Chenodeoxycholic acid treatment of gallstones. A follow-up report and analysis of factors influencing response to therapy.

We treated 70 patients with gallstones with chenodeoxycholic acid over 3 1/2 years and analyzed the factors influencing the outcome of therapy. This treatment was unsuccessful in 11 patients with radiopaque gallstones and in seven with nonfunctioning gallbladders, but 64 per cent with radiolucent gallstones treated for six months or more showed partial or complete gallstone dissolution, and of those whose bile became unsaturated with cholesterol, 100 per cent had evidence of dissolution. In patients with partial or complete gallstone dissolution, the mean post-treatment biliary cholesterol saturation index--0.78 +/- 0.04 (S.E.M.)--was significantly less (P less than 0.001), and the dose of chenodeoxycholic acid (14.4 +/- 1.0 mg per kilogram of body weight per day) significantly more (P less than 0.025) than in those whose gallstones did not change (1.15 +/- 0.04 and 10.6 +/- 1.2 respectively). In patients with radiolucent gallstones, the dose of chenodeoxycholic acid should be based on body weight; 14 to 15 mg per kilogram of body weight per day effectively lowers the saturation index and dissolves gallstones.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

The transplanted kidney as a source of cytomegalovirus infection.

To determine the incidence of cytomegalovirus infection in renal-transplant recipients we followed 32 prospectively for six months after operation. As judged by serologic change and virus isolation the infection rate for the entire group was 66 per cent (21 of 32 patients) - 59 per cent (13 of 22) for seronegative patients and 80 per cent (eight of 10) for seropositive patients. Of 10 seronegative patients who received kidneys from seronegative donors, only three became infected. However, of 12 seronegative patients who received kidneys from seropositive donors, 10 became infected. Thus, there was a significant correlation between development of infection and seropositivity of the donor (P = 0.03), particularly when the recipient was seronegative (P = 0.02). Five possible and four definite recognizable clinical illnesses were associated with cytomegalovirus infection; all except two were in initially seronegative subjects who received kidneys from seropositive donors. Primary infection and disease in nonimmune recipients may be caused by cytomegalovirus transmitted by the kidneys of latently infected seropositive donors.     

Interaction of Angiotensin with Disseminated Intravascular Coagulation: A Possible Mechanism in the Genesis of Acute Renal Failure

Because of the importance of the renin-angiotensin system in renal homeostatic mechanisms, the effect of angiotensin administration upon disseminated intravascular coagulation has been studied in rabbits. An infusion of angiotensin II (0.1 μg/kg/min for 2 hours) produced neither histologic abnormalities in the kidneys nor an elevation of creatinine. After an infusion of thrombin (2.0 units/kg/min for 2 hours) only 3 of 10 rabbits, when sacrified 24 hours later, showed histologic lesions comprised of occasional fibrin thrombi and foci of tubular necrosis. Creatinine levels did not rise. In contrast, the combination of angiotensin and thrombin resulted in renal lesions in 12 of 14 animals. Four had frank cortical necrosis, while combinations of tubular necrosis, glomerular thrombosis and segmental glomerular infarction occurred in the others, together with elevated creatinine levels. Blockade of α-adrenoreceptors with phenoxybenzamine in 12 animals did not prevent either these histologic changes or creatinine elevation, showing that the effect of angiotensin was independent of α-adrenoreceptor stimulation. The synergistic interaction between angiotensin and disseminated intravascular coagulation was not explained by differences in the consumption of plasma fibrinogen but apparently was due to localization of fibrin thrombi within glomerular capillaries by the vasomotor actions of angiotensin, as has previously been shown to occur with α-adrenoreceptor simulation. Such a mechanism might contribute to renal glomerular deposition of fibrin in acute ischemic renal failure.     

IMPT1, an imprinted gene similar to polyspecific transporter and multi- drug resistance genes

Human chromosome 11p15.5 and distal mouse chromosome 7 include a megabase-scale chromosomal domain with multiple genes subject to parental imprinting. Here we describe mouse and human versions of a novel imprinted gene, IMPT1 , which lies between IPL and p57 KIP2 and which encodes a predicted multi-membrane-spanning protein similar to bacterial and eukaryotic polyspecific metabolite transporter and multi- drug resistance pumps. Mouse Impt1 and human IMPT1 mRNAs are highly expressed in tissues with metabolite transport functions, including liver, kidney, intestine, extra-embryonic membranes and placenta, and there is strongly preferential expression of the maternal allele in various mouse tissues at fetal stages. In post-natal tissues there is persistent expression, but the allelic bias attenuates. An allelic expression bias is also observed in human fetal and post-natal tissues, but there is significant interindividual variation and rare somatic allele switching. The fact that Impt1 is relatively repressed on the paternal allele, together with data from other imprinted genes, allows a statistical conclusion that the primary effect of human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domain-wide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting might regulate placental and fetal growth.      

One-year prospective study of cases of suspected acute myocardial infarction managed by urban and rural general practitioners.

BACKGROUND: The role of the general practitioner in the management of patients with suspected acute myocardial infarction is important and specific. It has been recommended that eligible patients should receive thrombolysis within 90 minutes of alerting medical or ambulance services. The administration of prehospital thrombolysis by general practitioners is controversial. Most research into the management of acute myocardial infarction has been hospital based and has not explored differences between urban and rural general practice. AIM: In 1993-94 a one-year prospective survey was undertaken of samples of urban and rural general practitioners to examine their management of cases of suspected acute myocardial infarction and to determine whether differences in management existed between the two settings. METHOD: General practitioners were recruited through the continuing medical education faculty network of the Irish College of General Practitioners. Participating general practitioners completed a report form for cases of suspected acute myocardial infarction. Six-week follow-up forms were also completed. RESULTS: A total of 113 general practitioners (54 urban and 59 rural) participated in the study. A total of 57 general practitioners contributed 195 cases, 49 from urban and 146 from rural areas. The mean number of cases of suspected acute myocardial infarction per participant for urban and rural doctors was 0.9 and 2.5, respectively. Median delay time from onset of symptoms to contacting the general practitioner was 90 minutes for both urban and rural patients. Median general practitioner response times for urban and rural doctors were 10 and 15 minutes, respectively. Median estimated journey times from location of the patient to hospital for urban and rural patients were 10 and 40 minutes, respectively (P<0.001). Rural doctors were more likely, in comparison with their urban counterparts, to administer aspirin (given to 40% of patients versus 16%, P<0.01) but less likely to administer intravenous morphine (26% versus 41%, P<0.05). Twenty one patients (11%) died at the scene; follow-up forms were received for 94% of the remaining patients. Of these 163 patients, 99% were admitted to hospital; 49% were discharged with a diagnosis of acute myocardial infarction and a further 25% had final diagnoses consistent with acute coronary heart disease. CONCLUSION: This study suggests that the management of patients with suspected acute myocardial infarction differs in urban and rural settings. Delay times suggest that in order to meet current guidelines, prehospital thrombolysis must become a reality in rural areas.     

Role of nitric oxide in the biology, physiology and pathophysiology of reproduction

Following its benchmark discovery, nitric oxide (NO) is nowknown to play important functional roles in a variety of physiologicalsystems. Within the vasculature, NO induces vasodilation, inhibitsplatelet aggregation, prevents neutrophil/platelet adhesionto endothelial cells, inhibits smooth muscle cell proliferationand migration, regulates programmed cell death (apoptosis) andmaintains endothelial cell barrier function. NO generated byneurons acts as a neurotransmitter, whereas NO generated bymacrophages in response to invading microbes acts as an antimicrobialagent. Because neurons, blood vessels and cells of the immunesystem are integral parts of the reproductive organs, and inview of the important functional role that NO plays in thosesystems, it is likely that NO is an important regulator of thebiology and physiology of the reproductive system. Indeed, inthe past 10 years, NO has established itself as a polyvalentmolecule which plays a decisive role in regulating multiplefunctions within the female as well as the male reproductivesystem. This review provides an overview of the role of NO invarious reproductive organs under physiological and pathologicalconditions.     

ATRX encodes a novel member of the SNF2 family of proteins: mutations point to a common mechanism underlying the ATR-X syndrome

It was shown recently that mutations of the ATRX gene give rise to a severe, X-linked form of syndromal mental retardation associated with alpha thalassaemia (ATR-X syndrome). In this study, we have characterised the full-length cDNA and predicted structure of the ATRX protein. Comparative analysis shows that it is an entirely new member of the SNF2 subgroup of a superfamily of proteins with similar ATPase and helicase domains. ATRX probably acts as a regulator of gene expression. Definition of its genomic structure enabled us to identify four novel splicing defects by screening 52 affected individuals. Correlation between these and previously identified mutations with variations in the ATR-X phenotype provides insights into the pathophysiology of this disease and the normal role of the ATRX protein in vivo.