A retrospective study of long-term psychosocial consequences and satisfaction after carrier testing in childhood in an autosomal recessive disease: aspartylglucosaminuria

Genetic carrier testing of children is usually not recommended. However, there are no data concerning long-term psychological consequences, experience, and satisfaction of those tested as well as their recall of the test results. We evaluated these items retrospectively 10–24 years after carrier testing performed in childhood. Study material comprised 25 families with aspatylglucosaminuria (AGU), an autosomal recessive disorder, with 35 healthy sibs from all parts of Finland tested for carriership during childhood between 1973 and 1987. Of these sibs, 25 participated in our study. The questionnaire comprised multiple-choice and open-ended questions. The psychosocial well-being of the study subjects measured by the RAND 36 item Health Survey 1.0 (RAND) was, in general, at least as good as that of controls, and showed no significant differences between carriers and non-carriers (p>0.154). All tested individuals were satisfied with the fact that they had been tested and stated that the decision to perform carrier testing on a child can be made by the parents. Of the 25 tested, 23 knew and understood their test result correctly at the time of our study. Most of the tested individuals (60%) stated that the best time for carrier testing would be in the childhood or in the teen years.
This study indicates that carrier testing in childhood for an autosomal recessive disorder (AGU) had caused no measurable disturbance of quality of life in adulthood, and those tested reported being satisfied. However, we do not recommend testing in childhood, as the result is not needed prior to the time for reproductive decisions.     

Molecular analysis of HLA-D region genes in seropositive rheumatoid arthritis

Analysis of HLA DRB1 and DQB1 Bam HI RFLPs revealed four DRB1 (4.8, 5.2, 6.0 and 7.0 kb) fragments and a 3.2 kb DQB1 fragment to be significantly increased in Caucasians with seropositive RA compared to healthy individuals. The 4.8, 5.2 and 7.0 kb DRB1 fragments were found in 86.5% of RA patients and in 56% of the controls (p = 10(-3), relative risk (RR) = 5.0), while the 6.0 kb fragment was found in 79% of RA patients compared to 32% of controls (p = 2 x 10(-5), RR = 8.0). The 3.2 kb DQB1 fragment was observed in 63.5% of RA patients versus 38.0% of controls (p = 10(-2), RR = 2.8). Analysis of these fragments relative to HLA phenotypes revealed that the 4.8, 5.2 and 7.0 kb DRB1 fragments were strongly correlated with DR4, -7, -9 and -w53 serotypes, the 6.0 kb RFLP with DR4 and the 3.2 kb DQB1 fragment with DR1 and DQw1. Using probes specific for the 5' or 3' regions of the DRB1 gene, the 5.2 and 6.0 kb DRB RFLPs were mapped to the 5' end and the 4.8 and 7.0 kb RFLPs to the 3' end of the DRB1 gene. A probe generated from the second exon of the DRB4 (DRw53) gene recognized only the 5.2 and the 6.0 kb RFLPs corroborating the 5' location of these RFLPs. Family studies further confirmed that these RFLP's segregated with HLA phenotypes.     

Carrier Frequency of the Bloom SyndromeblmMutation in the Ashkenazi Jewish Population

Bloom syndrome is more common in individuals of Ashkenazi Jewish descent than in any other population, and one particular mutation in the Bloom syndrome gene,blm^Ash,is homozygous in nearly all Ashkenazi Jewish persons with Bloom syndrome. We have determined the frequency ofblm^Ashin 1491 Ashkenazi Jewish persons with no known history of Bloom syndrome and found that 1 in 107 persons was heterozygous. Although not common, genetic screening for Bloom syndrome is feasible in this population.     

Clinical significance of the ST-segment response and other early exercise test variables in uncomplicated vs complicated myocardial infarction

An exercise test was performed in 455 patients in the thirdweek after acute myocardial infarction (AMI). One hundred andseventeen (26%) of them were considered as having a complicatedAMI. During a follow-up of 4.5 years their mortality was 49%vs 23% in the remaining patients with uncomplicated AMI. Thesurvival of the patients was assessed in each clinical groupin relation to various exercise variables. Exercise-inducedST-segment depression, irrespective of its degree, did not discriminatesignificantly between dead and living patients in any of theclinical groups. A high value of the rise of the pressure-rateproduct (PRP) from rest to maximal exercise (dPRP) and absenceof significant exercise-induced ventricular arrhythmias identifiedin both clinical groups patients with a very low risk of dying.A low dPRP and/or occurrence of significant ventricular arrhythmiasidentified a relatively high risk in uncomplicated AMI patientsand a very high risk of dying in complicated A MI subjects.The difference in the probability of survival between low-riskand high-risk patients was highly significant in each clinicalgroup (P<0.0001 in uncomplicated, and <0.005 in complicatedAMI, respectively).     

The effect of isosorbide-5-mononitrate (5-ISMN) Durules(R) on exercise tolerance in patients with exertional angina pectoris. A placebo controlled study

Twenty-four patients with stable exercise-induced angina pectorisentered a double-blind cross-over study. Isosorbide-5-mononitrate(5-ISMN) 60 mg in a controlled release formulation (Durules^®)given once daily was compared with identical placebo. The exercisetolerance was determined by bicycle ergometry before and 3 hafter a single dose of 5-ISMN and following one week's treatmentwith 5-ISMN and placebo. Nineteen patients completed the study.Exercise tolerance until the onset of chest pain and until 1mm ST segment depression increased significantly 3 h after dose.The same increase was seen both after a single dose and thesame dose under steady-state conditions. No increase was seenwith placebo. The heart rate and systolic blood pressure reactionsin the standing position were less pronounced 3 h after dosein steady-state than after a single dose of 5-ISMN. Headachewas the only bothersome side-effect reported. The study demonstratesthat 60 mg 5-ISMN in a Durules^® formulation given once dailyhas a significant anti-anginal effect and that tolerance doesnot develop.     

Mathematical model of volume kinetics and renal function after burn injury and resuscitation

This paper presents a mathematical model of blood volume kinetics and renal function in response to burn injury and resuscitation, which is applicable to the development and non-clinical testing of burn resuscitation protocols and algorithms. Prior mathematical models of burn injury and resuscitation are not ideally suited to such applications due to their limited credibility in predicting blood volume and urinary output observed in wide-ranging burn patients as well as in incorporating contemporary knowledge of burn pathophysiology. Our mathematical model consists of an established multi-compartmental model of blood volume kinetics, a hybrid mechanistic-phenomenological model of renal function, and novel lumped-parameter models of burn-induced perturbations in volume kinetics and renal function equipped with contemporary knowledge on burn-related physiology and pathophysiology. Using the dataset collected from 16 sheep, we showed that our mathematical model can be characterized with physiologically plausible parameter values to accurately predict blood volume kinetic and renal function responses to burn injury and resuscitation on an individual basis against a wide range of pathophysiological variability. Pending validation in humans, our mathematical model may serve as an effective basis for in-depth understanding of complex burn-induced volume kinetic and renal function responses as well as development and non-clinical testing of burn resuscitation protocols and algorithms.     

The peril and promise of sensitivity in eating disorders

Differential susceptibility, a reconceptualization of the diathesis-stress model of psychopathology, describes gene–environment interactions that reflect individual differences in responsiveness to environmental influences, both detrimental and beneficial. This model has been described metaphorically by the classification of orchids, which thrive under optimal care but wither under adverse conditions, and dandelions, which weather broad environmental circumstances but are less responsive to careful cultivation. Etiological research in the field of eating disorders has largely focused on the identification of specific behavioral phenotypes, temperamental traits, genotypes and neurobiological processes that confer risk. In this article, we propose that these putative vulnerability factors represent phenotypes and endophenotypes of a genetic predisposition towards environmental sensitivity. We assert that this sensitivity not only transmits eating disorder risk but also confers resilience, depending on the circumstances. In particular, we propose that differential susceptibility can be used as a framework to organize disparate temperamental and neurobiological findings and their complex interplay with various developmental, environmental and sociocultural influences to increase eating disorder risk and treatment responsiveness. Finally, we assert that viewed through the lens of differential susceptibility, sensitivity can be leveraged to refine our interventions and develop novel treatment and prevention strategies to support favorable outcomes for individuals with eating disorders.