Profound pulmonary shunting without edema following stereotaxic biopsy of hypothalamic germinoma. Case report

Hypoxemia is a nearly constant accompaniment of head injury. Diverse theories have been proposed to explain this relationship. The authors report the case of a patient who suffered an episode of severe, transient, arterial oxygen desaturation during "controlled" brain trauma: an otherwise uneventful stereotaxic biopsy of a small germinoma of the hypothalamus. Evidence is provided that pure ventilation-perfusion mismatching, without pulmonary edema, underlay the hypoxemia. The hypothalamus is intimately involved in matching pulmonary ventilation to perfusion; the hypoxemia of various brain injuries may be mediated by perturbation of this structure.     

Independent living and the physical environment: aspects that matter to residents

Field interviews were conducted with seven clients with disabilities for the purpose of developing design guidelines for apartments suitable for independent living. Analysis of these data generated six factors that were highly valued and felt to contribute to the success of these individuals' venture into community living. Control appears to be the central construct and to subsume the other concepts: safety/security, accessibility/mobility, function, flexibility and privacy. These findings are presented and discussed here as a working model of environmental control. These ideas are suggested as hypotheses which would need to be tested and refined further before being used as a model to guide clinical interventions.     

Rudimentary meningocele: a variant of "primary cutaneous meningioma"

We studied 5 primary cutaneous meningiomas. All were congenital. Four were nodules or plaques on the scalp, and one was a lumbar polyp. Two were alopecic. A skull defect was present deep to one lesion, and the lumbar polyp was attached to dura. The tumors were concentrated in the subcutis, where strands of meningocytes were embedded in dense collageous tissue. Meningocytes wrapped around collagenous fibers, producing "collagen bodies". These formed the nidus for calcification that included psammoma bodies. Meningocytes also dissected between collagenous fibers, creating anastomosing spaces that mimicked a vascular tumor. Meningothelial-lined clefts, several milimeters in length, were present in 4 cases. Two lesions extended through dermal defects into the superficial dermis, where adnexa were reduced or absent. The meningocytes contained vimentin and epithelial membrane antigen. They lacked cytokeratin, S100 protein, and endothelial markers. The meningothelial lesions described herein lack the nodular and sheet-like growth patterns that typify meningiomas of the central nervous system and most primary ectopic meningiomas, including some that develop within the skin. They appear closely related to meningoceles and should be viewed as developmental abnormalities rather than neoplasms. The term "rudimentary meningocele" seems appropriate for these lesions.     

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.     

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.     

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.     

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%).     

Simultaneous turnover of normal and dysfunctional C1 inhibitor as a probe of in vivo activation of C1 and contact activatable proteases.

Simultaneous turnover of normal and dysfunctional C1-inhibitor (C1-INH) was carried out in 10 normal subjects and 13 patients with rheumatoid arthritis as a measure of the in vivo activation of C1 and the contact activatable enzymes. In the first series of experiments, dysfunctional protein We was used in simultaneous turnover studies in five normal subjects and nine patients. The fractional catabolic rate of the dysfunctional C1-INH, We, (FCR(d)) was unchanged in both groups but the fractional catabolic rate of the normal C1-INH (FCR(n)) was faster in the patients compared to the controls, in particular patients with vasculitis. The enzyme-dependent catabolism defined as FCR(n-d) X concentration of C1-INH X plasma volume, was raised in the patient group, and correlated with disease activity score (r = 0.83, P less than 0.05). Neither FCR(n) nor FCR(d) was dependent on C1-INH concentration. The latter was higher in the patients (206 mg/l compared with 155 mg/l) indicating a very high synthetic rate in the patients (280.81 micrograms/kg/h compared with 179.77 micrograms/kg). In the second series of turnovers in six patients and five normal subjects, another dysfunctional C1-INH, at, was used. The FCR of C1-INH was slower than C1-INH (We) (1.88%/h compared with 2.7%/h). Enzyme-dependent catabolism of C1-INH in these patients were raised and also correlated with disease activity score (r = 0.82, P less than 0.05).