The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

Terminal-Phase Chronic Myelogenous Leukemia: Approaches to Treatment

The prognosis of patients with CML has improved little in the past 50 years. The relatively benign chronic phase invariably deteriorates to a refractory and rapidly fatal terminal phase. This terminal stage has been found to have two major subtypes as defined by morphologic, cytochemical, immunologic, and enzymatic criteria--myeloblastoid and lymphoblastoid. Aggressive combination chemotherapy has achieved minimal improvement in survival once the terminal phase has begun, perhaps because only Ph1-positive stem cells remain to repopulate the marrow at this stage. Bone marrow transplantation has also been unsuccessful as therapy for the terminal phase, possibly because the patients are too debilitated to tolerate transplantation once the terminal phase has begun. Combination chemotherapy has been applied in an effort to eliminate the Ph1 chromosome-containing clone during the chronic phase. This goal has not yet been consistently achieved. Chemotherapy has also not been able to delay the onset of the terminal phase nor to prolong survival. Even in those patients in whom the Ph1 chromosome-containing clone has been eliminated, relapse to the chronic phase with return of the Ph1 chromosome has generally occurred within a brief period of time. Bone marrow transplantation during the chronic phase may hold the promise of true cure for CML, with permanent elimination of the malignant clone. However, the chronic phase can be unpredictably long and patients in the chronic phase often have few, if any symptoms. Therefore, there has been a reluctance to employ drastic therapy during the chronic phase. Techniques to predict the transformation to the terminal phase prior to overt morphologic or clinical conversion are now being developed. It may be possible in the future to attempt HLA-matched sibling donor bone marrow transplantation at the earliest signs of transformation from the chronic to the terminal phase. In this manner, optimal survival might be achieved by allowing patients to be maintained in the chronic phase for as long as possible prior to the initiation of aggressive therapy. Until this is routinely possible, continued research designed to improve the therapy of the terminal phase must be pursued. These attempts are likely to include the development and evaluation of new chemotherapeutic agents, novel methods of administration of existing drugs to better exploit their pharmacokinetics (for example, continuous infusion), and the utilization of newly described treatment approaches (such as the use of "differentiating" agents in an attempt to prevent progression to blastic transformation).(ABSTRACT TRUNCATED AT 400 WORDS)     

Cost containment with the use of "mini-cholecystectomy" and intraoperative cholangiography

During an era when cost containment has become increasingly important, a new approach to elective cholecystectomies through a 4 to 5 cm incision is reported. Over an approximately 2-year period, 96 patients have undergone "mini-cholecystectomies" with intraoperative cholangiograms. Six of these patients have had concomitant common bile duct explorations. The average postoperative stay was 2.5 days. The average procedure lasted 45 minutes. Pain medication postoperatively was required less frequently than with the routine subcostal incision. Time away from work was greatly reduced. No complications were encountered. When a more complicated cholecystectomy is discovered, which may place the patient in danger, the small incision can be easily lengthened in order to provide better exposure and thus aid in dissection. On the basis of almost 600,000 cholecystectomies performed per year, hospital costs ranging from $100 to $150 per day, and the procedure being acceptable in 80 per cent of the elective procedures, the potential yearly cost-savings could range up to $250,000,000 per year when this procedure is used.     

Paramagnetic macrocyclic complexes as contrast agents for MR imaging: proton nuclear relaxation rate enhancement in aqueous solution and in rat tissues

Paramagnetic macrocyclic chelates show promise as magnetic resonance (MR) imaging contrast agents due to stability and relaxivity comparable to those of DTPA-type chelates. For the three copper and manganese macrocyclic complexes studied in aqueous solution, T1 and T2 relaxivities ranged from 0.14 to 5.88 mM-1sec-1 at 6.25 MHz. In rats, the intravenous administration of 16 mumol/kg of Mn(cyclam) caused the liver T1 relaxation rate to double at 15 minutes after injection. T1 measurements by pulsed MR imaging and manganese analyses on excised tissue showed that both relaxation rate (1/T1) and manganese content of liver and kidney increase linearly with the dosage of Mn(cyclam). The linear relationship between 1/T1 and manganese content can be considered an "in tissue" relaxivity plot for the agent. The resulting relaxivity is 54 mM-1sec-1 in liver, compared with 3.1 mM-1sec-1 in aqueous solution. Although this work is preliminary, the implication for medical MR imaging applications is that macrocyclic contrast agents can be effective at approximately one-tenth the current typical dose used for gadolinium DTPA.     

Genetic Analysis Workshop II: combined segregation, linkage, and association analysis

A combined segregation, linkage, and association analysis using the program COMBIN was performed on the simulated pedigree data prepared for the Second Genetic Analysis Workshop. The model used in COMBIN is described and the presented results illustrate its effectiveness in the analysis of such data. Linkage analysis was performed and maps for each linkage group are presented.     

Segregation analysis of peripheral neurofibromatosis (NF1).

Four studies of NF1 support a prevalence of 0.0003 and a carrier incidence at birth of 0.0004. The gene frequency (q) is therefore 0.0002, and the proportion of cases owing to fresh mutation is 0.56. The mutation rate (xq) is 10(-4), an unusually high value suggestive of a large gene. Penetrance among subjects examined is virtually complete, and there is no evidence of phenocopies or somatic mutations.     

Hanganutziu-Deicher antigen as a possible target for immunotherapy of melanoma

Hanganutziu-Deicher (H-D) antigen is classified as a heterophile antigen and chemically defined as a glycoconjugate which contains N-glycolylneuraminic acid. H-D antigens are absent from normal human tissues, but can be expressed on a variety of human malignant cells, including melanoma. Natural anti-H-D antibodies have been detected in man with and without malignancies, but in this study when the level of antibody was compared between healthy adults and patients with melanoma, elevated anti-H-D antibody levels were found more frequently in melanoma patients for both IgM (p = 0.0001) and IgG (p = 0.0001). The present study was designed to evaluate the significance of the H-D antigen-antibody system in melanoma suppression. Sera from melanoma patients containing anti-H-D antibody reacted strongly to H-D antigen expressed on melanoma by means of flow cytometry. In a complement-dependent cytotoxicity assay this antibody killed melanoma cells in vitro. In vivo significance of the antibody was assessed by evaluating the relationship between the antibody levels and the clinical course in patients with stage II melanoma. Antibody levels were measured by enzyme-linked immunosorbent assay using a H-D glycoprotein antigen isolated from bovine erythrocytes. A significantly higher level of IgG (p = 0.0640) and IgM (p = 0.0644) anti-H-D antibody was demonstrated in those patients who were free of disease more than 5 years after surgery than in those who relapsed within 2 years. This study provides a rational basis for immunotherapy targeting H-D antigen in human melanoma.     

Monitoring exercise stress by changes in metabolic and hormonal responses over a 24-h period

Summary Metabolic and endocrine responses of 14 subjects of varying levels of fitness to an intensive anaerobic interval training session were assessed before exercise and at 2 h, 4 h, 8 h and 24 h postexercise. The endocrine response of the same subjects to a control day, where they were required not to exercise, was also assessed and compared with the values obtained on the interval training day. Uric acid, urea, and creatine phosphokinase concentrations still remained elevated above pre-exercise values 24 h postexercise. Lactate, creatinine, testosterone and cortisol concentrations were significantly elevated above pre-exercise values immediately postexercise but these had reversed by 2 h postexercise. Over the remainder of the recovery period testosterone concentrations remained significantly lower than values measured at similar times on the control day. This was shown to be due directly to a change in testosterone as sex hormone binding globulin concentration remained constant throughout the recovery period. The data indicate that when comparisons of data were made to control (rest) days, imbalances in homeostasis, due to intensive training, are not totally reversed within the next 24-h. The data also demonstrate that the parameters measured undergo the same variations in subjects with a wide range of physical fitness, indicating that these parameters could be used to monitor exercise stress and recovery in athletes of a wide range of abilities. The more acute responses to exercise could be mistaken for overtraining if insufficient recovery time were not permitted between the final exercise session and taking blood samples, further emphasising the need to be able to recognise the difference between the fatigue associated with acute exercise and a state of chronic fatigue that may result from too little regeneration time within the training programme.