The influence of dual-task conditions on movement in young adults with and without Down syndrome

This investigation compared spatial and temporal movement parameters of a sample of young adults with Down syndrome (DS) (N = 12) and individuals without disabilities (IWD) (N = 12) under dual-task conditions. Subjects performed a walking task at a preferred speed in isolation and again while holding a plate and cup, carrying tray and cups, talking on a phone, or buttoning a shirt. Spatial and temporal values were compared using a 2 (group) × 5 (conditions) repeated measures analysis of variance. Analysis of spatial components separately indicated that step length, step width, stride length and stride width revealed significant group and condition interactions (p ≤ .01). Temporal components yielded significance in velocity and single-leg support time (p ≤ .01). The current results support the notion that along with impairments to qualitative motor skills, individuals with DS are also impaired in higher order executive functioning (EF), as measured by a dual-task paradigm. It was concluded that movements are less efficient and functional in individuals with DS when an additional task is encountered while walking. We theorized that the motor program was sufficient for general locomotion but was not sufficiently developed to allow individuals with DS to modify or alter their movements to changing cognitive conditions that increasingly taxed EF. As gait and balance are trainable in this population, we recommend developing appropriate exercise and motor skill interventions during childhood and adolescents to increase strength, stability, and more “robust” ambulatory motor schema.     

Serine proteases of the classical and lectin pathways: similarities and differences

C1r, C1s, MBL-associated serine protease (MASP)-1, MASP-2 and MASP-3 are mosaic serine proteases of the classical and lectin pathways of complement. They form a family of enzymes with identical domain organization and similar overall structure, but with different enzymatic properties. MASP-2 of the lectin pathway can autoactivate and cleave C4 and C2 components. In the classical pathway two enzymes mediate these functions: C1r autoactivates and activates C1s, while C1s cleaves C4 and C2. The substrate specificity and the biological function of MASP-1 and MASP-3 have not yet been completely resolved. MASP-1 can autoactivate and the activated MASP-1 has more relaxed substrate specificity than the other members of the family. It was demonstrated that MASP-1 can specifically cleave C2, C3 and fibrinogen, but the physiological relevance of these findings has to be proved. We do not know how MASP-3 becomes activated and its biological function is also not clear. In this review, we will summarize current knowledge about the structure and function of these proteases. Special emphasis will be laid on the specificity, autoactivation and evolution of these enzymes.     

Surgical ventricular reconstruction and subendocardial resection for the treatment of refractory ventricular tachycardia

We describe a case of 64-year-old female patient with ventricular tachycardia intractable to medical treatment and acute heart failure following myocardial infarction. Emergency surgical ventricular reconstruction and subendocardial resection was undertaken. We discuss the option of surgical intervention in this difficult and unusual clinical scenario.     

Independent effect of endogenous dehydroepiandrosterone-sulphate levels and birth weight on bone turnover parameters in young adults

Data indicate that bone turnover is higher in young adults born with a low birth weight (LBW). Moreover, several data support the presence of altered adrenal hormone production in this population. The aim of our study was to investigate whether there is any connection between altered bone homeostasis and adrenal hormone levels. Bone mineral density (BMD), serum osteocalcin (OC), and urinary deoxypyridinoline (DPD) excretion were related to dehydroepiandrosterone-sulphate (DHEAS), cortisol, estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels in 47 healthy young women (of those, 33 were LBW) and 65 healthy young men (of those, 49 were LBW). The age of the subjects was 19–21 years. BMD values were normal and did not correlate with any of the factors investigated. Cortisol did not have any independent effect on bone turnover parameters in either men or women. In women, birth weight, DHEAS levels, and free estradiol index were responsible for almost 50% (corrected r² = 0.45) of serum OC variability. Independent positive associations were observed between DHEAS and OC, and between DHEAS and DPD excretion. In men, birth weight and DHEAS levels together were responsible for more than one-third (corrected r² = 0.36) of the variability of serum OC. In contrast with women, DHEAS and OC were inversely correlated in men. Our results suggest that bone turnover depends on the subjects' birth weight. Moreover, DHEAS is also an independent determinant. The effect of DHEAS on bone turnover is different in women and men. DHEAS increases bone turnover in fertile women, while it decreases this in men.     

Gene conversion is a likely cause of mutation in PKD1

Approximately 70% of the gene responsible for the most common form of autosomal dominant polycystic kidney disease ( PKD1 ) is replicated in several highly homologous copies located more proximally on chromosome 16. We recently have described a novel technique for mutation detection in the duplicated region of PKD1 that circumvents the difficulties posed by these homologs. We have used this method to identify two patients with a nearly identical cluster of base pair substitutions in exon 23. Since pseudogenes are known to be reservoirs for mutation via gene conversion events for a number of other diseases, we decided to test whether these sequence differences in PKD1 could have arisen as a result of this mechanism. Using changes in restriction digest patterns, we were able to show that these sequence substitutions are also present in N23HA, a rodent-human somatic cell hybrid that contains only the PKD1 homologs. Moreover, these changes were also detected in total DNA from several affected and unaffected individuals that did not harbor this mutation in their PKD1 gene copy. This is the first example of gene conversion in PKD1 , and our findings highlight the importance of using gene-specific reagents in defining PKD1 mutations.      

Monocytes in active multiple sclerosis: intact regulation of HLA-DR density in vitro despite decreased HLA-DR density in vivo

HLA-DR expression on circulating monocytes varies as a function of disease activity in patients with multiple sclerosis (MS), a putative immunopathological demyelinating disorder. Specifically, monocytes isolated from subjects with active MS exhibit reduced HLA-DR antigen density, and immunoregulatory aberrations such as impaired T lymphocyte-mediated suppression correlate strongly with this quantitative defect. To address the mechanism underlying this phenomenon, we compared in vitro regulation of HLA-DR by interferon beta (IFN beta), interferon gamma (IFN gamma), and lipopolysaccharide (LPS) in monocytes from patients with stable and active MS and normal individuals. Interferon-gamma and LPS enhanced monocyte expression of HLA-DR equally in both MS patient groups, suggesting that underexpression of HLA-DR in active MS was not explained by impaired in vivo monocyte responsiveness. Furthermore, interferon regulation of HLA-DR in normals and stable MS subjects was indistinguishable, indicating that aberrant interferon-mediated regulation of class II major histocompatibility complex (MHC) on circulating monocytes does not appear to be a characteristic of the MS disease state.     

Epigenetic modulation at birth – altered DNA-methylation in white blood cells after Caesarean section

Aim:  Delivery by C-section (CS) has been associated with increased risk for allergy, diabetes and leukaemia. Whereas the underlying cause is unknown, epigenetic change of the genome has been suggested as a candidate molecular mechanism for perinatal contributions to later disease risk. We hypothesized that mode of delivery affects epigenetic activity in newborn infants.
Methods:  A total of 37 newborn infants were included. Spontaneous vaginal delivery (VD) occurred in 21, and 16 infants were delivered by elective CS. Blood was sampled from the umbilical cord and 3–5 days after birth. DNA-methylation was analyzed in leucocytes.
Results:  Infants born by CS exhibited higher DNA-methylation in leucocytes compared with that of those born by VD (p < 0.001). After VD, newborn infants exhibited stable levels of DNA-methylation, as evidenced by comparing cord blood values with those 3–5 days after birth (p = 0.55). On postnatal days 3–5, DNA-methylation had decreased in the CS group (p = 0.01) and was no longer significantly different from that of VD (p = 0.10).
Conclusion:  DNA-methylation is higher in infants delivered by CS than in infants vaginally born. Although currently unknown how gene expression is affected, or whether epigenetic differences related to mode of delivery are long-lasting, our findings open a new area of clinical research with potentially important public health implications.     

Bone mineral density and bone acquisition in children and young adults with cystic fibrosis: a follow-up study

OBJECTIVE: To investigate bone mineral density and bone homeostasis in cystic fibrosis (CF) and to assess changes in a 2-year period. METHODS: Thirty-eight patients with clinically stable CF (11 children, 16 adolescents, 11 young adults) were enrolled. No patient was treated with corticosteroids before or during the study. Weight and height Z scores and bone mineral density (BMD) Z-score at the femoral neck and the lumbar spine were recorded at the beginning of the study and after 2 years. Osteocalcin and cross-link excretion, both measurements of bone turnover were also measured. Correlations between BMD, bone turnover parameters, disease severity, pubertal stage, and nutritional state were calculated. The maternal BMD was also determined and related to that of the child. RESULTS: Height and weight Z scores were normal in children and below normal in adolescents. Puberty was delayed in most patients. Bone age was lower than chronological age in adolescents. Lumbar spine and femoral neck BMD Z scores were below normal in each age group. Disease severity determined by Schwachman score correlated with lumbar BMD (r = 0.45, P < 0.02). BMD Z scores did not change during 2 year follow-up. Maternal and patient lumbar and femoral BMD correlated significantly (r = 0.51, P < 0.01, and r = 0.54, P < 0.01, respectively). CONCLUSIONS: Bone deficit is present in patients with CF who have never received steroid treatment. Delay of puberty, chronic inflammation, or genetic susceptibility might be responsible for this phenomenon which was found in patients who had never received steroids and who were in relatively good clinical state.     

Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.      

Lymphocyte Calcium Influx Characteristics and their Modulation by Kv1.3 and IKCa1 Channel Inhibitors in Healthy Pregnancy and Preeclampsia

Citation Toldi G, Stenczer B, Treszl A, Kollár S, Molvarec A, Tulassay T, Rigó J, Vásárhelyi B. Lymphocyte calcium influx characteristics and their modulation by Kv1.3 and IKCa1 channel inhibitors in healthy pregnancy and preeclampsia. Am J Reprod Immunol 2011; 65: 154–163 Problem Calcium handling of T lymphocytes is altered in healthy pregnancy (HP) and preeclampsia (PE) compared to non‐pregnant (non‐P) women. We compared the activation‐elicited calcium influx in T lymphocytes in HP, PE and non‐P women and tested its alteration upon inhibition of Kv1.3 and IKCa1 potassium channels. Method of study The alteration of calcium influx was measured in major T‐lymphocyte subsets of 9 non‐P, HP and PE women with flow cytometry with or without treatment of cells with potassium channel inhibitors. Results The elicited calcium response was lower in HP compared to non‐P. In HP, calcium influx was sensitive to potassium channel inhibition in CD8 and Th1, but not in Th2 cells. In PE, calcium influx and its sensitivity to inhibition were comparable to non‐P. Conclusion There is a characteristic pattern of calcium influx in T lymphocytes and its sensitivity to potassium channel inhibition in HP that is missing in PE, raising the notion that T‐lymphocyte calcium handling may have a role in the characteristic immune status of HP.