25-Hydroxyvitamin D3 metabolism in a human leukemia cell line

Summary 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) is a potent inducer of monocytic differentiation of the human promyelocytic leukemia cell line, HL-60. We have noted that 25-hydroxyvitamin D₃ (25(OH)D₃) in high doses is also capable of promoting monocytic differentiation of this cell line. To test the possibility that the latter activity is due to conversion of 25OHD₃ to 1,25(OH)₂D₃ by HL-60, we exposed HL-60 cells to 25OHD₃ and analyzed the products by HPLC and radioreceptor assay. When chromatographed in the traditional solvent system (isopropanol-hexane), a new peak appears which migrates with authentic 1,25(OH)₂D₃. However, in a solvent system containing dichloromethane, 90% of the peak migrates with another metabolite, 19-Nor-10-Keto-25OHD₃ (19-Nor-25OHD₃). Production of this metabolite is enhanced by living cells and is synthesized by both virgin HL-60 and those which have undergone differentiation. We next determined if authentic 19-Nor-25OHD₃ also promotes differentiation of this cell. As assessed by appearance of the monocyte-specific surface antigen (63D3) and macrophage-specific esterase activity, we find that this metabolite does, in fact, induce monocytic differentiation of HL-60 with a potency of approximately 1/200 that of 1,25(OH)₂D₃ and similar to that of 25OHD₃. In agreement with the effect upon cell maturation, 19-Nor-25OHD₃ displaces³H-1,25(OH)₂D₃ from its HL-60 receptor with an efficiency comparable to 25OHD₃. Hence, HL-60 cells convert 25OHD₃ to 19-Nor-25OHD₃, and 19-Nor-25OHD₃ induces monocytic differentiation of HL-60 with comparable efficiency to its precursor, 25OHD₃.     

Naturally acquired human antibodies which recognize the first epidermal growth factor-like module in the Plasmodium falciparum merozoite surface protein 1 do not inhibit parasite growth in vitro.

Merozoite surface protein 1, one of the major surface proteins of the invasive blood stage of the malaria parasite, is a prime candidate for the development of a vaccine against the human disease. Previously, monoclonal antibodies which both inhibited the growth of Plasmodium falciparum in vitro and bound to the first of two epidermal growth factor-like modules located near the carboxy terminus of the protein had been identified. In this study, we have used affinity chromatography on a recombinant fusion protein corresponding to the first epidermal growth factor-like module in P. falciparum merozoite surface protein 1 to prepare antibody induced by natural infection. The antibody was purified from the total immunoglobulin G fraction of adult West African donors, shown to passively confer immunity against falciparum malaria. Such affinity-purified antibodies were shown to recognize the native protein by a number of separate criteria and to block the binding of an inhibitory monoclonal antibody, but they failed to inhibit parasite invasion in an in vitro growth assay. These results indicate that antibody alone is not sufficient to interfere with erythrocyte invasion.     

Models of commissioning health services in the British National Health Service: a literature review.

The commissioning of health services is an under-researched area and yet it is critical to the way services meet health needs and to the quality of care. Recent emphasis in the United Kingdom and elsewhere has been on a 'primary care led National Health Service', particularly on locality commissioning through primary care groups. However, there are other models of commissioning using 'programmes of care' (focused on diseases or patient groups rather than geography) which may offer greater benefits. There is little research comparing the benefits and costs of these models, and most are not even clearly enough described to be replicated. There will always be a political dimension to models of commissioning, dependent, for example, on the balance of power in the decision-making process. None the less, a broader knowledge of possible models and a willingness to evaluate rigorously are needed if commissioning of health services is to result in better patient care.     

A comparison of biopsy techniques in suspected focal liver disease

This prospective study was designed to determine the most accurate method of obtaining a tissue diagnosis in patients with suspected focal liver disease. Computed tomography (CT) was performed initially in all patients. Patients with extensive right lobe disease on CT had a blind, percutaneous liver biopsy. Those with focal lesions on CT were randomized to either a CT or laparoscopic directed biopsy. Patients with no lesions on CT had laparoscopy for further evaluation. The results indicate that blind percutaneous biopsy is sufficient if extensive right lobe disease is present. There is no significant difference in the sensitivity of laparoscopy and CT directed biopsy if focal lesions are detected by CT. However, a negative CT directed biopsy does not exclude malignancy. Laparoscopy has a significant yield in patients with a negative CT and is the procedure of choice in evaluating these patients.     

Pseudodystrophy at the lower limb in children

Summary The authors describe a 12-year old girl with a painful syndrome at the distal side of the left leg, resulting in limping, incapacity and severe muscle atrophy. Full investigation — no inflammatory laboratory signs, diffuse osteoporosis at the left leg, decreased bone mineral content at the same place, marked hypofixation on bone and vascular scintigraphy — suggested pseudodystrophy (5), which is often induced by psychological factors. Successful treatment was obtained by physiotherapy, hydrotherapy, slight doses of NSAID and psychological assistance. With regard to recent literature, the authors believe that reflex sympathetic dystrophy (RSD) in children is often over-diagnosed, since there are no recognised criteria for diagnosiing RSD. Besides the clinical picture, changes on radiography (focal osteoporosis) and on scintigraphy (disturbed vascular scintigraphy with increased pooling in the initial phase and hyperfixation on bone scintigraphy) are necessary. When these are not available, pseudodystrophy is a more correct diagnosis.     

Polyclonal anti-thymocyte globulins influence apoptosis in reperfused tissues after ischaemia in a non-human primate model

Reperfusion triggers the expression of inflammatory cytokines and adhesion molecules that increase the rate of apoptosis in the reperfused tissues after ischaemia, thus worsening the outcome of the grafts. Polyclonal anti-thymocyte globulins (pATGs) are able to reduce the number of lymphocytes as well as block adhesion molecules and induce apoptosis in T-lymphocytes through Fas-ligand. The aims of this study were to investigate the influence of pATGs on the prevention of apoptosis of reperfused tissues after ischaemia and to monitor their capability to enhance lymphocyte apoptosis thus decreasing the deleterious effects of ischaemia/reperfusion injury (IRI). Extremities of cynomolgus monkeys (n=8) were flushed via either the femoral or the brachial artery. After 60 min of ischaemia the limbs were reperfused with human blood. ATG was added to the blood in a therapeutic dose 20 min prior to reperfusion of the extremities. Surgically available limbs (n=20) were assigned to the following groups: ATG group (n=10) and control group (without ATG; n=10). DNA fragmentation analysis was performed in situ to detect apoptosis at the single-cell level. Our study shows an increased rate of muscle and connective tissue apoptosis in the control group compared with the ATG-treated group. Cells found in the vascular areas present different rates of apoptosis, with enhanced cellular death of endothelium and connective perivascular areas being observed in the control group. The group treated with ATG shows an increased rate of white blood cell (WBC) apoptosis in vascular and perivascular areas. Previous studies have shown that pATGs are able to induce apoptosis as well as complement-mediated cell death in peripheral T-lymphocytes in vitro. Our results confirm that pATGs not only increase the rate of apoptosis of WBCs in vivo but also have a protective effect on the reperfused tissue. This may alleviate the damage after reperfusion of solid-organ transplantation.     

Three-dimensional venography of the brain with a volumetric interpolated sequence

Informed consent was obtained from all patients before participation; study was approved by institutional review board. Three-dimensional (3D) gradient-echo magnetic resonance sequences can be optimized for rapid acquisition through asymmetric k-space sampling and interpolation of image data. A T1-weighted volumetric interpolated brain examination sequence (acquisition time, 1 minute 24 seconds) was prospectively compared qualitatively and quantitatively with magnetization-prepared rapid acquisition gradient-echo sequence (acquisition time, 6 minutes 6 seconds) for venography of cerebral venous structures in 21 female and seven male consecutive patients (mean age, 52.9 years; range, 16-81 years). Although signal- and contrast-to-noise ratios were substantially lower for volumetric interpolated sequence, difference in the subjective quality of visualization of cerebral venous structures was not significant (P >.05). Volumetric interpolated brain examination seems promising as a more time-efficient alternative for 3D imaging of cerebral venous structures.     

Impact of small variations of ischemia time after polyclonal antithymocyte globulins in a nonhuman primate model of ischemia-reperfusion injury

Ischemia-reperfusion injury leads to increased leukocyte adherence enhancing acute cellular rejection, causing microvascular dysfunction and tissue damage. The length of the ischemic time is important in clinical transplantation. Polyclonal antithymocyte globulins (pATGs) induce T-cell depletion and functional impairment of nondepleted lymphocytes. In this study cynomolgus monkeys were used to evaluate the impact of three different pATGs on the microcirculation, on leukocyte behavior and infiltration, as well as on tissue damage after two different periods of ischemia (60 and 150 minutes). pATGs were administered 30 minutes before ex vivo reperfusion. Using intravital fluorescence microscopy, the postreperfusion microcirculation was visualized in vivo. Morphologic analyses were performed on biopsies obtained after the experiments. Significant differences were observed between the two periods of ischemia in both the ATG-treated and control groups. Minimizing ischemia time, even in short intervals, improves the outcome of ischemia-reperfusion injury by reducing leukocyte adherence to the antigen-presenting endothelial cells, improving the microcirculation, and reducing tissue damage.     

Residual adenoid tissue post‐curettage: role of nasopharyngoscopy in adenoidectomy

Objective: Curettage adenoidectomy is one of the most common methods of adenoidectomy. This study reports the incidence of residual adenoid tissue after curettage and grades the degree of post‐nasal space obstruction using fibre‐optic nasopharyngoscopy. Methods: A retrospective study of 425 consecutive patients undergoing curette adenoidectomy in a 5‐year period. Results: Of the 425 patients, 288 (68%) had some residual adenoid tissue evident with nasopharyngoscopy, of which 104 (24%) had significant obstruction (grade 2 or 3). No age or sex difference was found in the likelihood or severity of residual adenoid tissue. Conclusions: A significant proportion of patients will have residual adenoid tissue following curette adenoidectomy alone. Nasopharyngoscopy permits a more complete resection in a cost‐effective, quick and easily performed additional step.     

Teaching public health to medical students in the United Kingdom--are the General Medical Council's recommendations being implemented?

BACKGROUND: Despite frequent calls to improve undergraduate medical public health teaching, little is known about whether curricula have changed. We report a survey of undergraduate public health teaching in UK medical schools in 1996. The survey aimed to assess whether the General Medical Council's 1993 recommendations to strengthen undergraduate medical education in public health have been implemented. METHODS: We asked heads of academic departments of public health at all 26 UK medical schools to complete a questionnaire and provide supporting documentation for each undergraduate public health course or module. We compared results from the 1996 survey with those from a similar survey in 1992. RESULTS: Twenty-one out of 26 (81 per cent) medical schools responded. All responding medical schools included public health teaching within their curriculum. The median number of public health courses per medical school was unchanged since 1992. A wide variety of topics were taught. Core public health subjects were taught at most schools, though over a quarter of medical schools did not cover some core topics. Between 1992 and 1996 the proportion of time devoted to teaching by lectures decreased, whereas the following all increased: teaching by small group methods; the proportion of courses using methods of assessment encouraging active learning; and the contribution of public health courses to the final degree assessment. CONCLUSION: The findings suggest that many of the General Medical Council's recommendations for improving the delivery of undergraduate education are being addressed by public health teaching in UK medical schools. However, addressing the gaps in undergraduate public health teaching revealed in this survey is a continuing challenge for academic public health departments. Medical schools should review the content of their undergraduate public health teaching to ensure that tomorrow's doctors are adequately equipped with public health knowledge and skills.