Biomedical subjects
Publications and source records attributed to M A Brown.
Recent changes in the way that some hospitals are run have created particular problems for junior medical staff. Here we describe a new system of managing such staff, under evaluation at a large Sydney teaching hospital, which seems to be working well and which has been positively appraised by the Postgraduate Medical Council and the Australian Council on Healthcare Standards.
BACKGROUND: There is debate about whether diastolic blood pressure should be recorded as the fourth (muffling, K4) or fifth (disappearance, K5) Korotkoff sound in pregnancy. We compared maternal and fetal outcomes and the likelihood that episodes of severe hypertension would be recorded when hypertensive pregnancies were managed according to either K4 or K5. METHODS: 220 pregnant women with diastolic hypertension (K4 > or =90 mm Hg) after the 20th week of gestation were enrolled in a prospective randomised study at two obstetric units in Australia; they were randomly assigned management with K4 (n=103) or K5 (n=117) for the remainder of the pregnancy. Clinical management was according to a uniform department protocol. Analysis was by intention to treat. All the women completed the trial. FINDINGS: An episode of severe hypertension (systolic > or =170 mm Hg, diastolic > or =110 mm Hg, or both) was more likely to be recorded with use of K4 than with use of K5 (39 [38%] vs 30 [26%] women, p=0.051), mainly because of a greater likelihood that severe diastolic hypertension would be recorded (34 [33%] vs 20 [17%], p=0.006). The frequency of severe systolic hypertension and simultaneous severe systolic and diastolic hypertension did not differ between groups. Pregnancy was prolonged by an average of 2 weeks in both groups, and there were no significant differences between the groups in laboratory data, requirements for antihypertensive treatment, birthweight, fetal growth retardation, or perinatal mortality. There was no eclampsia or significant maternal morbidity in either group. INTERPRETATION: A change from use of K4 to K5 would mean that one fewer case of severe diastolic hypertension would be recorded for every six hypertensive pregnancies, but all other episodes of severe hypertension would be recorded with similar frequency. Since the K4/K5 difference is smaller in hypertensive than in normotensive pregnant women and since K5 is closer to the actual intra-arterial pressure and more reliably detected, universal adoption of K5 to record diastolic blood pressure in hypertensive pregnancy should be considered.
OBJECTIVE: To analyze the effect of HLA-DR genes on susceptibility to and severity of ankylosing spondylitis (AS). METHODS: Three hundred sixty-three white British AS patients were studied; 149 were carefully assessed for a range of clinical manifestations, and disease severity was assessed using a structured questionnaire. Limited HLA class I typing and complete HLA-DR typing were performed using DNA-based methods. HLA data from 13,634 healthy white British bone marrow donors were used for comparison. RESULTS: A significant association between DR1 and AS was found, independent of HLA-B27 (overall odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8, P = 0.02; relative risk [RR] 2.7, 95% CI 1.5-4.8, P = 6 x 10(-4) among homozygotes; RR 2.1, 95% CI 1.5-2.8, P = 5 x 10(-6) among heterozygotes). A large but weakly significant association between DR8 and AS was noted, particularly among DR8 homozygotes (RR 6.8, 95% CI 1.6-29.2, P = 0.01 among homozygotes; RR 1.6, 95% CI 1.0-2.7, P = 0.07 among heterozygotes). A negative association with DR12 (OR 0.22, 95% CI 0.09-0.5, P = 0.001) was noted. HLA-DR7 was associated with younger age at onset of disease (mean age at onset 18 years for DR7-positive patients and 23 years for DR7-negative patients; Z score 3.21, P = 0.001). No other HLA class I or class II associations with disease severity or with different clinical manifestations of AS were found. CONCLUSION: The results of this study suggest that HLA-DR genes may have a weak effect on susceptibility to AS independent of HLA-B27, but do not support suggestions that they affect disease severity or different clinical manifestations.
OBJECTIVE: To localize the regions containing genes that determine susceptibility to ankylosing spondylitis (AS). METHODS: One hundred five white British families with 121 affected sibling pairs with AS were recruited, largely from the Royal National Hospital for Rheumatic Diseases AS database. A genome-wide linkage screen was undertaken using 254 highly polymorphic microsatellite markers from the Medical Research Council (UK) (MRC) set. The major histocompatibility complex (MHC) region was studied more intensively using 5 microsatellites lying within the HLA class III region and HLA-DRB1 typing. The Analyze package was used for 2-point analysis, and GeneHunter for multipoint analysis. RESULTS: When only the MRC set was considered, 11 markers in 7 regions achieved a P value of < or =0.01. The maximum logarithm of odds score obtained was 3.8 (P = 1.4 x 10(-5)) using marker D6S273, which lies in the HLA class III region. A further marker used in mapping of the MHC class III region achieved a LOD score of 8.1 (P = 1 x 10(-9)). Nine of 118 affected sibling pairs (7.6%) did not share parental haplotypes identical by descent across the MHC, suggesting that only 31% of the susceptibility to AS is coded by genes linked to the MHC. The maximum non-MHC LOD score obtained was 2.6 (P = 0.0003) for marker D16S422. CONCLUSION: The results of this study confirm the strong linkage of the MHC with AS, and provide suggestive evidence regarding the presence and location of non-MHC genes influencing susceptibility to the disease.
OBJECTIVE: Noninvasive 24-hour ambulatory blood pressure monitoring holds great promise as a useful tool in the management of hypertensive pregnancies and pregnancies considered "at risk" for development of preeclampsia. The purpose of this study was to define ambulatory blood pressure monitoring parameters throughout normal pregnancy, including women considered at risk for development of hypertension who continued to have a completely normal pregnancy. STUDY DESIGN: Two hundred seventy-six 24-hour ambulatory blood pressure monitoring studies were made cross-sectionally with use of a Spacelabs 90207 device (validated for use in pregnancy), at one or more of 9 to 17, 18 to 22, 26 to 30, and >30 weeks' gestation. Upper limits of normal were defined as the mean plus 2 SDs for awake and sleep ambulatory blood pressure monitoring results at each stage. RESULTS: Average awake upper limits of normal were 130/77, 132/79, 133/81, and 135/86 mm Hg at the four stages of pregnancy, respectively. Systolic blood pressure fell significantly by 12% to 14% (p < 0.0001) and diastolic blood pressure by 18% to 19% (p < 0.0001) during sleep at all stages of pregnancy. Awake ambulatory blood pressure monitoring systolic measurements were 11 to 12 mm Hg higher than "clinic" measurements (p < 0.001) and diastolic measurements were 5 to 11 mm Hg higher (p < 0.0001) throughout pregnancy. Maximum blood pressure variability ranged from 8 to 13 mm Hg. CONCLUSIONS: The upper limits of normal ambulatory blood pressure monitoring-derived measurements rise slightly as pregnancy progresses. Awake measurements are higher than "clinic" measurements recorded under relaxed conditions by a clinical researcher. The diurnal blood pressure fall and variabilities are similar during pregnancy to those seen in nonpregnant subjects. These data should provide valuable references for further studies of ambulatory blood pressure monitoring in high risk pregnancies.
Hypocalciuria has been associated with preeclampsia (gestational hypertension with proteinuria or other maternal organ dysfunction) but not usually with pure gestational hypertension or normal pregnancy. We hypothesized that hypocalciuria would be a marker of emerging preeclampsia in women presenting with gestational hypertension who later developed preeclampsia. Eighty-one women with de novo hypertension in the second half of pregnancy (n = 81) were enrolled prospectively. At first assessment, calcium/creatinine ratio was determined in a spot urine. Patients were followed until delivery and were classified subsequently according to the occurrence of preeclampsia. Gestational hypertensive patients who became preeclamptic (n = 31) had lower urinary calcium/creatinine ratios at presentation (ratio = 0.07, interquartile range [IQR] = 0.04-0.11) than women who remained as gestational hypertensives (n = 50; ratio = 0.17, IQR = 0.08-0.21; P = .002). Intact plasma parathyroid hormone (PTH) concentrations were similar between groups. Using a receiver operator curve, the best threshold value for the development of preeclampsia was a calcium/creatinine ratio of 0.10, which yielded a sensitivity of only 68% and a specificity of 70%. A low calcium/creatinine ratio preceded the emergence of preeclampsia by 12 (7-24) (median [IQR]) days among a group of women with gestational hypertension. Though this implies primary or secondary disturbances of renal calcium handling even before preeclampsia is clinically apparent, this measurement does not have sufficient sensitivity to recommend its use as a screening test for the emergence of preeclampsia.
Beta2-Microglobulin (beta2-m) is a polypeptide that is freely filtered and then mostly reabsorbed and degraded in the proximal renal tubule. Beta2-m is a marker of glomerular filtration (GFR) in renal failure, whereas urinary beta2-m is a marker of proximal renal tubular dysfunction. Preeclampsia (PE) (ie, de novo hypertension in pregnancy with accompanying renal, cerebral, or liver disease or thrombocytopenia) often has renal involvement characterized by proteinuria, decreasing glomerular filtration, or renal tubular dysfunction. The aim of this study was to determine whether serum beta2-m concentration or urinary beta2-m excretion were greater in women with PE than in women with gestational hypertension (GH) (ie, isolated de novo hypertension in the second half of pregnancy) and normal pregnant women. Seventy-five pregnant women (35 with PE, 22 with GH, and 18 normotensives) were studied prospectively. Serum creatinine and beta2-m concentrations, 24-hour proteinuria, and fractional excretion (FE) of beta2-m were measured. Preeclamptics had similar serum creatinine but higher serum beta2-m (3.26+/-0.99 mg/L) than gestational hypertensives (2.44+/-0.77 mg/L; P = 0.016), and both groups had higher serum beta2-m than controls (1.62+/-0.54 mg/L; P = 0.001). FE of beta2-m was similar amongst groups (PE: 0.27%; interquartile range [IQR]: 0.20-0.86; GH: 0.21%; IQR: 0.11-0.40; controls: 0.26%, IQR: 0.12-0.69). PE is characterized by higher serum beta2-m but similar serum creatinine to GH. Because FE beta2-m is similar in these groups, this implies reduced filtering of beta2-m in PE rather than altered tubular handling of beta2-m. Further studies are now necessary to assess whether measurement of serum beta2-m is helpful in the clinical management of the hypertensive disorders of pregnancy.
The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda > or = 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.
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1. Parathyroid hypertensive factor (PHF) has been implicated in the pathogenesis of several forms of hypertension. We aimed to establish a PHF bioassay using spontaneously hypertensive rat (SHR) plasma. 2. Spontaneously hypertensive rats were confirmed hypertensive and their plasma was dialysed and injected into anaesthetized normotensive rats. 3. Haemodynamic responses to injected SHR plasma were uninterpretable during pentobarbital anaesthesia due to blood pressure (BP) fluctuation. Under halothane anaesthesia, BP was stable but did not rise following SHR plasma injection. Using filtered, undialysed plasma and a different brand of pentobarbital, no consistent BP response was observed following SHR plasma injection. 4. We were unable to detect PHF in the SHR.
OBJECTIVE: To determine the likelihood of progression from gestational hypertension (GH) to pre-eclampsia (PE) in hypertensive pregnant women and whether this change can be identified in advance by available clinical and laboratory measures. DESIGN: A retrospective analysis and a prospective study. SETTING: St George Hospital, Sydney, a teaching hospital of the University of New South Wales delivering 2500 women per year. POPULATION: Eight hundred and forty-five women with new hypertension in the second half of pregnancy, managed by a uniform protocol (661 in the retrospective analysis, 184 in the prospective study). METHODS: Clinical and laboratory data at initial presentation were compared among women with GH who developed PE and those who remained with a diagnosis of GH until delivery. Data predictive for progression from GH to PE were analysed by logistic regression analysis. MAIN OUTCOME MEASURED: Progression from GH to PE. RESULTS: In the retrospective analysis, 416 women initially presented as having GH and 62 (15%) progressed to PE. In the prospective study, 112 women initially presented with GH and 29 (26%) progressed to PE, giving an overall progression of 17%. In both studies, women who developed PE from GH presented earlier than those who remained with GH until delivery. In multiple logistic regression analyses prior miscarriage and early gestation at presentation were associated with increased likelihood of progressing from GH to PE. CONCLUSION: Approximately 15-25% of women initially diagnosed with GH will develop PE and this is more likely with earlier presentation or if the woman has had a prior miscarriage. Women with gestational hypertension diagnosed after 36 weeks of gestation have only about 10% risk of developing PE. These data should help stratify the risks of mildly hypertensive pregnant women being managed as outpatients in their third trimester.
Automated blood pressure recorders are used with increasing frequency by pregnant women, mostly without proper evaluation of their accuracy. We compared blood pressures (BP) recorded by 2 automated noninvasive devices, the Spacelabs 90207 ambulatory blood pressure monitor and the OMRON HEM 705 CP portable self-initiated device, with blood pressures recorded by routine sphygmomanometry in 79 pregnant women either considered 'at risk' for preeclampsia or with mild hypertension in pregnancy. The Spacelabs device tended to overestimate systolic BP by a mean 11 (SD=8) mmHg and diastolic BP by 5 (SD=7) mmHg for phase 5 pressure (p<0.001) but was similar to routine BPs for diastolic phase 4 pressures. The OMRON device tended to underestimate diastolic (phase 4) pressure by 4 (SD=6) mmHg (p<0.001) but gave similar systolic and diastolic (phase 5) pressures to routine sphygmomanometry. However, for both devices there was considerable individual patient variability in accuracy. When using these devices to record a limited number of blood pressure recordings, as in this study, we suggest that individual comparison with mercury sphygmomanometry be made in each pregnant woman before accepting the validity of these recordings.
The transition from student to primary care practitioner is exciting and challenging and offers seemingly limitless opportunities. This article presents results of a model generated from a longitudinal study of 35 newly graduated primary care nurse practitioners during their first year of practice. Stages of development include laying the foundation (recuperating from school, negotiating the bureaucracy, looking for a Job, and worrying); launching (feeling real, getting through the day, battling time, and confronting anxiety); meeting the challenge (increasing competence, gaining confidence, and acknowledging system problems); and broadening the perspective (developing system savvy, affirming oneself, and upping the ante). Anticipatory guidance is offered for new graduates and their mentors and colleagues. Mentors can provide crucial information about appropriate expectations and create key structures to facilitate new practitioners' needs for consultation and advice.
Merozoites of an Atoxoplasma species were present within parasitophorous vacuoles in the cytoplasm of leucocytes in the blood vessels in the small intestine of the greenfinch (Carduelis chloris). The merozoites indented the nucleus of the leucocytes. Merozoites, macrogametes, and microgamonts were present in the epithelial cells of the intestines. No merogony was observed. Experiments provided circumstantial evidence linking disporocystid-octozoic oocysts with the blood and intestinal infections.
BACKGROUND: Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates. METHODS AND RESULTS: Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg x kg(-1) x h(-1) for 12 hours then 0.125 mg x kg(-1) x h(-1)), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg x kg(-1) x h(-1) for 12 hours then 0.25 mg x kg(-1) x h(-1)). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01). CONCLUSIONS: Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.
Short-acting oral nifedipine has been withdrawn from the Australian market because of reports of its adverse effects after long-term treatment in non-pregnant patients with heart disease. This will have a major impact on the treatment of acutely hypertensive pregnant women, in whom the drug has proven to be safe, effective and easy to administer. Should pregnant women be forced to use less suitable agents, thus threatening their own and their babies' health?
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