001) and % diameter change along the pDAo segment (R = −0.64, p < 0.001). CONCLUSIONS: MFS children and young adults have altered aortic flow patterns and differences in aortic WSS that were most pronounced in the pAAo and pDAo, segments where aortic dissection or rupture often originate. The presence of vortex flow patterns and abnormal WSS correlated with regional size of the pDAo and are potentially valuable additional markers of disease severity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12968-017-0345-7) contains supplementary material, which is available to authorized users

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. Whereas sumoylation of the C-terminal regulatory domain (CRD) is known to have a major impact on the activity of c-Myb, no role for noncovalent binding of small ubiquitin-like modifier (SUMO) to c-Myb has been described. Based on the consensus SUMO-interacting motif (SIM), we identified and examined putative SIMs in human c-Myb. Interaction and reporter assays showed that the SIM in the in the transactivation domain of c-Myb (V 267 NIV) is functional. This motif is necessary for c-Myb to be able to interact noncovalently with SUMO, preferentially SUMO2/3. Destroying the SUMO-binding properties by mutation resulted in a large increase in the transactivation potential of c-Myb. Mutational analysis and overexpression of conjugation-defective SUMO argued against intramolecular repression caused by sumoylated CRD and in favor of SUMO-dependent repression in trans. Using both a myeloid cell line-based assay and a primary hematopoietic cell assay, we addressed the transforming abilities of SUMO binding and conjugation mutants. Interestingly, only loss of SUMO binding, and not SUMO conjugation, enhanced the myeloid transformational potential of c-Myb. c-Myb with the SIM mutated conferred a higher proliferative ability than the wild-type and caused an effective differentiation block. This establishes SUMO binding as a mechanism involved in modulating the transactivation activity of c-Myb, and responsible for keeping the transforming potential of the oncoprotein in check

Key signalling nodes in mammary gland development and cancer. The Snail1-Twist1 conspiracy in malignant breast cancer progression

Breast cancer is the most common cancer among women, and despite significant advances in diagnosing and treating it, metastatic spread of cancer cells results in a high mortality rate. Epithelial-to-mesenchymal transition (EMT) is an embryonic program in which epithelial cells lose their characteristics and gain mesenchymal features. Therefore, EMT might play a very important role during malignant tumour progression. In this review we summarise recent advances in breast cancer research with a particular focus on the transcription factors Snail1 and Twist1. Besides discussing the role of EMT in normal mammary gland development, we describe regulatory mechanisms involving newly discovered upstream regulators and microRNAs, the association of EMT with breast cancer stem cells, and the involvement of the tumour microenvironment in breast cancer progression

Seroprevalence of 34 Human Papillomavirus Types in the German General Population

The natural history of infections with many human papillomavirus (HPV) types is poorly understood. Here, we describe for the first time the age- and sex-dependent antibody prevalence for 29 cutaneous and five mucosal HPV types from 15 species within five phylogenetic genera (alpha, beta, gamma, mu, nu) in a general population. Sera from 1,797 German adults and children (758 males and 1,039 females) between 1 and 82 years (median 37 years) were analysed for antibodies to the major capsid protein L1 by Luminex-based multiplex serology. The first substantial HPV antibody reactions observed already in children and young adults are those to cutaneous types of the genera nu (HPV 41) and mu (HPV 1, 63). The antibody prevalence to mucosal high-risk types, most prominently HPV 16, was elevated after puberty in women but not in men and peaked between 25 and 34 years. Antibodies to beta and gamma papillomaviruses (PV) were rare in children and increased homogeneously with age, with prevalence peaks at 40 and 60 years in women and 50 and 70 years in men. Antibodies to cutaneous alpha PV showed a heterogeneous age distribution. In summary, these data suggest three major seroprevalence patterns for HPV of phylogenetically distinct genera: antibodies to mu and nu skin PV appear early in life, those to mucosal alpha PV in women after puberty, and antibodies to beta as well as to gamma skin PV accumulate later in life

ISSN exercise & sport nutrition review: research & recommendations

Sports nutrition is a constantly evolving field with hundreds of research papers published annually. For this reason, keeping up to date with the literature is often difficult. This paper is a five year update of the sports nutrition review article published as the lead paper to launch the JISSN in 2004 and presents a well-referenced overview of the current state of the science related to how to optimize training and athletic performance through nutrition. More specifically, this paper provides an overview of: 1.) The definitional category of ergogenic aids and dietary supplements; 2.) How dietary supplements are legally regulated; 3.) How to evaluate the scientific merit of nutritional supplements; 4.) General nutritional strategies to optimize performance and enhance recovery; and, 5.) An overview of our current understanding of the ergogenic value of nutrition and dietary supplementation in regards to weight gain, weight loss, and performance enhancement. Our hope is that ISSN members and individuals interested in sports nutrition find this review useful in their daily practice and consultation with their clients

Trace elements in glucometabolic disorders: an update

Many trace elements, among which metals, are indispensable for proper functioning of a myriad of biochemical reactions, more particularly as enzyme cofactors. This is particularly true for the vast set of processes involved in regulation of glucose homeostasis, being it in glucose metabolism itself or in hormonal control, especially insulin. The role and importance of trace elements such as chromium, zinc, selenium, lithium and vanadium are much less evident and subjected to chronic debate. This review updates our actual knowledge concerning these five trace elements. A careful survey of the literature shows that while theoretical postulates from some key roles of these elements had led to real hopes for therapy of insulin resistance and diabetes, the limited experience based on available data indicates that beneficial effects and use of most of them are subjected to caution, given the narrow window between safe and unsafe doses. Clear therapeutic benefit in these pathologies is presently doubtful but some data indicate that these metals may have a clinical interest in patients presenting deficiencies in individual metal levels. The same holds true for an association of some trace elements such as chromium or zinc with oral antidiabetics. However, this area is essentially unexplored in adequate clinical trials, which are worth being performed