Autonomic dysregulation as a basis of cardiovascular, endocrine, and inflammatory disturbances associated with obstructive sleep apnea and other conditions of chronic hypoxia, hypercapnia, and acidosis

Obstructive sleep apnea has traditionally been viewed as a structural disease. A multitude of systemic endocrine and cardiovascular abnormalities have been previously attributed to the prevalence of obesity in these patients. A growing body of clinical evidence, however, points to a relationship between sleep apnea and its systemic abnormalities independent of obesity. We hypothesize that this association is based on a maladaptive autonomic response of chemoreceptors, reacting to the hypoxia, hypercapnia, and acidosis of sleep apnea. The elevated sympathetic response triggers an inflammatory cascade that results in a myriad of downstream consequences including insulin resistance, hypertension, diabetes, atherosclerosis and metabolic syndrome. The sympathetic bias and endocrine disturbances may further exacerbate sleep disturbance in a potentially pernicious cycle. Our proposal may extend to any chronic respiratory or metabolic conditions that manifest hypoxia, hypercapnia, and acidosis and elicit a maladaptive autonomic and inflammatory response.     

Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.     

Effect of experimental parameters on the formation of alginate-chitosan nanoparticles and evaluation of their potential application as DNA carrier

This study introduces a new procedure to prepare alginate-chitosan nanoparticles and examines several experimental parameters in relation to their formation and characteristics. Using DLS and TEM analysis, nanoparticle formation was shown to be predominantly affected by the ratio of alginate to chitosan, the molecular weight of the biopolymers and the solution pH. We report a method that results in spherical particles with mean diameters ranging from 323 nm to 1.6 microm, depending on the preparation conditions. The smallest particles were formed using lower molecular weight polymers with pH between 5.0 and 5.6 and having an alginate/chitosan weight ratio of 1:1.5. We have shown that DNA can be loaded with 60% association efficiency. Our system demonstrates suitable size, loading and release characteristics for application in drug- and gene-delivery systems.     

Cannabinoid agonist, CP 55,940, facilitates intake of palatable foods when injected into the hindbrain

Cannabinoids have been shown to influence food intake, and until recently, the neural pathways mediating these effects have remained obscure. It has been previously shown that intracerebroventricular injection of delta-9-tetrahydrocannabinol (Δ⁹-THC) causes increased consumption of palatable foods in rats, and we postulated the involvement of the hindbrain in this cannabinoid-induced food intake. Cannulated rats (both female and male groups) trained to consume sweetened condensed milk received either lateral or fourth ventricle injections of CP 55,940 and were presented with sweetened condensed milk 15 min after injection. Rats were injected over a range of doses between 100 pg and 10 μg per rat. Milk intake was recorded for a total of 3 h. Lateral ventricle injection of CP 55,940 increased milk intake at doses in the microgram range. However, CP 55,940 was effective in increasing food intake at nanogram doses when injected into the fourth ventricle. Finally, male rats appeared to be more sensitive to CP 55,940 than female rats inasmuch as milk consumption was increased at the 1 ng dose in male rats, whereas only the 10 ng dose was effective in females. These results indicate that CP 55,940 may act in the hindbrain to influence feeding behavior in rats.     

The Complete Set of Predicted Genes from Saccharomyces cerevisiae in a Readily Usable Form

Nearly all of the open reading frames (ORFs) of the yeast Saccharomyces cerevisiae have been synthesized by PCR using a set of ~6000 primer pairs. Each of the forward primers has a common 22-base sequence at its 5′ end, and each of the back primers has a common 20-base sequence at its 5′ end. These common termini allow reamplification of the entire set of original PCR products using a single pair of longer primers—in our case, 70 bases. The resulting 70-base elements that flank each ORF can be used for rapid and efficient cloning into a linearized yeast vector that contains these same elements at its termini. This cloning by genetic recombination obviates the need for ligations or bacterial manipulations and should permit convenient global approaches to gene function that require the assay of each putative yeast gene.     

Results of a high-resolution genome screen of 437 Alzheimer's disease families

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.