The case of the disappearing generalist: does it need to be solved?

The proportion of generalist physicians in the United States has declined steadily over 50 years, bringing it to the lowest percentage of trained primary care physicians of any developed country; the trend toward subspecialization is accelerating. Many analysts believe this imbalance between generalists and subspecialists to be a major cause of America's high health care costs, heavy dependence on biotechnology, and consumer dissatisfaction. Others argue that sub-specialists can provide excellent primary care services, and the decrease in the number of generalists is not a problem. Three contrasting views on the implications of this trend state that today's generalists are an important and scarce resource that must be bolstered; that subspecialists can replace generalists as providers of primary care; and that the free market will determine the best manpower mix. A final view, on the marketplace option, posits that generalism will not recover until it creates a vital, and unique, role in handling the primary care challenges of the twenty-first century. These competing viewpoints are used to clarify assumptions underlying our major policy options in the arena of health manpower.     

Multiplex PCR analysis of in vivo-arising deletion mutations in the hprt gene of human T-lymphocytes

A multiplex polymerase chain reaction (PCR) procedure was adapted for the rapid and efficient evaluation of deletions of the hypoxanthine guanine phosphoribosyltransferase (hprt) gene in human T-lymphocytes. The hprt clonal assay was used to isolate in vivo-arising hprt-deficient T-cells from six healthy males. Mutant frequencies ranged from 9-27 × 10^?6. Simple crude cellular extracts from 223 mutants were analyzed for hprt gene deletion. Sixteen (7.2%) were found to be due to total gene deletion and 22 (9.9%) were due to partial gene deletion. The relatively high frequency of total gene deletions was caused by replicate isolates of a single mutational event as shown by single-strand conformation polymorphism (SSCP) analysis of rearranged T-cell receptor (TCR)-γ genes. Eighteen of the 22 partial hprt gene deletion mutants were determined to be of independent origin based on a unique hprt mutation or SSCP-TCR-γ pattern. One-half (9/18) of the partial deletion mutants involved all or part of exon 4 alone, suggesting that this region of the hprt gene is prone to deletion. The small deletions effecting exon 1 (1 mutant), exon 2 (2 mutants), and exon 4 (6 mutants) would not have been detected by conventional Southern blot analysis and may represent a new, previously unrecognized class of mutations. The ready isolation of such intragenic deletions will allow the characterization of breakpoint junctions and may provide insights into the important processes of DNA breakage and rejoining. © 1994 Wiley-Liss, Inc.     

Biopterin in Parkinson''s disease.

Tetrahydrobiopterin is an essential co-factor in the natural synthesis of dopamine. Oral tetrahydrobiopterin was given in small doses to four patients with early Parkinson's disease but had no discernible effect.     

Short-term respiratory effects of cleaning exposures in female domestic cleaners.

Symptoms of obstructive lung disease in domestic cleaners have been related to the use of bleach and other irritant cleaning products. The short-term effects of cleaning exposures on respiratory symptoms and peak expiratory flow (PEF) were investigated in domestic cleaners with respiratory disorders. In a panel study, 43 female domestic cleaners with a recent history of asthma and/or chronic bronchitis completed a 2-week diary, collecting information on respiratory symptoms, PEF and cleaning exposures. Mixed regression models were used to assess daily changes in symptoms and PEF associated with specific cleaning exposures. The probability of having work-related asthma was individually assessed by a computerised diagnostic system and an occupational asthma expert. Lower respiratory tract symptoms were more common on working days and were predominantly associated with exposure to diluted bleach, degreasing sprays/atomisers and air fresheners. Associations with upper respiratory tract symptoms and PEF were less apparent. Eleven (30%) subjects scored positively for work-related asthma. It is concluded that exposure to certain irritant cleaning products aggravates lower respiratory tract symptoms in female domestic cleaners with asthma or chronic bronchitis.     

Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation.

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Time-dependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome.     

Brain microvascular smooth muscle and endothelial cells produce granulocyte macrophage colony-stimulating factor and support colony formation of granulocyte-macrophage-like cells.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of macrophages and neutrophils and plays a role in inflammatory diseases. In this article, we report that mouse brain-derived microvascular smooth muscle cells (SM) and endothelial cells (En) in coculture with splenocytes support the colony proliferation of immature granulocyte-macrophage-like (GM) cells. Unstimulated SM and En cells release GM-CSF as shown by ELISA assay and SM expresses mRNA for GM-CSF by polymerase chain reaction (PCR). Stimulation of SM and En by a nonspecific activator (lipopolysaccharide) results in upregulation of GM-CSF production. GM colonies cannot be grown on cultured astrocytes or on extracellular matrix alone prepared from smooth muscle or endothelium. However, colonies form on the extracellular matrix and on astrocytes, either in the presence of SM- or En-conditioned medium or after the addition of recombinant GM-CSF. The GM cells are positive for nonspecific esterase, peroxidase, and MAC-1 markers but are negative for FC gamma receptors and for Thy 1.2, CD8, CD4, MHC class II, and Asialo GM1 markers. These observations emphasize the possibility for active participation of brain microvasculature SM and En in acute inflammatory reactions of the central nervous system.     

Acute intermittent porphyria and mental illness – a family study

All cases of acute intermittent porphyria (AIP) are believed to be caused by a mutation in the gene encoding for porphobilinogen deaminase, a rate-limiting enzyme in the haem synthetic pathway. This gene has been mapped to the long arm of chromosome 11, a region of the genome that has recently attracted considerable attention as a possible location for genes implicated in major mental disorder. This study was designed to show whether major mental illness co-segregated with acute intermittent porphyria in families where the two conditions are found. The study also investigated the relation between clinical mental symptoms and biochemical parameters of acute intermittent porphyria. The case records of 344 consecutive patients admitted to the Porphyrias Research Group in the Western Infirmary in Glasgow between 1950 and 1988 with acute intermittent porphyria were examined for evidence of psychiatric contact. Of 16 individuals identified, 12 were available for the study. Forty relatives of these 12 probands, including 9 who were asymptomatic carriers of AIP, were interviewed for lifetime history of mental illness and current symptoms. Comparisons were made between 4 groups of patients based on urinary porphyrin levels and erythrocyte enzyme activity; 1) manifest acute intermittent porphyria, 2) latent acute intermittent porphyria, 3) normal relatives and 4) total acute intermittent porphyria (latent and manifest combined). No association was found between AIP and schizophrenia or manic-depressive illness. Only one patient with schizophrenia was found in the sample of 344 case notes, and in 2 families bipolar illness was found but did not segregate with acute intermittent porphyria. The commonest psychiatric diagnosis in patients was generalized anxiety. In the total AIP group (latent and manifest), compared with normals, the rating scale measures of anxiety were significantly correlated with the level of porphyrin metabolites in the urine at the time of rating. This was true even in subjects with latent AIP, who were not at the time of testing aware that they were asymptomatic carriers of the illness. AIP should be considered in the differential diagnosis of generalized anxiety disorder.