Musculoskeletal tuberculosis in Bradford - a 6-year review.

INTRODUCTION: Tuberculosis (TB) remains the most common cause of death from infectious disease world-wide. In the UK, the incidence of TB has risen by 25% over the last 10 years; extrapulmonary diagnosis remains challenging and can be delayed. This study evaluates the epidemiology of musculoskeletal tuberculosis in a large multi-ethnic UK city. PATIENTS AND METHODS: A review of prospectively recorded data of incidence, anatomical site, ethnic distribution, treatment and drug resistance of musculoskeletal tuberculosis over a 6-year period was performed. RESULTS: From January 1999 to December 2004, there were 729 TB notifications; 61 cases (8.4%) had musculoskeletal involvement. Of the patients, 74% were immigrants from the Indian subcontinent; nearly 50% had spinal involvement; 24 patients underwent surgical intervention; 29 were subjected to either diagnostic or therapeutic radiological intervention; and resolution of symptoms was achieved in 59 out of 61 cases. CONCLUSIONS: This study highlights the high proportion of musculoskeletal TB in immigrant patients in an area with a relatively large at-risk population, but will also serve to alert physicians, in areas with smaller at-risk populations, of the possibility of musculoskeletal TB.

Semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor for patients with metastatic gastrointestinal adenocarcinomas: a pilot phase I study.

The authors report the results of a phase I clinical study using semiallogeneic cancer vaccines formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat patients with metastatic adenocarcinomas of the gastrointestinal tract. A specially engineered cell line, FO1-12, was used to generate semiallogeneic hybrids by fusion with patient-derived tumor cells; the hybrids express HLA class I and II haplotypes derived from both parental cells. For treatment, the vaccine was mixed with GM-CSF, irradiated, and injected intradermally into patients at weekly or biweekly intervals. Vaccinations were associated with minimal or no toxicity and showed that semiallogeneic hybrids formulated with GM-CSF can induce a specific antitumor immune response in some patients, as measured by a delayed-type hypersensitivity response to autologous tumor cells. Because of the simplicity, feasibility, and flexibility of this immunotherapeutic approach, semiallogeneic hybrid vaccines have the potential to be used in the treatment of virtually any type of cancer.

Role of mRNA stability and translation in the expression of cytochrome c oxidase during mouse myoblast differentiation: instability of the mRNA for the liver isoform of subunit VIa.

The role of mRNA stability and translation in mediating the expression of selected subunits of cytochrome c oxidase (COX) was examined during the differentiation of mouse myoblasts into myotubes in cell culture. The expression of the liver (L) and heart (H) isoforms of COX VIa, which undergo an isoform switch during muscle development, as well as of the Va subunit, which is expressed in all tissues, was analysed. The translational efficiencies of COX Va, VIa-L and VIa-H, as well as of mitochondrially encoded COX mRNAs, were inferred from their distribution in polysome gradients. These experiments suggest that the translational efficiencies of these mRNAs do not change during myoblast differentiation, although the nuclear mRNAs for COX Va, VIa-L and VIa-H are translated more efficiently than the mitochondrial mRNAs. Analysis of mRNA stability using the tetracycline-repressible promoter system and/or actinomycin D indicates that COX VIa-L mRNA decays with a half-life of approximately 5-6 h in both myoblasts and myotubes, whereas COX VIa-H and Va mRNAs decay with half-lives of > 15 h in myotubes. This relative instability of COX VIa-L mRNA serves to limit the accumulation of COX VIa-L mRNA in these myogenic cells, as compared with mRNAs for other COX subunits. Deletion/replacement mapping experiments suggest that the COX VIa-L 3' untranslated region contains a destabilization element. Analysis of the rate of poly(A) tail shortening on COX VIa-L and stable alpha-globin mRNAs suggests that the overall rate of poly(A) shortening per se is not rate limiting for the degradation of COX VIa-L mRNA.

Semi-allogeneic cell hybrids stimulate HIV-1 envelope-specific cytotoxic T lymphocytes.

OBJECTIVE: The present study was designed to determine whether the HLA allogeneic T helper response stimulated by semi-allogeneic cell lines could be used as an in vitro model of immune-based therapy to stimulate HIV-specific cytotoxic T lymphocytes. DESIGN AND METHODS: Semi-allogeneic cell hybrids were obtained by the fusion of peripheral blood mononuclear cells from HIV-infected patients with the allogeneic beta2-microglobulin-deficient FO1-12 melanoma cell line. These hybrids were used as antigen presenting cells for HIV envelope peptide (env)-specific cytotoxic assays. RESULTS: The hybrid cell lines express HLA class I and II antigens from both parental cells, as well as the CD86 costimulatory molecule. HIV-specific cytotoxic T lymphocyte activity was obtained when patients' peripheral blood mononuclear cells were costimulated with env peptides plus semi-allogeneic hybrids, in contrast with stimulation with either env or hybrid cells alone. Thus, the semi-allogeneic hybrids enhanced HIV-specific killing of target cells. CONCLUSIONS: Irradiated, semi-allogeneic cell hybrids engineered for individual AIDS patients provide efficient and simultaneous co-recognition of HLA allogeneic determinants and viral antigenic determinants presented by self-HLA molecules on the same antigen presenting cells and results in the generation of enhanced HIV-specific cytotoxic T lymphocyte activity.

Semiallogeneic cell hybrids as therapeutic vaccines for cancer.

The authors have engineered a cell line that can be used in human studies as a universal donor cell for the formation of semiallogeneic cell hybrids after fusion with patient-derived tumor cells. These hybrids can be irradiated and injected as a patient-tailored therapeutic vaccine in patients affected by virtually any type of cancer. A crucial step in this research effort has been the derivation of an allogeneic cell line (FO1-12) that expresses both a dominant selectable marker (neomycin resistance) and a recessive selectable marker (sensitivity to hypoxanthine, aminopterin, and thymidine), which allows easy selection of semiallogeneic cell hybrids derived from the fusion of FO1-12 cells with patient-derived tumor cells. Tumor-infiltrating lymphocytes derived from select patients with melanoma and exposed to semiallogeneic cell hybrids from the same patient were better able to specifically lyse autologous tumor cells. Furthermore, FO1-12 cells express carcinoembryonic antigen, which is ubiquitous in adenocarcinomas, and fusion of FO1-12 cells with various patient-derived adenocarcinoma cells showed that the hybrid cells also express carcinoembryonic antigen. Because of the results of these preclinical studies, the authors were given permission to use semiallogeneic cell hybrids for immunotherapy of patients with metastatic melanoma or metastatic adenocarcinoma who had not responded to standard treatment regimens. Treatment with semiallogeneic vaccines is associated with minimal or no toxicity and can induce a specific anti-tumor immune response.

Promoting institutional change to encourage primary care: experiences at New York Medical College and East Carolina University School of Medicine.

New York Medical College and East Carolina University School of Medicine significantly changed their curricula and organizational structures in response to The Robert Wood Johnson Foundation's Generalist Physician Initiative (GPI). Seven common elements essential to successful institutional change were retrospectively identified at these two markedly different schools. They are (1) using national priorities to promote need for change, (2) establishing internal and external financial support, (3) developing a planning process and organizational structure to effect change, (4) devising an ongoing evaluation strategy, (5) sustaining positive attitudes toward primary care, (6) integrating community-based physicians, and (7) sustaining interest in the GPI. Within this framework, the authors present the GPI objectives at both schools, discuss examples of methods for institutional change and describe successes, failures, and lessons learned. The authors conclude that both schools have significantly increased the number of students choosing primary care careers and note the general perception of improvement in the quality of primary care educational programs, student recruitment, departmental collaboration, and faculty development opportunities. Although these changes have not yet been fully institutionalized, the similarities of the processes described may be of value to others addressing similar issues.

Influence of medical school on medical students' opinions about primary care practice.

PURPOSE: To compare first- and fourth-year medical students' opinions about primary care practice. METHOD: A cross-sectional survey was made of medical students at New York Medical College (NYMC) and East Carolina University School of Medicine (ECUSOM) over three years (1993-94, 1994-95, and 1995-96). Three consecutive classes of first-year students from both schools (n = 807), two consecutive classes of fourth-year NYMC students (n = 373), and three consecutive classes of fourth-year ECUSOM students (n = 221) were given a self-administered questionnaire about professional aspects of primary care practice. Responses to ten items about primary care practice were the independent variables in a logistic regression analysis. Career choice, categorized as primary care or non-primary care, was the dependent variable. Independent, two-tailed t-tests were employed to compare the responses of the first-year students interested in primary care careers with those of the fourth-year students interested in primary care careers. RESULTS: In all, 639 (79%) of the first-year students and 396 (67%) of the fourth-year students returned completed questionnaires. The first-year students interested in primary care careers were significantly more likely to believe that primary care practice has more prestige, has more intellectual stimulation, needs a large knowledge base, and involves work that is more important than that of non-primary care physicians, and were significantly more likely to disagree with the assertion that in primary care practice, physicians have more control over their working hours. With one exception (prestige of primary care practice), all these independent variables were significant for the fourth-year students as well. The comparison of the first- and fourth-year students indicated that the fourth-year students were significantly more likely to believe that primary care practice has more intellectual stimulation, needs a large knowledge base, and requires knowledge that non-primary care practice may not; they were also significantly more likely to disagree with the assertions that primary care practice is adequately compensated, has more prestige, and allows more control over working hours. CONCLUSION: It appears that students' positive perceptions about primary care practice may change as realistic perceptions about the professional demands on primary care physicians develop during medical school.

What predicts medical student career choice?

The literature on medical student career choice has identified several influences that can be categorized as student demographics, medical school characteristics, students' perceptions of specialty characteristics, and student-held values. A logistic regression model that included demographics, medical school, and student-rated influences as a proxy for perceptions and values was used to determine their relative contribution to student career choice for three consecutive cohorts of senior medical students attending two schools (n = 649). This model identified a positive relation between choice of primary care career and both student-rated influences and one student demographic characteristic, but not between career choice and school attended. Variables positively correlated with primary care career choice were related to working with people and marital status. Negatively correlated variables were related to income and prestige.

Characterization of a sustained-release delivery system for combined cytokine/peptide vaccination using a poly-N-acetyl glucosamine-based polymer matrix.

Identification of tumor-associated antigens (TAAs) and their class I MHC-restricted epitopes now allows for the rational design of peptide-based cancer vaccines. A biocompatible system capable of sustained release of biologically relevant levels of cytokine and TAA peptide could provide a more effective microenvironment for antigen presentation. Our goal was to test a sustained-release cytokine/TAA peptide-based formulation using a highly purified polysaccharide [poly-N-acetyl glucosamine (p-GlcNAc)] polymer. Granulocyte-macrophage colony-stimulating factor (GM-CSF; 100 microgram) and MART-1(27-35) peptide (128 microgram in DMSO) were formulated into p-GlcNAc. Peptide release was assayed in vitro using interleukin 2 production from previously characterized MART-1(27-35)-specific Jurkat T cells (JRT22). GM-CSF release was assayed via ELISA and proliferation of M-07e (GM-CSF-dependent) cells. Local bioavailability of MART-1(27-35) peptide for uptake and presentation by antigen-presenting cells was demonstrated for up to 6 days (>0.5 microgram/ml). More than 1.0 microgram/ml GM-CSF was concomitantly released over the same period. Biocompatibility and local tissue response to p-GlcNAc releasing murine GM-CSF was determined in C57BL/6 mice via s.c. injection using murine GM-CSF (0. 2 microgram/ml) in 200 microliter of a 2.5% polymer gel. Significant lymphocytic and eosinophilic infiltration was observed 2-7 days after injection with polymer containing murine GM-CSF. The results of our studies show that this biocompatible system is capable of a sustained concomitant release of biologically active peptide and cytokine into the local microenvironment. These findings support further studies to validate a p-GlcNAc delivery system vehicle for a cytokine/TAA peptide-based cancer vaccine.

Sinusitis in children and adolescents.

Sinusitis is common in children and adolescents, most frequently as a complication of a viral upper respiratory tract infection or allergic rhinitis. The diagnosis usually is suggested by symptoms of a viral upper respiratory tract infection persisting beyond 10 days without improvement or severe symptoms with fever and purulent rhinitis. Young children frequently do not have the symptoms (headache) or physical findings (sinus tenderness) seen in older patients. Radiographic evaluation may be helpful if the clinical presentation is atypical or severe. Antibiotics remain the primary therapeutic agent of choice in pediatric sinusitis, with other therapeutic modalities having little proven efficacy.

First-year medical students' knowledge of and attitudes toward primary care careers.

BACKGROUND AND OBJECTIVES: This study compared the knowledge of and attitudes toward primary care in relation to anticipated career choices of first-year medical students at two medical schools that differ significantly in production of primary care physicians. METHODS: A cross-sectional survey was conducted at a private, urban school in the Northeast where only a small percentage of students enter family practice residencies and a public, rural school in the Southeast where entry into family practice is among the highest in the country. The survey was conducted during the first semester of medical school. RESULTS: Ninety-six percent of students correctly identified general internal medicine, general pediatrics, and family practice as primary care fields; 51.8% identified these fields as "specialties." Statistically significant differences were seen between the percentages of students at the two schools who planned careers in primary care, suggesting that selection processes may differ between the two schools. There were no significant differences between students at the two schools in correctly identifying the characteristics of primary care practice. Only minor differences between the schools were found in assessments of the need for or importance of primary care. CONCLUSIONS: Although a significant difference in student interest in becoming primary care physicians was detected at the two schools, a surprising similarity was shown in their knowledge and attitudes about primary care. New attitudinal markers will need to be developed to help admissions committees select students most likely to enter primary care careers.

Rogers' posterior cervical fusion--a 3-month radiological review.

Rogers described his technique of spinal fusion in 1942, and since then numerous other techniques have been described but no large series describing the anatomical results has been reported. To assess the technical success of Rogers' technique, to identify factors that contribute to less than ideal anatomical results, and to suggest methods of avoiding potential pitfalls, the anatomical results of Rogers' posterior cervical fusion were compared with what we consider an ideal anatomical result by analysis of the 12-week post-operative flexion/extension radiographs. One hundred and sixty-one Rogers-type posterior cervical fusions using either wire or Ethibond were performed for flexion injuries. The 12-week post-operative flexion extension radiographs were assessed for union, fusion of extra levels, residual kyphosis/listhesis, excessive lordosis, and hypermobility. Results were related to the presence of associated fractures, using the chi 2 test. Bony union was seen in 100 per cent of cases. Fusion of additional levels occurred in 40 (25 per cent), residual kyphosis in 54 (34 per cent), listhesis in 14 (9 per cent), and excessive lordosis in seven (4 per cent). Hypermobility at the adjacent level occurred in 10 (6 per cent), and at a distant level in five (3 per cent). Statistically significant associations occurred between fusion of extra levels and fractures, residual kyphosis and fractures, excessive lordosis with the use of wire rather than Ethibond, and the desired anatomical result with absence of fracture. The Rogers technique is a safe, easy and reliable method of achieving cervical fusion, with a 100 per cent fusion rate at 3 months in this series. However, the intended position of fusion, between 1 degree-5 degrees of lordosis, with normal alignment, is not always achieved. There is also a high incidence of fusion of levels other than those intended. We believe that the incidence of these problems could be reduced by more attention to surgical detail.

Dry powder inhalers are bioequivalent to metered-dose inhalers. A study using a new urinary albuterol (salbutamol) assay technique.

Metered-dose inhalers (MDIs) are extensively used to deliver drugs to the lungs but are driven by chlorofluorocarbon (CFC) propellants. The worldwide phasing out of CFCs within the next 5 to 10 years presents difficulties to the pharmaceutical industry. The mean +/- SD relative lung bioavailability of albuterol to the lung following inhalation of 400 micrograms of albuterol from an MDI, the Rotahaler and Diskhaler in 10 well-trained volunteers, was 2.83 (0.78), 1.72 (0.99), and 2.64 (1.23)%, respectively, expressed as a percentage of the nominal dose. The delivery of albuterol to the lungs from the MDI and Diskhaler was similar. In nine asthmatic subjects, the relative lung bioavailability of albuterol following inhalation with the MDI and Diskhaler was 1.19 (0.79) and 2.38 (1.46)%, respectively, expressed as a percentage of the nominal dose. There was no difference in reversibility 30 min after administration of the dose by the two methods. Similar lung deposition from the Diskhaler in volunteers probably is due to efficient MDI technique, which was absent in the asthmatic subjects. The Diskhaler does not rely on coordination during inhalation and therefore is easier to use.

Rural-urban blood lead differences in North Carolina children.

OBJECTIVE: To examine the prevalence of and risk factors for having a blood lead elevation among young children in a predominantly rural state. METHODS: 20,720 North Carolina children at least 6 months and < 6 years of age were screened between November 1, 1992 and April 30, 1993 using either capillary or venous measurements of blood lead. Children were tested through routine screening programs that target low-income families and, hence, were not randomly selected. Eighty-one percent of the children were screened through local public health departments, and 19% were tested at private clinics. RESULTS: The estimated prevalences of having an elevated blood lead level among those tested were: 20.2% (> or = 10 micrograms/dL), 3.2% (> or = 15 micrograms/dL), and 1.1% (> or = 20 micrograms/dL). Black children were at substantially increased risk of having a blood lead > or = 15 micrograms/dL (odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.7 to 2.5). Children aged 2 years old had an elevated risk (OR = 1.4, 95% CI = 1.1 to 1.7) compared to 1-year-olds, and males were at slightly increased risk (OR = 1.2, 95% CI = 1.0 to 1.4). Living in a rural county was nearly as strong a risk factor as race (OR = 1.9, 95% CI = 1.6 to 2.4). The effect of rural residence was even greater among certain subgroups of children already at highest risk of having an elevated blood lead. The type of clinic (public vs private) where a child was screened was not associated with blood lead outcome. These same trends were seen for children with blood lead levels > or = 20 micrograms/dL. CONCLUSIONS: Among children screened from rural communities, the prevalence of elevated blood lead is surprisingly high. Though few physicians have embraced universal lead screening, these data support the need for greater awareness of lead exposure in children living outside of inner-cities.

Rapid traction for reduction of cervical spine dislocations.

There is still some controversy about the reduction of unilateral and bilateral facet dislocations in the cervical spine. We have reviewed the notes and radiographs of 210 such patients; reduction was attempted by manipulation under anaesthesia (MUA) in 91, and by rapid traction under sedation in 119, using weights up to 150 lb (68 kg). Our results suggest that early reduction in patients with neurological deficit gives the best chance of neurological recovery, that rapid traction is more often successful than MUA, and that traction is safer than MUA. We found that the use of heavy weights with close monitoring was safe and brought about reduction in an average time of 21 minutes. We recommend this technique for the reduction of all cervical facet dislocations.

Investigations of an optimal inhaler technique with the use of urinary salbutamol excretion as a measure of relative bioavailability to the lung.

BACKGROUND: A simple non-invasive method, in which a urine sample is taken 30 minutes after drug administration, has previously been shown to be a measure of the relative bioavailability of salbutamol to the lungs. This technique has been used to determine an optimal inhaler technique with commercially available metered dose inhalers (MDI). METHODS: Ten healthy subjects were trained in the use of MDIs. Each inhaled 4 x 100 micrograms salbutamol in a series of experiments to examine the relative bioavailability to the lung after different respiratory manoeuvres. Urine collection intervals were 0-0.5 hours and 0.5-24 hours after administration. RESULTS: There was significantly greater elimination of unchanged salbutamol 30 minutes after administration, indicating a greater relative bioavailability of salbutamol to the lungs after (1) exhaling gently to residual volume rather than to functional residual capacity before inhalation; (2) slow inhalation (10 l/min) compared with fast inhalation (50 l/min); (3) breath holding for 10 seconds after inhalation compared with no breath holding. CONCLUSIONS: All patient information leaflets and healthcare personnel should standardise the instructions given to patients and should adopt the inhalation method proposed.

A retrospective study of spinal cord injuries in Cape Province rugby players, 1963-1989. Incidence, mechanisms and prevention.

A retrospective study was undertaken to determine aetiological factors for 117 catastrophic neck injuries in rugby players admitted to the Spinal Cord Unit, Conradie Hospital, Cape Town, between 1963 and 1989. Nineteen of these players were known to be dead; the files of another 10 were missing. Questionnaires were sent to the remaining 88 players and 52 responded (59%). Their data were supplemented with information obtained from the medical records of the patients who did not respond. The annual number of admissions increased dramatically after 1976 with 83% of all injuries occurring after that date. A further increase since 1984 contrasts with a falling incidence of these injuries in Britain, Australia and New Zealand. Increased risk of injury was related to the following factors: 98% of injuries occurred in matches and 81% were incurred by adults; 69% of injuries occurred in age-group A team or senior first team players; and 57% of injuries occurred in the tackle situation and 39% in scrums, rucks and mauls. Hooker, centre and flyhalf were the playing positions at greatest risk. Injuries were more common in early season matches and again after the mid-season break. This study confirmed that spinal cord injuries occur under predictable circumstances and are therefore foreseeable and preventable. The high incidence of these injuries in the Cape Province is as unacceptable today as it was when first reported in 1977.

Papilloedema and optic atrophy in chronic hypercapnia.

Two patients are described with hypercapnia of 10 and 13 years duration. Both patients had papilloedema at different stages of their illness and one patient developed optic atrophy. Whether such changes are due to local retinal vascular changes, general change in cerebral vasculature or the result of raised intracranial pressure is unknown. A combination of all seems likely. Computerized axial tomography brain scan on Case 2 was compatible with cerebral oedema and the development of optic atrophy (Case 1) suggests cerebral oedema and consequent raised intracranial pressure as the major factor in the development of papilloedema in hypercapnic patients. Skull radiographic changes have not previously been reported in hypercapnia. The duration of the papilloedema is critical in the development of atrophy.