Biomedical subjects
Publications and source records attributed to R Roberts.
Dilated cardiomyopathy is a heterogeneous disease, both clinically and genetically. Two genes responsible for X-linked DCM have been identified. Five genetic loci responsible for X-linked DCM have been identified. Five genetic loci responsible for autosomal dominant DCM have also been mapped but no genes identified so far. New paradigms may be necessary in order to elucidate the etiology of primary dilated cardiomyopathy.
OBJECTIVES: This study was undertaken to evaluate the ability of myocardial contrast echocardiography (MCE) to guide the targeted delivery of ethanol during nonsurgical septal reduction therapy (NSRT) and to assess the relation between the MCE risk area and infarct size determined by enzymatic and radionuclide methods. BACKGROUND: NSRT with intracoronary ethanol is a new promising treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM). Proper localization and quantification of the septal infarct before ethanol injection are highly desirable. MCE can provide accurate delineation of the vascular territory of the coronary arteries. METHODS: Twenty-nine patients with HOCM and maximal medical therapy underwent NSRT. The left ventricular outflow tract (LVOT) gradient by Doppler echocardiography at baseline was 53 +/- 16 mm Hg (mean +/- SD). Before NSRT, MCE was performed in all patients with intracoronary sonicated albumin (Albunex). Diluted sonicated albumin (Albunex) was selectively injected into the septal perforator arteries during simultaneous transthoracic imaging. Immediately after MCE, ethanol was injected into the same vessel. Plasma total creatine kinase (CK), total CK-MB fraction and CK-MB fraction subforms were measured at baseline and serially for 36 h. RESULTS: LVOT gradient decreased to 12 +/- 6 mm Hg (p < 0.001) after NSRT. Accurate mapping of the vascular beds of the septal perforators was successfully attained in all patients by MCE. Furthermore, the MCE risk area correlated well with peak CK (r = 0.79, p < 0.001). Six weeks after NSRT, 23 patients underwent myocardial perfusion studies performed with single-photon emission computed tomography (SPECT). Mean SPECT septal perfusion defect size involved 9.5 +/- 6% of the left ventricle and correlated well with MCE area (r = 0.7), with no statistically significant difference between the risk area estimated by MCE and that by SPECT. CONCLUSIONS: Estimation of the size of the septal vascular territory with MCE is accurate, safe and feasible in essentially all patients during NSRT. MCE can delineate the perfusion bed of the septal perforators and can predict the infarct size that follows ethanol injection.
This paper analyses the curricula of the four Australian university programs for health information managers (HIMs) in relation to their coverage of health and medical informatics (HMI). The overlap between HIMs and HMIs should be increased through exchange of information at conferences such as this as well as communication and co-operation between the Schools of HIM and those offering health informatics related training at other Australian universities.
Making a correct diagnosis in patients presenting with attack disorders is important. The clinical features of autosomal dominant nocturnal frontal lobe epilepsy and concussive seizures are reviewed. Recent work on the diagnosis and investigation of psychogenic non-epileptic attacks, drop attacks, falls, syncope and sleep disorders is discussed.
There is controversy over whether the method of feeding in infancy affects intellectual development. We investigated the relationship between breastfeeding status at 6 months of age and long-term cognitive development in a cohort of 375 children born in Port Pirie, South Australia, between 1979 and 1982. Cognitive assessments were conducted at ages 2, 4, 7 and 11 to 13 years. After adjustment for sociodemographic, environmental and biomedical factors, a small, statistically non-significant, beneficial effect of breastfeeding on cognitive functioning was observed. Compared with the bottle-fed children, the breast-fed children had a 3.4 (95% CI -0.1 to 6.9), 1.3 (-2.3 to 4.9), 1.2 (-2.0 to 4.4) and 0.8 (-1.9 to 3.5) point advantage on the Bayley Mental Developmental Index at age 2 years, the McCarthy General Cognitive Index at age 4 years and the Wechsler Full-Scale IQ at ages 7 and 11 to 13 years, respectively. Our data suggest that any beneficial effect of breastfeeding on cognitive development is quite small in magnitude.
Fifty-three consecutive patients with hypertrophic cardiomyopathy (HCM) and no history of sudden death underwent electrophysiology (EP) study. Sustained polymorphic ventricular tachycardia (VT) or ventricular fibrillation (VF) was induced in 19 patients (35%). Patients with prior syncope or near syncope had a higher incidence of VT/VF inducibility. An implantable cardioverter defibrillator (i.c.d.) was placed in 14 of the 19 patients. Of the remaining 5 patients with inducible VT/VF, three refused ICD implantation, while two underwent septal myectomy and VT/VF was no longer inducible after the operation. None of the patients received antiarrhythmic drugs. During a mean follow-up period of 47 +/- 31 (2-117) months, no events occurred in the 34 patients with negative EP study. Three events occurred among the 19 patients with inducible VT/VF. One patient died suddenly, one developed wide complex tachycardia which required resuscitation, and one patient received an appropriate ICD shock. In conclusion, sustained polymorphic VT/VF was inducible in about one-third of patients with HCM. Noninducibility of VT/VF appeared to predict a favorable prognosis. Although the overall event rate was low in patients with inducible VT/VF, prophylactic ICD implantation in patients with multiple risk factors may be appropriate.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. The disease is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. A large number of mutations in genes coding for the beta-myosin heavy chain (beta-MyHC), cardiac troponin T (cTnT), cardiac troponin I, alpha-tropomyosin, myosin binding protein C (MyBP-C), and myosin light chain 1 and 2 in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. The Gly256Glu, Val606Met, and Leu908Val mutations in the beta-MyHC are associated with a benign prognosis. In contrast, Arg403Gln, Arg719Trp, and Arg453Cys mutations are associated with a high incidence of sudden cardiac death (SCD). Mutations in cTnT are associated with a mild degree of hypertrophy, but a high incidence of SCD. Mutations in MyBP-C are associated with mild hypertrophy and a benign prognosis. However, it has become evident that factors other than the underlying mutations, such as genetic background and possibly environmental factors, also modulate phenotypic expression of HCM.
Neonatal respiratory distress syndrome (RDS) is associated with decreased plasma activity of antithrombin (AT) and increased formation of thrombin. We tested whether AT reduces thrombin formation, improves gas exchange, and decreases the duration of mechanical ventilation and supplemental oxygen. One hundred twenty-two infants were randomized to pasteurized AT concentrate or to placebo. Two ml/kg (equivalent to 100 IU AT/kg) were followed by 1 ml/kg (50 IU/kg) every 6 h for 48 h. Outcome measures included plasma AT activity, thrombin-AT (TAT) complex, prothrombin fragment (F1+2), the ratio of arterial to alveolar oxygen pressure [(a/A)PO2], and the ventilator efficiency index (VEI). In the AT group (n = 61), mean (SD) birth weight was 1,198 (301) g, mean (SD) gestational age (GA) was 28.3 (2.0) wk, 54% were male. In the placebo group (n = 61), mean (SD) birth weight was 1,201 (315) g, mean (SD) GA was 28.8 (2. 3) wk, 51% were male. In treated infants, AT activity was raised to means of 1.69 and 2.25 U/ml at 24 and 48 h, respectively. Corresponding means in control infants were 0.37 and 0.44 U/ml (p < 0.0001). F1+2, but not TAT, was significantly reduced by AT (p = 0. 004). VEI and (a/A)PO2 were similar in both groups throughout the first week of life. Median days receiving mechanical ventilation were 7.1 (AT) versus 4.8 (placebo), p = 0.0014. Median days receiving supplemental oxygen were 7.9 (AT) versus 5.5 (placebo), p < 0.0001. There were seven (11.5%) deaths in the AT group and three (4.9%) deaths in the placebo group. We conclude that treatment with AT cannot be recommended in premature infants with RDS.
Although intrapulmonary fibrin deposition is a pathognomonic feature of acute lung injury, it remains uncertain whether thrombin inhibitors affect clinically important outcomes. We hypothesized that both heparin and antithrombin (AT) concentrate improve gas exchange during experimental respiratory distress syndrome. We also tested whether combination therapy is more beneficial than monotherapy. Forty-eight newborn piglets were randomized within 12 litters to one of four groups in a factorial design: (1) AT; (2) heparin; (3) AT plus heparin; (4) untreated control animals. After lung lavage and 4 h of barovolutrauma, mechanical ventilation was continued for 24 h during which ventilator pressures and inspired oxygen were adjusted to maintain normal blood gases. The arterial/ alveolar oxygen tension ratio (a/A ratio) and the ventilator efficiency index (VEI) at 18 and 24 h were compared by repeated measures analysis of variance (ANOVA). In contrast to our hypothesis, only heparin improved gas exchange, and we found little evidence of an interaction with AT. The a/A ratio was 0.48 +/- 0.27 (mean +/- SD) in the presence of heparin versus 0.33 +/- 0.26 in its absence; p = 0.01. Corresponding VEI was 0.30 +/- 0.12 versus 0.25 +/- 0.14; p = 0.04. Hyaline membrane formation was also decreased in heparin-treated animals (p = 0.02).
Telemedicine provides the scope to remove the barrier of distance from delivery of health care. In so doing it has the potential to strengthen primary care and local health delivery, and to optimise the use of secondary and tertiary specialist resources. However, it can have disbenefits and perverse effects which are as yet inadequately addressed. Development of telemedicine to date has been led by new technological opportunities, linked to clinical interests. Whilst not inappropriate, this alone is not adequate. All health care activities should be to promote health and treat ill-health, and therefore the interests of the consumer and of society should predominate. More complete research and policy analysis of telemedicine are therefore needed. This paper argues for a more holistic and integrated view of telemedicine to be taken, to ensure that technology is harnessed to meet need. To this end, it puts telemedicine into the overall context of health care interests, and describes methodologies to assess patient attitudes and societal priorities. Given the need to avoid the unanticipated adverse effects which have bedevilled other new health care technologies, and the particular risks of uncontrolled consultations and commerce across national boundaries, the paper goes on to advocate routine use of integrated risk analysis of telemedicine applications at research and policy levels. The need for an effects-orientated analytic framework, and for international policy collaboration to protect users of services available by global telecommunications, is identified.
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Hypertension in pregnancy and gestational diabetes have in common a lack of universally accepted classification and nomenclature that hinders comparison of data between research groups and contributes to the lack of consensus in the literature on these conditions. The inter-relationship of hypertension and gestational diabetes can be considered from three viewpoints according to whether hypertension is present before, during, or after the pregnancy. The first question is whether hypertension predating pregnancy predisposes to gestational diabetes. Epidemiological evidence and physiological argument based on the common etiologic factor of insulin resistance would suggest that gestational diabetes should be more common in the presence of preexisting hypertension. The limited clinical data available support this hypothesis. There are three issues concerning the coexistence of hypertension and gestational diabetes: whether gestational diabetes predisposes to pregnancy-induced hypertension, whether pregnancy-induced hypertension predisposes to gestational diabetes and what effect the combination has on morbidity and mortality. A number of studies have investigated whether pregnancy-induced hypertension is more common in women with gestational diabetes, but no consensus has been reached. There is little direct clinical evidence on the reverse issue, but data are presented to suggest that pregnancy-induced hypertension may only predispose to gestational diabetes when its etiology is gestational hypertension and not preeclampsia. The issue of how the coexistence of pregnancy-induced hypertension and gestational diabetes affects maternal or neonatal morbidity and mortality is largely unanswered. The last question is whether gestational diabetes has any prognostic significance with regard to the future development of hypertension in the mother. It is well known that gestational diabetes predisposes to subsequent NIDDM and that NIDDM is associated with a high incidence of essential hypertension. Once again insulin resistance may be a unifying factor. However, there is no direct clinical evidence that gestational diabetes predisposes to future hypertension.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric proteins. It is characterized by left ventricular hypertrophy in the absence of an increased external load, and myofibrillar disarray. While hypertrophy is a common cardiac response to injury, disarray is the pathological hallmark of HCM. A large number of mutations in genes coding for sarcomeric proteins, ie the beta-myosin heavy chain (beta-MyHC), cardiac troponin (cTn)T, cTnI, alpha-tropomyosin, myosin-binding protein C (MyBP-C), and essential and regulatory myosin light chains in patients with HCM have been identified. Genotype-phenotype correlation studies have shown that mutations carry prognostic significance. Unlike mutations in the beta-MyHC gene, the prognostic significance of which reflect their hypertrophic expressivity, cTnT mutations are associated with a mild degree of hypertrophy, but a high incidence of sudden cardiac death. Mutations in MyBP-C are associated with mild hypertrophy, and a benign prognosis. However, the genetic background in which the mutations occur, and possibly environmental factors also, modulate phenotypic expression of HCM. Functional studies of mutations causing HCM have shed significant light into the pathogenesis of HCM and have led to the hypothesis that mutant sarcomeric proteins function as 'poison peptides' exerting a dominant-negative effect on the function of the cardiac myocytes, followed by structural changes and a compensatory hypertrophy.
Myotonic dystrophy (DM) is associated with expansion of CTG repeats in the 3'-untranslated region of the myotonin protein kinase (DMPK) gene. The molecular mechanism whereby expansion of the (CUG)n repeats in the 3'-untranslated region of DMPK gene induces DM is unknown. We previously isolated a protein with specific binding to CUG repeat sequences (CUG-BP/hNab50) that possibly plays a role in mRNA processing and/or transport. Here we present evidence that the phosphorylation status and intracellular distribution of the RNA CUG-binding protein, identical to hNab50 protein (CUG-BP/hNab50), are altered in homozygous DM patient and that CUG-BP/hNab50 is a substrate for DMPK both in vivo and in vitro. Data from two biological systems with reduced levels of DMPK, homozygous DM patient and DMPK knockout mice, show that DMPK regulates both phosphorylation and intracellular localization of the CUG-BP/hNab50 protein. Decreased levels of DMPK observed in DM patients and DMPK knockout mice led to the elevation of the hypophosphorylated form of CUG-BP/hNab50. Nuclear concentration of the hypophosphorylated CUG-BP/hNab50 isoform is increased in DMPK knockout mice and in homozygous DM patient. DMPK also interacts with and phosphorylates CUG-BP/hNab50 protein in vitro. DMPK-mediated phosphorylation of CUG-BP/hNab50 results in dramatic reduction of the CUG-BP2, hypophosphorylated isoform, accumulation of which was observed in the nuclei of DMPK knockout mice. These data suggest a feedback mechanism whereby decreased levels of DMPK could alter phosphorylation status of CUG-BP/hNab50, thus facilitating nuclear localization of CUG-BP/hNab50. Our results suggest that DM pathophysiology could be, in part, a result of sequestration of CUG-BP/hNab50 and, in part, of lowered DMPK levels, which, in turn, affect processing and transport of specific subclass of mRNAs.
OBJECTIVE: To compare thoracic radiographs of clinically normal dogs and dogs with mild clinical heartworm disease with images transmitted by a desk-top, two-way audiovisual teleconferencing system. DESIGN: Prospective, matched-set study. STUDY POPULATION: 50 thoracic radiographs from clinically normal and heartworm-infected dogs and the digitally transmitted images of those radiographs. PROCEDURE: Thoracic radiographs from 25 clinically normal dogs and 25 dogs infected with 1 to 24 heartworms were evaluated by 3 clinicians. Using classic criteria for heartworm disease, evaluations of radiographs and images transmitted digitally over 2 high-speed data-transfer telephone lines (56 kilobits/s/line) were performed. Clinicians were asked to determine whether dogs had radiographic signs of heartworm disease. RESULTS: Clinicians' ability to detect heartworm disease did not differ between interpretations of radiographs and those of transmitted images. CLINICAL IMPLICATIONS: Radiographic images transmitted via a teleconference system can be used to provide reliable diagnostic information. Thoracic radiographs can be interpreted at a remote site permitting rapid consultation and immediate advice on clinical management.
BACKGROUND: Although accelerated diagnostic protocols are being increasingly used in emergency departments to diagnose acute cardiac ischemia, there have been no prospective evaluations of a chest pain diagnostic protocol with serial determinations of creatine kinase MB isoenzyme and mandatory exercise electrocardiography (ExECG). METHODS: Prospective cross-sectional study in which chest pain protocol results were compared with final (reference) diagnoses of acute cardiac ischemia (including acute myocardial infarction and unstable angina). Patients in need of hospital admission but at low probability (by a validated algorithm) for acute myocardial infarction were examined for exclusions: known coronary artery disease, cardiac complications, severe comorbidities, or inability to perform exercise testing. A 12-hour diagnostic protocol included serial measurements of creatine kinase MB, ECG, and clinical assessments followed by ExECG for those with negative initial serial testing. Reference diagnoses were established during hospitalization and diagnostic accuracy was assessed. RESULTS: The study group of 317 patients was 54% male and 65% black, and had a mean age of 46.6 years; 9.5% had a final diagnosis of acute cardiac ischemia. For this diagnosis, the protocol had a sensitivity of 90.0% (95% confidence interval, 72.3%-97.4%); specificity, 50.5% (95% confidence interval, 44.6%-56.4%); positive predictive value, 16.0%; and negative predictive value, 98.0%. Creatine kinase MB, serial ECGs, and ExECG each made a contribution to improved sensitivity and accuracy, whereas clinical reassessments were less discriminating, as indicated by protocol's receiver operating characteristic curve. CONCLUSIONS: A chest pain diagnostic protocol achieved high sensitivity and improved specificity over the standard emergency department workup. There were no adverse advents associated with early ExECG.
BACKGROUND: Atrial fibrillation, the most common sustained cardiac-rhythm disturbance, affects over 2 million Americans and accounts for one third of all strokes in patients over 65 years of age. The molecular basis for atrial fibrillation is unknown, and palliative therapy is used to control the ventricular rate and prevent systemic emboli. We identified a family of 26 members of whom 10 had atrial fibrillation which segregated as an autosomal dominant disease. We subsequently identified two additional families in which the disease was linked to the same locus. METHODS: We screened the human genome with 300 polymorphic dinucleotide-repeat markers using an unconventional strategy of pooling the DNA samples into two groups (affected and unaffected), which reduced the sample size by approximately 90 percent, before performing linkage analysis to map the locus. This made it possible to identify potential loci within a few weeks. RESULTS: The lod scores for markers D10S569 and D10S607, located at 10q22-q24, were 3.60 in Family 1. The disease locus in Families 2 and 3 was also linked to the same markers, with lod scores of 6.02 and 5.35 for markers D10S569 and D10S607, respectively, when data on all three families were combined. Haplotype analysis of the three families showed that the locus was between D10S1694 and D10S1786, an interval of 11.3 centimorgans. CONCLUSIONS: Identification of the gene for familial atrial fibrillation will help to elucidate the molecular basis of the disease and provide insights into acquired forms. The strategy of pooling DNA samples for analysis is more time and cost effective than conventional screening and should accelerate the process of gene mapping in the future.
To explore the role of GTPases in endocytosis, we developed an assay using Xenopus oocytes injected with recombinant proteins to follow the uptake of the fluid phase marker HRP. HRP uptake was inhibited in cells injected with GTPgammaS or incubated with aluminum fluoride, suggesting a general role for GTPases in endocytosis. Injection of Rab5 into oocytes, as well as Rab5:Q79L, a mutant with decreased GTPase activity, increased HRP uptake. Injection of Rab5:S34N, the dominant-negative mutant, inhibited HRP uptake. Injection of N-ethylmaleimide-sensitive factor (NSF) stimulated HRP uptake, and ATPase-defective NSF mutants inhibited HRP uptake when coinjected with Rab5:Q79L, confirming a requirement for NSF in endocytosis. Surprisingly, injection of Rab7:WT stimulated both uptake and degradation/activation of HRP. The latter appears to be due to enhanced transport to a late endosomal/prelysosomal degradative compartment that is monensin sensitive. Enhancement of uptake by Rab7 appears to function via an Rab5-sensitive pathway in oocytes since the stimulatory effect of Rab7 was blocked by coinjection of Rab5:S34N. Stimulation of uptake by Rab5 was blocked by Rab5:S34N but not by Rab7:T22N. Our results suggest that Rab7, while functioning downstream of Rab5, may be rate limiting for endocytosis in oocytes.