Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite >50 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families (931 from an Australian group and 245 from a U.K. group), each with at least two members--mainly affected sister pairs--with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 (maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 (MLS = 2.09). Minor peaks (with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.     

Tempo and mode of concerted evolution in the L1 repeat family of mice

A 300-bp DNA sequence has been determined for 30 (10 from each of three species of mice) random isolates of a subset of the long interspersed repeat family L1. From these data we conclude that members of the L1 family are evolving in concert at the DNA sequence level in Mus domesticus, Mus caroli, and Mus platythrix. The mechanism responsible for this phenomenon may be either duplicative transposition, gene conversion, or a combination of the two. The amount of intraspecies divergence averages 4.4%, although between species base substitutions accumulate at the rate of approximately 0.85%/Myr to a maximum divergence of 9.1% between M. platythrix and both M. domesticus and M. caroli. Parsimony analysis reveals that the M. platythrix L1 family has evolved into a distinct clade in the 10-12 Myr since M. platythrix last shared a common ancestor with M. domesticus and M. caroli. The parsimony tree also provides a means to derive the average half-life of L1 sequences in the genome. The rates of gain and loss of individual copies of L1 were estimated to be approximately equal, such that approximately one-half of them turn over every 3.3 Myr.      

The age-cause proxy relationship in infant mortality

Data presented in this brief note show that one of the consequences of recent gains in the control of neonatal mortality has been an increase in the frequency of endogenous causes of death in the postneonatal period. Several conclusions are readily apparent from the data presented here. 1st, with respect to total infant mortality, the vast majority of the deaths under 1 year of age today are caused by the endogenous conditions that are most closely associated with the physiological processes of gestation and births. 2nd, both the exogenous and endogenous cause-specific death rates are inversely associated with family income status. The strength of the relationship, as measured by the difference between the death rates of the highest and lowest income areas, is much greater for the environmentally related exogenous causes. Further, there is an obvious tendency for the exogenous causes to account for an increasing proportion of total deaths as income status decreases. While these data support research findings that challenge the validity of the traditional age/cause of death proxy relationship in infancy, they suggest that recommendations for enhancing the neonatal/endogenous relationship by shortening the neonatal period may be premature.     

Low levels of environmental ammonia increase susceptibility to disease in Chinook salmon smolts

Ammonia criteria are established using data from standardized toxicity tests involving healthy animals. Both intrinsic and extrinsic environmental changes affect the immune system, but few toxicity studies consider the overall impact on this system and potential changes in resistance to infection. To investigate the effects of subacute levels of ammonia in coastal waters on physiological and immunological systems of fish, juvenile Chinook salmon were maintained in seawater (10 degrees C, pH 7.8) and exposed to two concentrations of ammonia, 2.5 and 10 mg/L total nitrogen. Both test levels resulted in increased internal levels of ammonia in the fish. Neither treatment level affected feeding rates. Over a time course of 10 d, numerous significant effects were observed. White blood cell counts changed significantly, as did respiratory burst activity, plasma lysozyme activity, and plasma glucose concentration in both treatments compared to controls. In an experimental infection with Vibrio anguillarum, fish previously exposed to subacute levels of ammonia were more susceptible to pathogenic challenge. The findings of this study indicate that a more thorough investigation into the effects of environmental ammonia on fish populations in coastal waters should be undertaken and the current environmental standards reassessed.     

The effect of sub-lethal ammonia exposure on fed and unfed rainbow trout: the role of glutamine in regulation of ammonia

Many species of fishes have evolved mechanisms for coping with ammonia caused by either high ammonia environments or an inability to excrete nitrogenous wastes. Rainbow trout (Oncorhynchus mykiss), have not been known to have such a mechanism. The present study investigated whether rainbow trout can use amino acid synthesis and storage to cope with ammonia. Experiments were performed on fed and unfed rainbow trout under both control and elevated ammonia conditions (0 and 10 mgN/l (total ammonia nitrogen), pH 7.2). The results indicate that both feeding and ammonia exposure increased plasma ammonia significantly 6 h postprandial and post ammonia exposure. After 48 h the fed/ammonia exposed fish had plasma ammonia levels that were not significantly different than the fed/control fish. Plasma ammonia was reduced by more than 50%, attributable to ammonia being converted to glutamine in brain, liver and muscle tissue. Feeding alone also increased glutamine levels in brain tissue. Activity of glutamine synthetase in brain and liver was increased corresponding to an increase in glutamine concentrations when fish were exposed to ammonia. This is the first report showing that rainbow trout can detoxify endogenous and exogenous ammonia.     

The effect of iodination of particular tyrosine residues on the hormonal activity of insulin

Insulin dissolved in aqueous or methanolic buffer was iodinated to give preparations containing an average of between one and five iodine atoms per insulin monomer. The resultant preparations were fragmented in various ways and the ratio of tyrosine to monoiodotyrosine and di-iodotyrosine was determined in each fragment. This has allowed the distribution of iodine between the combined A-chain tyrosine residues and the individual B-chain tyrosine residues to be determined. The hormonal activity of each of these iodinated insulin preparations was measured from their effect on the production of (14)CO(2) from [1-(14)C]glucose by isolated adipose cells. The results were interpreted as meaning that the iodination of tyrosine residue A19 or B16 leads to the inactivation of insulin. Speculations are made about the nature of an interaction between insulin and a receptor site on the target tissue.     

Evaluation of an Online Platform for Multiple Sclerosis Research: Patient Description,Validation of Severity Scale,and Exploration of BMI Effects on Disease Course

Objectives

To assess the potential of an online platform, PatientsLikeMe.com (PLM), for research in multiple sclerosis (MS). An investigation of the role of body mass index (BMI) on MS disease course was conducted to illustrate the utility of the platform.

Methods

First, we compared the demographic characteristics of subjects from PLM and from a regional MS center. Second, we validated PLM’s patient-reported outcome measure (MS Rating Scale, MSRS) against standard physician-rated tools. Finally, we analyzed the relation of BMI to the MSRS measure.

Results

Compared with 4,039 MS Center patients, the 10,255 PLM members were younger, more educated, and less often male and white. Disease course was more often relapsing remitting, with younger symptom onset and shorter disease duration. Differences were significant because of large sample sizes but small in absolute terms. MSRS scores for 121 MS Center patients revealed acceptable agreement between patient-derived and physician-derived composite scores (weighted kappa = 0.46). The Walking domain showed the highest weighted kappa (0.73) and correlation (rs = 0.86) between patient and physician scores. Additionally, there were good correlations between the patient-reported MSRS composite and walking scores and physician-derived measures: Expanded Disability Status Scale (composite rs = 0.61, walking rs = 0.74), Timed 25 Foot Walk (composite rs = 0.70, walking rs = 0.69), and Ambulation Index (composite rs = 0.81, walking rs = 0.84). Finally, using PLM data, we found a modest correlation between BMI and cross-sectional MSRS (rho = 0.17) and no association between BMI and disease course.

Conclusions

The PLM population is comparable to a clinic population, and its patient-reported MSRS is correlated with existing clinical instruments. Thus, this online platform may provide a venue for MS investigations with unique strengths (frequent data collection, large sample sizes). To illustrate its applicability, we assessed the role of BMI in MS disease course but did not find a clinically meaningful role for BMI in this setting.     

Chamaedorea (xatÉ) in the Greater Maya Mountains and the chiquibul forest reserve, Belize: An economic assessment of a non-timber forest product

Of the twelve species ofChamaedorea palm recorded for Belize, three are of international economic value because their cut leaves (xaté) are traded in the floricultural industry. Traditionally, Belize has not harvested xaté, the industry being based in Mexico and Guatemala. However, a decline in wild xaté stocks in these countries means Guatemalan leaf harvesters now illegally harvest xaté in Belize. To assess the local abundance of the BelizeanChamaedorea resource, its economic value, and the extent to which it has been illegally harvested, 209 plots measuring 20 meters (m) by 20 m were established in the Greater Maya Mountains (GMM) in western Belize, which includes the Chiquibul Forest Reserve (CFR). We estimate that 37.8 million leaves with a value of U.S. 0.3 million to xateros have been extracted from the CFR. The standing export value is calculated as U.S.0.3 million to xateros have been extracted from the CFR. The standing export value is calculated as U.S. 1.8 million for the CFR and U.S. $5 million for the GMM.