Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10−12 at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10−9 at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.

A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10-8) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10-9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder.

Our findings suggest that response to lithium treatment in pediatric bipolar disorder is associated with normalization of white matter microstructure in regions associated with emotion processing.

The analysis of twins and siblings with CF indicates a prominent role for genes other than CFTR to BMI variation. Specifically, regions on chromosomes 1 and 5 appear to harbor genetic modifiers of substantial effect.

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI ( P = 1.99×10 −5 to 1.08×10 −6 ; Bonferroni P = 0.057 to 3.1×10 −3 ). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival ( P = 1.2×10 −4 ). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr −/− and Cftr −/− Msra −/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.

Objectives: To design and evaluate a rapid polymerase chain reaction (PCR)-based assay for detecting Eubacteria and performing early screening for selected Class A biothreat bacterial pathogens. Methods:The authors designed a two-step PCR-based algorithm consisting of an initial broad-based universal detection step, followed by specific pathogen identification targeted for identification of the Class A bacterial biothreat agents. A region in the bacterial 16S rRNA gene containing a highly variable sequence flanked by clusters of conserved sequences was chosen as the target for the PCR assay design. A previously described highly conserved region located within the 16S rRNA amplicon was selected as the universal probe (UniProbe, Integrated DNA Technology, Coralville, IA). Pathogen-specific TaqMan probes were designed for Bacillus anthracis, Yersinia pestis, and Francisella tularensis. Performance of the assay was assessed using genomic DNA extracted from the aforementioned biothreat-related organisms (inactivated or surrogate) and other common bacteria.Results: The UniProbe detected the presence of all tested Eubacteria (31 ⁄ 31) with high analytical sensitivity. The biothreat-specific probes accurately identified organisms down to the closely related species and genus level, but were unable to discriminate between very close surrogates, such as Yersinia philomiragia and Bacillus cereus.Conclusions: A simple, two-step PCR-based assay proved capable of both universal bacterial detection and identification of select Class A bacterial biothreat and biothreat-related pathogens. Although this assay requires confirmatory testing for definitive species identification, the method has great potential for use in ED-based settings for rapid diagnosis in cases of suspected Category A bacterial biothreat agents.ACADEMIC EMERGENCY MEDICINE 2008; 15:388-392 ª

The idea of an edible vaccine is coming closer to reality as scientists have found a way to incorporate the protein gene with some antigen in some plants. The major hurdles in the path of an emerging vaccine technology are being overcome. In this context, genetically modified (GM) plants are being investigated for the production of vaccines, antibodies and therapeutic proteins. The development of GM crops to produce drugs and vaccines has received considerable investment and is relatively well advanced. The myth surrounding edible vaccines and 'food as pill' is the difficulty to control their intake and distribution, particularly in developing countries where education levels and literacy may be low. However, this concept suffers from the fact that the potency of this class of vaccines and drugs remains unmasked to the majority of the population, which has to be publicized and campaigned in a scientific manner, to make it realistic and useful for the common man. Creating edible vaccines involves introduction of selected desired genes into plants and then inducing these altered plants to manufacture the encoded proteins. This process is known as "transformation," and the altered plants are called "transgenic plants." Like conventional subunit vaccines, edible vaccines are composed of antigenic proteins and are devoid of pathogenic genes. Thus, they have no way of establishing infection, assuring its safety, especially in immuno-compromised patients. Conventional subunit vaccines are expensive and technology-intensive, need purification, require refrigeration and produce poor mucosal response. In contrast, edible vaccines would enhance compliance, especially in children and because of oral administration, would eliminate the need for trained medical personnel. Their production is highly efficient and can be easily scaled up. If the technology is properly nurtured and given the right direction, it may usher into a new era where we will be asked to take “food” rather than “drugs” when we are ill. This review attempts to discuss the current status and future of this new preventive modality

There are currently no known early neuroanatomical markers predictive of the development of major depression or depressive symptoms after mild traumatic brain injury (mTBI). The authors conducted a 1-year longitudinal pilot study to determine whether diffusion tensor imaging (DTI) measures collected within 1 month of mTBI could predict incident depression. Of the 14 subjects who met study inclusion criteria, 4 (28.6%) developed major depression over the follow-up period. Compared with the nondepressed group, those who developed depression had white-matter abnormalities in the fronto-temporal regions measured by DTI. These preliminary results highlight the need for additional studies, including studies using a larger sample and appropriate controls.