Who manages the managers? The 1989 Harvey Cushing oration

New medical knowledge is emerging at a tremendous rate. Diseases such as Alzheimer's disease. Parkinson's disease, cancer, and others (diseases once considered beyond the scope of medicine) are receiving a great deal of attention. Yet it is a paradox that, at a time when we are learning more about the biology of the human being, it is more difficult to creatively develop the new knowledge into diagnostic tests, surgical interventions, and preventive strategies. The pace of biomedical innovation is being slowed by an increase in the intervention of nonmedical "managers of care." The driving force behind managed care is concern over cost. The managers of medical care have sought to control costs by controlling the doctor's decision making. This is the focus of managed care. The physicians of today, therefore, face a remarkable challenge. They must respond to the needs of patients while being held accountable to an increasing number of overseers in the public and private sectors. These managers of care justify their activities on the notion that the patient will be better off and the cost less if the doctor-patient encounter is regulated by protocols, statistical comparison, utilization review, and fee schedules. While doctor's decisions are being managed by others, who is managing the managers? The answer should be the medical community, principally doctors. Unfortunately, the answer at the moment is the payors--governmental reimbursement agencies, intermediaries, employers, hospitals, or new corporations designed to manage medical costs. The challenge to the physician is to retain the responsibility for those things for which he or she is held accountable. The challenge should not be ignored.     

Serum and testicular testosterone and androgen binding protein profiles following subchronic treatment with carbendazim

While the general toxicity of the benzimidazole pesticides for mammals is low, one of these compounds, carbendazim (MBC), causes degeneration of testicular tissue and decreases spermatogenic activity at doses well below the LD50 value. A study conducted by S. D. Carter, R. A. Hess, and J. W. Laskey (1987, Biol. Reprod. 37, 709-717) showed that treatment with 400 mg/kg/day MBC resulted in severe seminiferous tubular atrophy and infertility. Since spermatogenesis is an androgen-dependent process, we characterized the effects of MBC (0-400 mg/kg/day) on the endocrine function of the rat testes. Following subchronic (85 day) exposure, serum hormones (TSH, LH, FSH, and Prl) were measured as were androgen binding protein (ABP) and testosterone in testicular fluids (interstitial fluid and seminiferous tubule fluid). In addition, the functional capacity of the Leydig cell to secrete testosterone was assessed in vitro following an hCG challenge. Subchronic treatment with MBC at doses of 50-100 mg/kg/day had no effect on pituitary or testicular hormone concentrations: 200 mg/kg/day elevated the testosterone concentration in the seminiferous tubule fluid and the ABP concentration in both the interstitial fluid and the seminiferous tubule fluid without affecting serum testosterone or ABP concentrations. The 400 mg/kg/day dose resulted in increased concentration of both testosterone and ABP in the interstitial fluid and seminiferous tubule fluid and elevated serum ABP, with no change in serum testosterone. This endocrine profile is consistent with the testicular atrophy and "Sertoli cell-only" syndrome seen in these animals as reported by Gray et al. (1987, Toxicologist 7, 717). We conclude that seminiferous tubule fluid testosterone may be a result of two factors: (1) increased interstitial fluid testosterone concentrations and (2) decreased testosterone outflow from the testis to the general circulation. Also, increased ABP in the interstitial fluid may reflect a change in the relative secretion of ABP into the interstitial fluid and the seminiferous tubules.     

An association between variants in the IGF2 gene and Beckwith-Wiedemann syndrome: interaction between genotype and epigenotype

Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth disorder involving the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. In sporadic BWS cases the majority of patients have epimutations in this region. Loss of imprinting of the IGF2 gene is frequently observed in BWS, as is reduced CDKN1C expression related to loss of maternal allele-specific methylation (LOM) of the differentially methylated region KvDMR1. The causes of epimutations are unknown, although recently an association with assisted reproductive technologies has been described. To date the only genetic mutations described in BWS are in the CDKN1C gene. In order to screen for other genetic predispositions to BWS, the conserved sequences between human and mouse differentially methylated regions (DMRs) of the IGF2 gene were analyzed for variants. Four single nucleotide polymorphisms (SNPs) were found in DMR0 (T123C, G358A, T382G and A402G) which occurred in three out of 16 possible haplotypes: TGTA, CATG and CAGA. DNA samples from a cohort of sporadic BWS patients and healthy controls were genotyped for the DMR0 SNPs. There was a significant increase in the frequency of the CAGA haplotype and a significant decrease in the frequency of the CATG haplotype in the patient cohort compared to controls. These associations were still significant in a BWS subgroup with KvDMR1 LOM, suggesting that the G allele at T382G SNP (CAGA haplotype) is associated with LOM at KvDMR1. This indicates either a genetic predisposition to LOM or interactions between genotype and epigenotype that impinge on the disease phenotype.     

The biology and tumour-related properties of monocyte tissue factor

Tissue factor (TF, coagulation factor III, CD142) is not only the main physiological initiator of normal blood coagulation, but is also important in the natural history of solid malignancies in that it potentiates metastasis and angiogenesis and mediates outside-in signalling. TF is expressed constitutively by many tissues which are not in contact with blood and by other cells upon injury or activation; the latter include endothelial cells, tissue macrophages, and peripheral blood monocytes. It can exist encrypted and unavailable functionally in the plasma membrane and the appearance of functional TF may be due to synthesis and/or de-encryption. Inflammatory cells often express TF and act to induce its production or de-encryption by other cells locally and, apparently, at remote sites. Inappropriate expression of TF by endothelial cells, macrophages or monocytes is thought to be an important trigger of coagulation in various pathological conditions. Several studies have shown that measurements of monocyte TF (mTF) may provide clinically significant information, particularly in patients with malignant and inflammatory diseases.     

Purification of cold agglutinins from patients with chronic cold haemagglutinin disease. Evidence of their homogeneity from starch gel electrophoresis of isolated light chains

A method is described for the large scale purification of serologically active high-titre cold agglutinins from the sera of patients with chronic cold haemagglutinin disease. Eighteen purified cold agglutinins have been reduced and alkylated and separated into heavy and light chain pools by Sephadex G-100 filtration. The isolated light chains were examined by alkaline urea starch gel electrophoresis and found to be far more homogeneous than normal light chains and comparable in some cases to Bence Jones light chains. However, light chains from different cold agglutinins with the anti-I specificity gave different banding patterns; this might be caused by the fact that they are directed against different parts of the I antigen.     

Meta-analysis of gross insertions causing human genetic disease: novel mutational mechanisms and the role of replication slippage

Although gross insertions (>20 bp) comprise <1% of disease-causing mutations, they nevertheless represent an important category of pathological lesion. In an attempt to study these insertions in a systematic way, 158 gross insertions ranging in size between 21 bp and approximately 10 kb were identified using the Human Gene Mutation Database (www.hgmd.org). A careful meta-analytical study revealed extensive diversity in terms of the nature of the inserted DNA sequence and has provided new insights into the underlying mutational mechanisms. Some 70% of gross insertions were found to represent sequence duplications of different types (tandem, partial tandem, or complex). Although most of the tandem duplications were explicable by simple replication slippage, the three complex duplications appear to result from multiple slippage events. Some 11% of gross insertions were attributable to nonpolyglutamine repeat expansions (including octapeptide repeat expansions in the prion protein gene [PRNP] and polyalanine tract expansions) and evidence is presented to support the contention that these mutations are also caused by replication slippage rather than by unequal crossing over. Some 17% of gross insertions, all >or=276 bp in length, were found to be due to LINE-1 (L1) retrotransposition involving different types of element (L1 trans-driven Alu, L1 direct, and L1 trans-driven SVA). A second example of pathological mitochondrial-nuclear sequence transfer was identified in the USH1C gene but appears to arise via a novel mechanism, trans-replication slippage. Finally, evidence for another novel mechanism of human genetic disease, involving the possible capture of DNA oligonucleotides, is presented in the context of a 26-bp insertion into the ERCC6 gene.     

Clinical and cost-effectiveness of a new nurse-led continence service: a randomised controlled trial

BACKGROUND: Continence services in the UK have developed at different rates within differing care models, resulting in scattered and inconsistent services. Consequently, questions remain about the most cost-effective method of delivering these services. AIM: To evaluate the impact of a new service led by a continence nurse practitioner compared with existing primary/secondary care provision for people with urinary incontinence and storage symptoms. DESIGN OF STUDY: Randomised controlled trial with a 3- and 6-month follow-up in men and women (n = 3746) aged 40 years and over living in private households (intervention [n = 2958]; control [n = 788]). SETTING: Leicestershire and Rutland, UK. METHOD: The continence nurse practitioner intervention comprised a continence service provided by specially trained nurses delivering evidence-based interventions using predetermined care pathways. They delivered an 8-week primary intervention package that included advice on diet and fluids; bladder training; pelvic floor awareness and lifestyle advice. The standard care arm comprised access to existing primary care including GP and continence advisory services in the area. Outcome measures were recorded at 3 and 6 months post-randomisation. RESULTS: The percentage of individuals who improved (with at least one symptom alleviated) at 3 months was 59% in the intervention group compared with 48% in the standard care group (difference of 11%, 95% CI = 7 to 16; P<0.001) The percentage of people reporting no symptoms or 'cured' was 25% in the intervention group and 15% in the standard care group (difference of 10%, 95% CI = 6 to 13, P = 0.001). At 6 months the difference was maintained. There was a significant difference in impact scores between the two groups at 3 and 6 months. CONCLUSIONS: The continence nurse practitioner-led intervention reduced the symptoms of incontinence, frequency, urgency and nocturia at 3 and 6 months; impact was reduced; and satisfaction with the new service was high.     

Job satisfaction and occupational stress among general practitioners — a pilot study

Questionnaires assessing levels of job satisfaction and possible sources of stress were distributed to a random sample of general practitioners in the Greater Manchester area. The highest levels of job satisfaction were reported for `intrinsic' job factors such as freedom to choose method of working, amount of responsibility and amount of variety, rather than `extrinsic' factors such as rate of pay and hours of work. The main causes of stress appeared to be interruptions of various kinds. Factor analysis revealed four major sources of stress: interruptions; emotional involvement; administrative workload and work/home interface; and routine medical work. Of these, all but routine medical work were associated with job satisfaction. It is concluded that the major sources of stress for the general practitioner are not medical, but social.     

Post-marketing surveillance of enalapril: experience in 11 710 hypertensive patients in general practice

Post-marketing surveillance in general practice represents an important part of the monitoring of adverse events associated with newly introduced drugs. Such a study of the angiotensin-converting enzyme inhibitor enalapril maleate has been undertaken in 11 710 patients with essential hypertension. Serious adverse events occurred in 1.7% of patients, though most of these were not thought to be related to the treatment. The incidence rates of death (0.09%), stroke (0.11%) and myocardial infarction (0.15%) were compatible with rates predicted from age, sex and blood pressure considerations. Other events reported were hypotension (0.3%), angioneurotic oedema (0.03%), rash (0.5%), taste disturbance (0.2%) and cough (1.0%). The degree of blood pressure reduction attained was similar to that previously reported from pre-marketing development studies, as was the overall nature and frequency of both serious and non-serious adverse events. The most frequently reported event during enalapril therapy was of an improvement in well-being (19.8%).     

Development of Duchenne-type cardiomyopathy. Morphologic studies in a canine model.

The development of cardiac lesions was studied in xmd dogs aged from 1 day to 6 years. Cardiac lesions were not present in dystrophic dogs up to 3 months of age. Foci of mineralization were first seen at 6.5 months. A 1-year-old dog had foci of myocyte hypercontraction. Linear and anastomosing fibrosis was present in all dogs 1 year of age or older, most prominently and most consistently within the subepicardial region of the left ventricular (LV) free wall, the LV papillary muscles, and the right ventricular (RV) aspect of the septum. Ultrastructurally, endomysial fibrosis, decreased myofibrillar density, and prominence of mitochondria were consistent features. Severe degenerative changes were present in two dogs and included prominent intracytoplasmic myelin figures, lipid droplets, and lipofuscin. Immunocytochemical studies of an affected dog confirmed the absence of dystrophin in LV myocardium. Characteristic late-onset cardiac lesions, similar to those occurring in Duchenne dystrophy, are a consistent feature of canine X-linked muscular dystrophy (CXMD).