The role of occupational and environmental exposures in the aetiology of acquired severe aplastic anaemia: a case control investigation.

Aplastic anaemia is a rare but serious disorder with a high morbidity and mortality rate. The causes of aplastic anaemia are, for the most part, unknown. We report on the hypothesis that aplastic anaemia may be caused by occupational and/or environmental exposures to certain chemicals. The UK Aplastic Anaemia Study was an interview-based case-control study covering the whole of Great Britain. Those patients diagnosed between 1 July 1993 and 20 October 1997, aged < or =75 years and born and diagnosed in the UK were eligible for the study. Two hundred eligible cases of aplastic anaemia were compared with 387 age- and sex-matched controls. A number of occupational exposures showed increases in risk. In a multivariate model of these exposures the odds ratios (ORs) for solvents/degreasing agents, pesticides and radiation were >2 and statistically significant. Reported chemical treatment of houses within 5 years of diagnosis had a significantly raised risk for adults [OR = 2.51, 95% confidence interval (CI) 1.02-12.01], particularly for woodworm treatment (OR = 5.1, 95% CI 1.5-17.4). This study identified significant risks associated with self-reported exposure to solvents, radiation and pesticides in the workplace. Self-reported chemical treatment of houses was also associated with an increased risk of developing aplastic anaemia, in keeping with previous literature.

A nurse-delivered advice intervention can reduce chronic non-steroidal anti-inflammatory drug use in general practice: a randomized controlled trial.

OBJECTIVE: To find out whether a nurse-delivered educational package can reduce chronic oral non-steroidal anti-inflammatory drug (NSAID) usage in general practice. METHOD: A prospective randomized controlled trial with assessment of economic cost/benefits was carried out in five general practices in Nottinghamshire with computerized prescribing systems, representing a mix of rural/urban and fundholding/non-fundholding practices. Patients suffering from non-malignant, non-inflammatory musculoskeletal pain received repeat prescriptions for oral NSAIDs. Two hundred and twenty-two patients were randomized to a control group (simple advice regarding NSAID use) or an intervention group (asked to withdraw their NSAIDs and employ appropriate alternative drug and non-drug therapies). All advice was supported by patient literature and delivered by a nurse practitioner trained in musculoskeletal assessment. The primary outcome measure was change in NSAID use 6 months after the intervention. Secondary outcome measures were changes in health and quality of life (SF-36 and EQ-5D questionnaires) and drug, health service and patient costs. RESULTS: An extra 28% of patients in the intervention group either stopped taking oral NSAIDs or reduced dosage by > or =50% at 6 months compared with controls. There was no detrimental effect on health and well-being. Oral NSAID prescription costs were significantly lowered in the intervention group but not in the control group. A non-significant increase in total drug prescription costs occurred in both groups. CONCLUSIONS: Nurse-based intervention can reduce chronic NSAID usage and costs in primary care and would be cost-effective if maintained in the long term. This intervention package would be readily applicable in primary care.

Epithelioid trophoblastic tumor of the uterus in a postmenopausal woman: a case report and review of the literature.

We report an epithelioid trophoblastic tumor (ETT), a recently delineated type of gestational trophoblastic tumor (GTT), discovered in the uterus of a 66-year-old woman. She had been treated for a hydatidiform mole 17 years previously without chemotherapy. The resected uterus contained a solid/cystic tumor located entirely within the myometrium. Microscopically, there was an epithelial-like growth pattern. The tumor was circumscribed, with a pushing border, and the tumor cells grew in cords, nests, and sheets within which were aggregates of hyaline material and necrotic debris. Most tumor cells were mononuclear and had an epithelioid appearance with distinct cell borders, eosinophilic cytoplasm, and nuclei with occasional indistinct nucleoli. Scattered multinucleated cells consistent with syncytiotrophoblastic cells were also present. Immunohistochemical staining revealed strong diffuse reactivity for cytokeratins (CK7, AE1/AE3, CAM 5.2, CK18) and epidermal growth factor receptor, and focal reactivity, mainly in syncytiotrophoblastic cells, for beta-human chorionic gonadotropin, human placental lactogen, and inhibin-alpha. The histologic and immunohistochemical features were characteristic of ETT, and helped to distinguish the tumor from other trophoblastic tumors and squamous cell carcinoma. An unusual observation was a high mitotic count, reflected in a Ki-67 proliferative index of 68.6%. Our findings indicate that ETT, like other types of GTT, can occur in postmenopausal women, even years after a gestational event.

Physiotherapy for anterior knee pain: a randomised controlled trial.

OBJECTIVE: To determine the efficacy of the individual components of physiotherapy in subjects with anterior knee pain. METHODS: An observer blind, prospective, factorial design randomised controlled trial. 81 young adults with anterior knee pain were randomly allocated to one of four treatment groups: (1) exercise, taping, and education; (2) exercise and education; (3) taping and education; and (4) education alone. Each group received six physiotherapist-led treatments over three months. Follow up took place at three months using the following outcome measures: patient satisfaction (discharge/refer for further treatment); a visual analogue pain score; the WOMAC lower limb function score; the Hospital Anxiety and Depression scale (HAD); and quadriceps strength. At 12 months the WOMAC and HAD were assessed by postal questionnaire. RESULTS: All groups showed significant improvements in WOMAC, visual analogue, and HAD scores; these improvements did not vary significantly between the four groups or between exercising/non-exercising and taped/non-taped patients at three and 12 months. However, patients who exercised were significantly more likely to be discharged at three months than non-exercising patients (chi(2), p<0.001). Taping was not significantly associated with discharge. Significantly greater improvements in WOMAC, visual analogue, and the anxiety score (but not the depression score) were seen in patients who were discharged than in those who were referred. CONCLUSIONS: The proprioceptive muscle stretching and strengthening aspects of physiotherapy have a beneficial effect at three months sufficient to permit discharge from physiotherapy. These benefits are maintained at one year. Taping does not influence the outcome.

Construction and evaluation of a capillary array DNA sequencer based on a micromachined sheath-flow cuvette.

A capillary array electrophoresis DNA sequencer is reported based on a micromachined sheath-flow cuvette as the detection chamber. This cuvette is equipped with a set of micromachined features that hold the capillaries in precise registration to ensure uniform spacing between the capillaries, in order to generate uniform hydrodynamic flow in the cuvette. A laser beam excites all of the samples simultaneously, and a microscope objective images fluorescence onto a set of avalanche photodiodes, which operate in the analog mode. A high-gain transimpedance amplifier is used for each photodiode, providing high duty-cycle detection of fluorescence.

Groundwater activation at the Superconducting Super Collider: a new design model.

A groundwater activation model was developed for use in designing the accelerators at the Superconducting Super Collider Laboratory. This model is based on the concept of a 4-m-thick "activation zone" surrounding the accelerator enclosure, which contains over 99% of the soil activation caused by beam losses. Empirical shielding formulae based on computer simulations indicate that the soil activation in the activation zone decreases exponentially with distance from the tunnel enclosure. From this assumption, the average activation in the activation zone is derived. It is shown that the average activity concentration in the activation zone is equal to the activity concentration 1 m from the accelerator enclosure. The activation concentration in the water averaged over the volume of the activation zone is compared to the drinking water standards. The goal of this model is to meet the drinking water regulatory standards by averaging the activation in the activation zone. Groundwater activation concentrations have been calculated for the Super Collider utilizing experimental measurements of production cross sections and leachability factors. Comparison is made to the groundwater activation criterion for both routine and accidental beam losses.

Isolation and molecular cloning of a novel bone phosphoprotein related in sequence to the cystatin family of thiol protease inhibitors.

We describe here the isolation of a novel non-collagenous protein from the acid demineralization extract of bovine cortical bone. This 24-kDa protein is multiply phosphorylated at serine residues in Ser-X-Glu/Ser(P) sequences, a recognition motif for phosphorylation by the secretory pathway protein kinase, and we have termed this protein secreted phosphoprotein 24 (spp24). The cDNA structure of spp24 was determined by sequencing cDNA fragments obtained by reverse transcription-polymerase chain reaction, 3'-rapid amplification of cDNA ends, and screening a lambda gt11 cDNA library. This cDNA sequence predicts a 200-residue initial translation product which consists of a 20-residue signal sequence and the 180-residue mature spp24. Northern blot analysis using the spp24 cDNA showed that spp24 mRNA is in liver and bone but not in heart, lung, kidney, or spleen. A search of existing protein sequences revealed that the N-terminal 107 residues of mature spp24 are related in sequence to the cystatin family of thiol protease inhibitors, which suggests that spp24 could function to modulate the thiol protease activities that are known to be involved in bone turnover. Several of the proteins in the cystatin family that are most closely related to spp24 are not only thiol protease inhibitors but are also precursors to peptides with potent biological activity, peptides such as bradykinin and the neutrophil antibiotic peptides. It is therefore possible that the intact form of spp24 found in bone could also be a precursor to a biologically active peptide, a peptide which could coordinate an aspect of bone turnover.

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Comparing the medical school curricula followed by students in an independent study program and a traditional one.

This 1988 retrospective study examined the medical school curricula followed by students from two classes using two curricular styles at one medical school. By consulting school records, the authors ascertained the courses actually taken, the number of weeks that students actually devoted to them, and the sequence of courses, both for those students following an independent-study curriculum and for those following a traditional one. These data were compared with the corresponding data concerning the traditional curriculum requirements to determine whether the curricula the students actually followed, in either style, showed any marked difference from the required curriculum. The findings showed that the curricula followed by the independent-study students deviated considerably from both the requirements of the traditional curriculum and also the actual curricula followed by the students using the traditional curriculum, who almost never chose to deviate from the requirements. The independent-study students showed considerable intragroup variation in the ways they organized their curricula, most commonly in eliminating selected formal clerkship or specialty medicine courses, or altering the duration of clerkships. Elective coursework was substituted for formal clerkship experiences in the majority of cases where clerkship courses were eliminated.

A biopsychosocial treatment approach to the management of diabetes mellitus.

The relationship among recent life stress, social support, a patient's locus of control, and the control of blood glucose is evaluated in persons with diabetes mellitus, using objective measures of these psychosocial variables. Short-term [fasting blood sugar (FBS)] and long-term [glycosylated hemoglobin (Hgb A-1C)] control measures are taken at two points in time in order to evaluate the effects of the psychosocial variables on change in diabetes control. For life events, a significant positive association was found between the number of recent life events and blood glucose control. Decrease in social support predicted a worsening of longer-term (Hgb A-1C) control over time. An external locus of control within the patient was associated both with poor short-term control at time one and prediction of poorer long-term control over time. The implications of these findings are discussed in support of a biopsychosocial approach to the management of diabetes mellitus.

Medical student training in the performance of diagnostic laboratory procedures.

A study was conducted to determine what diagnostic laboratory procedures medical students recalled being taught during pre-clerkship training, how well they felt they could perform these procedures on entrance to and exit from their clerkship year, and the estimate of frequency of personal performance during the clerkship year. Surveys were mailed to 223 graduating senior students of a medical school. They were asked to supply data regarding 15 pre-selected procedures. In only seven cases did a majority of students recall being taught a procedure. Higher percentages of students who trained at health science centres and a Veterans Administration hospital recalled being taught procedures compared to students who trained at community hospitals. In general, students who performed their pre-clerkship training at the health science centres rated their ability to perform procedures without assistance on entrance to the clerkship year higher than the other two groups. Students who performed at least one half of their clerkships at a health science centre rated their ability to perform procedures without assistance at the termination of their clerkship year higher than those who performed a majority of clerkships at community hospitals. The former group also reported a higher frequency of performance of the procedures than the community hospital group. Most of the procedures for all groups, however, were performed at a rate of less than one/month.

Characterization of a soluble prolactin-binding activity in rat liver cytosol.

Soluble binding activity for lactogenic hormones has been detected in high-speed cytosolic preparations from the livers of 21-day-old male and female rats. No lactogenic hormone binding was detected in cytosols from rat heart, kidney, skeletal muscle or adipose tissue. Liver cytosol binding of 125I-labelled human growth hormone or ovine prolactin was dependent on time, temperature, and protein and calcium concentrations. Binding was specific for lactogenic hormones and not somatotrophic hormones. Scatchard analysis revealed linear plots with an affinity of 2.9-4.6 litres/nmol. By gel filtration the molecular weight of the lactogen-binding activity was greater than 450,000. The cytosolic binding activity may be an internalized form of the membrane-bound lactogen receptor, which has similar binding characteristics, or alternatively it may be a distinct binding species, with a defined role in mediating intracellular effects of prolactin in the liver.

A method to determine attitudes of faculty members toward use of laboratory tests.

Investigators have suggested that attitudes of faculty members toward diagnostic testing may encourage inappropriate laboratory use. In the present paper, the authors present a method for determining faculty attitudes on laboratory tests and the results of an analysis of such attitudes at one institution. The attitudes were determined from case simulations prepared by the faculty for senior medical student examinations. At the time the examination was being constructed, the faculty members weighted each laboratory test option following the case presentation for its appropriateness as positive, zero, or negative. The investigators subsequently categorized all of the laboratory tests according to their purpose and appropriateness with respect to the likelihood of diagnostic possibilities generated by the case. The results of the analysis showed that screening tests and tests to investigate unlikely diagnoses usually received weights close to zero and rarely received negative weights. This apparent indifference to tests with limited usefulness that generate some costs may be perceived by students as permission for their continued use.

Neutron skyshine measurements at Fermilab.

Neutron skyshine has been a significant source of environmental radiation exposure at many high-energy proton accelerators. A particularly troublesome source of skyshine neutrons has existed at Fermilab during operation of the 400-GeV high-energy physics program. This paper reports on several measurements of this source made with a DePangher precision long counter at large distances. The spatial distribution of the neutron skyshine can approximately be described as an inverse square law dependence multiplied by an exponential with an approximate attenuation length of 1200 +/- 300 m. The absolute magnitude of the distributions can be matched directly to the conventionally measured absorbed dose distribution near the source.

Physical characterization of neutron beams produced by protons and deuterons of various energies bombarding beryllium and lithium targets of several thicknesses.

Protons of 35 and 65 MeV and deuterons of 35 MeV were used to bombard beryllium and lithium targets of various thicknesses. Four types of experiments were conducted in order to characterize the neutron fields. They were (1) central axis depth-dose measurements in a water phantom, (2) dose buildup at small depths in tissue-equivalent plastic, (3) microdosimetric measurements and LET distributions, and (4) neutron yields and energy spectra at an angle of 0 deg. The results generally show that (a) the central axis depth doses for the 35 and 65 MeV particles roughly approximate those of 60Co and 4-MeV bremsstrahlung photons, respectively, (B) the neutron dose buildups are more rapid than those of the above-mentioned photon sources, (C) the microdosimetric spectra show differences which are consistent with the measured neutron energy spectra, and (D) P-Li compared to p-Be neutron spectra have larger high-energy particle flux for similar target and beam configurations.