Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test.

BACKGROUND: Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals. METHODS: Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4. RESULTS: One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result. CONCLUSIONS: This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.     

Cystic fibrosis detection in high-risk Egyptian children and CFTR mutation analysis.

BACKGROUND: Knowledge about Cystic Fibrosis (CF) in Egypt is very limited. The objective of this study was to screen for CF in Egyptian children with suggestive clinical features and to identify causative genetic mutations. METHODS: Sixty-one patients from the Chest Unit, Cairo University Children's Hospital, Egypt, were included. Subjects presented with persistent or recurrent respiratory symptoms, failure to thrive, diarrhea and/or steatorrhea and unexplained persistent jaundice. Patients were screened using the CF Indicatortrade mark sweat test system (PolyChrome Medical, Inc., Brooklyn Center, MN). A quantitative sweat testing was conducted on 10 of the 12 positive patients. Seven probands and one sibling underwent molecular analysis by direct DNA sequencing of the coding region and of the intronic sequences adjacent to the 27 exons of the CFTR gene. RESULTS: Of 61 patients, 12 (20%) had positive sweat chloride screening. Ten of the 12 patients underwent quantitative sweat testing and were positive. Eight CFTR sequence changes were identified in seven affected probands and two were confirmed in one sibling by direct DNA sequencing. CONCLUSION: The study results suggest that CF is more common in Egypt than previously anticipated. Larger studies are warranted to identify the incidence, molecular basis and clinical pattern of CF in the Egyptian population.     

Human Herpesvirus 6 in Bronchalveolar Lavage Fluid after Lung Transplantation: A Risk Factor for Bronchiolitis Obliterans Syndrome?

Bronchiolitis obliterans syndrome (BOS) is the limiting factor to long-term survival after lung transplantation. Previous studies suggested respiratory viral tract infections are associated with the development of BOS. To identify the impact of virus detection in bronchoalveolar lavage (BAL) fluid, we analyzed BAL samples from 87 consecutive lung transplant recipients for human herpesvirus (HHV)-6, Epstein-Barr virus, Herpes simplex virus 1/2, Cytomegalovirus, respiratory syncytical virus and adenovirus by PCR. Acute rejection, BOS and death were recorded for a mean follow-up time of 3.27 +/- 0.47 years. Results of PCR analysis and other potential risk factors were entered into a Cox regression analysis of BOS predictors and death. Only acute rejection was a distinct risk factor for BOS of all stages, death and death from BOS. HHV-6 was detected in 20 patients. Univariate and multivariate analysis revealed that HHV-6 was associated with an increased risk to develop BOS > orb = stage 1 and death, separate from the risk attributable to acute rejection. Identification of HHV-6 DNA in BAL fluid is a potential risk factor for BOS. Our results warrant further studies to elucidate a possible causal link between HHV-6 and BOS.     

Expression of the protein related to Dan and Cerberus gene--prdc--During eye, pharyngeal arch, somite, and swim bladder development in zebrafish.

The protein related to Dan and Cerberus, or PRDC, is a secreted glycoprotein, which belongs to the DAN subfamily of bone morphogenetic protein (BMP) antagonists. In zebrafish, prdc is expressed initially around 17 hours postfertilization in the developing eyes and the first two pharyngeal arches. Expression in the eye starts in the outer layers of the optic cup. Later, prdc expression domains are juxtaposed at the edges of the optic cup surrounding the choroid fissure, then gradually becoming restricted to a small site in the ventral marginal zone. Prdc expression in the arch mesenchyme expands stepwise to the remaining posterior arches. Prdc is also detectable in the ventral part of the somites and the mesenchyme of the swim bladder. The relatively late appearance during development is a unique feature of Prdc among BMP antagonists. Moreover, the complexity of the prdc expression pattern suggests possible roles in eye development, pharyngeal arch remodeling, somitogenesis, and swim bladder organogenesis.     

Reflex tear ascorbate in Hong Kong Chinese subjects: method comparison and biological variation.

BACKGROUND: Tear ascorbate is important for corneal health. A rapid and simple method for measurement of ascorbate in tears is needed, and adequate knowledge of physiological variation of tear ascorbate is important to facilitate comparative studies of the effect of, for example, contact lens wear and environmental conditions and stresses. However, there are currently no data on physiological variation of tear ascorbate. This study validated a simple and speedy method for tear ascorbate and investigated between-eye and between-day variation in tear ascorbate in healthy young adults. METHODS: Yawn-induced reflex tears were collected from 32 healthy Hong Kong Chinese subjects and measured by both high-performance liquid chromatography (HPLC) and by an enzyme-linked colorimetric method known as FRASC (total ferric reducing (antioxidant) activity and ascorbate concentration measurement). For between-eye variation, yawn reflex tears were collected from each eye of the same 32 healthy subjects, and ascorbate was measured using HPLC; in a separate experiment for between-day variation, tears were collected on two separate days from 14 subjects, and ascorbate was measured by FRASC. RESULTS: Both HPLC and FRASC showed high precision, and results obtained using FRASC were not statistically different from those using HPLC; mean +/- SD were, respectively, 18.5 +/- 4.4 microM and 18.5 +/- 4.8 microM for HPLC and FRASC methods (p = 0.943). No significant between-eye difference in tear ascorbate was found (p = 0.386), and no significant between-day variation was found overall: mean +/- SD ascorbate was 20.0 +/- 6.2 microM on day 1 and 19.3 +/- 6.8 microM on day 2 (p = 0.772). However, between-day variation was large in seven of 14 subjects. CONCLUSION: FRASC is an acceptable alternative to HPLC for measurement of tear ascorbate. Tears for ascorbate investigation can be collected from either eye or, if necessary, from both eyes and pooled. However, tear ascorbate may vary widely from day to day in the same individual. The reasons for this variation require further study but may relate to differences in ascorbate supply or demand within the precorneal tear layer.     

Allicin inhibits SDF-1alpha-induced T cell interactions with fibronectin and endothelial cells by down-regulating cytoskeleton rearrangement, Pyk-2 phosphorylation and VLA-4 expression

Allicin, a major ingredient of fresh garlic extract that is produced during the crushing of garlic cloves, exerts various beneficial biological effects, including a broad spectrum of antimicrobial activity, antihyperlipidaemic and antihypertensive effects. However, how allicin affects the immune system is less well known, and its effect on human T cells has never been studied. Here, we examined the in-vitro effects of allicin on the functioning of T cells related to their entry to inflamed extravascular sites. We found that allicin (20-100 microm) inhibits the SDF-1alpha (CXCL12)-induced T cell migration through fibronectin (FN), and that this inhibition is mediated by the down-regulation of (i) the reorganization of cortical actin and the subsequent T cell polarization, and (ii) T cell adhesion to FN. Moreover, allicin also inhibited T cell adhesion to endothelial cells and transendothelial migration. The mechanisms underlying these inhibitory effects of allicin are associated with its ability to down-regulate the phosphorylation of Pyk2, an intracellular member of the focal adhesion kinases, and to reduce the expression of the VCAM-1- and FN-specific alpha4beta1-integrin (VLA-4). The ability of allicin to down-regulate these chemokine-induced and VLA-4-mediated T cell functions explains its beneficial biological effects in processes where T cells play an important role and suggests that allicin may be used therapeutically with chronic inflammatory diseases.     

Human recombinant neutralizing antibodies against hantaan virus G2 protein

Old world hantaviruses, causing hemorrhagic fever with renal syndrome (HFRS), still present a public health problem in Asia and Eastern Europe. The majority of cases has been recorded in China. The aim of our study was to generate human recombinant neutralizing antibodies to a hantavirus by phage display technology. To preserve the structural identity of viral protein, the panning procedure was performed on native Hantaan (HTN) (76-118) virus propagated in Vero-E6 cells. In total, five complete human recombinant IgG antibodies were produced in a baculovirus expression system. All of them were able to completely neutralize HTN, and Seoul (SEO) virus in a plaque reduction neutralization test (PRNT). Three of these antibodies could also completely neutralize Dobrava (DOB) virus but not Puumala (PUU) virus. All antibodies bind to Hantaan virus G2 protein localized in the virus envelope. The sequence areas within the HTN (76-118)-G2 protein detected by five selected antibodies were mapped using peptide scans. Two partial epitopes, 916-KVMATIDSF-924 and 954-LVTKDIDFD-963, were recognized, which presumably are of paramount importance for docking of the virus to host cell receptors. A consensus motif 916-KVXATIXSF-924 could be identified by mutational analysis. The neutralizing antibodies to the most widely distributed hantaviruses causing HFRS might be promising candidates for the development of an agent for prevention and treatment of HFRS in patients.