The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis.

The nature of the glomerular-bound antibody and the putative antigen was investigated in one of the patients with sickle cell disease and immune deposit membranoproliferative glomerulonephritis by immunohistologic and glomerular antibody elution. Renal proximal tubular epithelial antigen was localized in association with immunoglobulins G (IgG), M (IgM), Clq fraction of the first component of complement (Clq) and the third component of complement (C3) in a granular pattern along the glomerular basement membrane of the patient's kidney. IgG and IgM were eluted from glomeruli. These immunoglobulins fixed to the proximal tubules of normal human kidney by direct immunofluorescence. This localization was abolished by absorption of the eluted immunoglobulins with renal tubular epithelial (RTE) antigen. The IgG eluted from the glomeruli blocked the fixation of rabbit anti-RTE antigen to normal proximal tubular brush border. These studies suggest that the nephritis in this patient was due to deposition of complexes or RTE antigen and specific antibody. An autologous immune complex nephritis may develop in some patients with sickle cell anemia secondary to RTE antigen released possibly after renal ischemia or some other phenomenon causing renal tubular damage.     

Budd-Chiari syndrome following pregnancy: Report of 16 cases,with roentgenologic,hemodynamic and histologic studies of the hepatic outflow tract

Budd-Chiari syndrome following pregnancy is an extremely rare disease as reported in the literature. Reported here are 16 such cases in a total of 105 patients with Budd-Chiari syndrome seen at Postgraduate Institute of Medical Education and Research, Chandigarh, from 1963 to 1978. The clinical pointer to the diagnosis was sudden occurrence of abdominal pain and ascites following childbirth. Eleven patients had diuretic-resistant ascites. Percutaneous hepatography was valuable in detecting the site and the nature of the outflow block. The prognosis was uniformly bad, and eight patients died within one year from the onset of their illness. The various treatment schedules, including anticoagulant therapy, Rhodiascit ascitic fluid re-infusion and portasystemic shunt surgery, had no beneficial effect on the survival of these patients.     

Guillain-Barré syndrome following administration of live measles vaccine.

In a 19 month old girl and a 10 month old girl the Guillain-Barre syndrome developed within a week after they received, respectively, live measles-rubella vaccine and live measles vaccine. The older child was immune to the rubella at the time of vaccination, but both girls demonstrated a primary measles antibody response. Serum obtained during the acute and convalescent stages from the younger child was tested for antibodies against the herpes viruses (herpes simplex, Epstein-Barr virus, cytomegalovirus and varicella-zoster) and found to be negative.     

Granulocytopenia in hospitalized patients: I. Prognostic factors and etiology of fever

The clinical course of 126 hospitalized patients during 192 episodes of granulocytopenia and fever was studied. Fever was a regular accompaniment of granulocytopenia, occurring in 94 per cent of granulocytopenic episodes. The mean duration of granulocytopenia (less than 1,000/mm3) was 18 days, with fever (temperature greater than 38 degrees C) being present during 44 per cent of those days. Fever was present during 69 per cent of days with a granulocyte count less than 10/mm3. A presumed infection was present in 86 of 128 febrile granulocytopenic episodes in adults and in 19 of 64 febrile granulocytopenic episodes in children. A fungal infection was found in 11 patients; a viral infection in 23 patients. Bacteremia occurred during 44 granulocytopenic episodes with 16.8 bacteremias/1,000 days of granulocytopenia in adults and 12.7 bacteremias/1,000 days in children. The mortality was 33 per cent per granulocytopenic episode in adults and only 8 per cent per episode in children.     

Chromatin-positive Klinefelter's syndrome with undetectable peripheral FSH levels.

An 18 year old phenotypic man is described with chromatin-positive Klinefelter's syndrome and undetectable peripheral human follicle stimulating hormone levels. The subject manifested chromosomal mosaicism consisting of three stem cell lines (45X; 46XY; and 47XXY). Testicular biopsy specimen showed germinal cell aplasia: the tubules were lined by Sertoli cells only, whereas the Leydig cells appeared normal. Serum human follicle stimulating hormone levels were undetectable and rose to only 5 mIU/ml after the administration of luteinizing hormone releasing hormone. Serum human luteinizing hormone varied between normal and moderately elevated values, and serum testosterone was in the low normal range. We discuss the features which distinguish this syndrome from isolated gonadotropin deficiency and from classic germinal cell aplasia. We suggest that the patient represents a new variant of Klinefelter's syndrome, with failure of human follicle stimulating hormone release secondary to prolonged hypersecretion.     

Total occlusion of the left main coronary artery. A clinical, hemodynamic and angiographic profile

Although left main coronary artery stenosis has been extensively revicwed, total occlusion of the left main coronary artery has received scant attention. Six patients were diagnosed at cardiac catheterization as having total occlusion of the left main coronary artery over a period of seven years at two institutions. They ranged in age from 32 to 72 years, and all had symptoms ranging from NYHA Class 1-IV at initial presentation. One patient died three days after coronary artery bypass graft surgery. Of the remaining five, two treated medically are alive four and 40 months after catheterization, and three treated with coronary artery bypass graft surgery are alive three, 66 and 68 months after catheterization. Electrocardiogram showed prior myocardial infarction in three patients, stress tests were positive in three of four patients, and hyperlipidemia was present in the five tested. In the three patients without prior myocardial infarction, left ventricular function was preserved (ejection fractions = 0.52, 0.55 and 0.64; left ventricular end-diastolic pressures = 6, 9 and 14 mm Hg). Injection of the right coronary artery in this group revealed extensive collaterals filling the left coronary artery. The three patients with prior myocardial infarction had impaired left ventricular function (ejection fractions = 0.18, 0.30 and 0.33; left ventricular end diastolic pressures = 26, 35 and 35 mm Hg) and sparse intercoronary collaterals. Patients with total occlusion of the left main coronary artery have a varying clinical presentation and may have prolonged survival. In patients with good collaterals, left ventricular function may be preserved.     

A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients.

Oral trimethoprim/sulfamethoxazole (TMP/SMZ) therapy was investigated in the prophylaxis of infections in granulocytopenia. Hospitalized granulocytopenic patients were allocated at random to receive TMP/SMZ (group 1) or to a control group (group 2). The percentage of febrile granulocytopenic days was significantly reduced in group 1, 19 per cent compared to 39 per cent in group 2 (P less than 0.01). In group 1, there were no bacteremias in 59 episodes of granulocytopenia (909 days). In group 2, there were nine bacteremias in 52 episodes of granulocytopenia (796 days)(P = 0.001). Disseminated candidiasis developed in two patients in each group. Candida occurred in similar numbers in surveillance cultures in both groups; Staphylococcus aureus and Pseudomonas aeruginosa were slightly decreased, and Enterobacteriaceae resistant to TMP slightly increased in group 1. This study suggest that oral prophylactic TMP/SMZ therapy is an effective, well tolerated, easily administered alternative to "gut sterilization" with nonabsorbable antibiotics.     

A nationwide outbreak of Reye's syndrome: Its epidemiologic relationship to influenza B

Between December 15 and June 30, 1974, 379 cases of confirmed Reye's syndrome were reported to the Center for Disease Control. Of these, 316 occurred during February and March 1974. A simultaneous surveillance system for influenza B indicated that this clustering of cases of Reye's syndrome correlated both temporally and geographically with influenza B outbreaks. The incidence of Reye's syndrome was higher in rural than in urban centers. Epidemiologically, two groups of cases of Reye's syndrome emerge: those which occur in older children (median age 11 years), cluster in time and geographic region, and are associated with antecedent influenza B infection; and those which occur sporadically throughout the year, are isolated in occurrence, occur in younger children (median age 6 years), and are associated with a wide variety of antecedent viral illnesses.     

Blood in the lymph (hemochylia) and intestinal lymphangiectasia associated with Lutembacher's syndrome

A 31 year old man presenting with Lutembacher's syndrome and protein-losing enteropathy is described. Reversal of the protein-losing enteropathy 7 months after cardiac surgery suggested that it was secondary to the cardiac disorder. Spontaneous rupture of a congenital aneurysm of the splenic artery created a spleno-portal arteriovenous fistula which caused a massive sequestration of blood into the dilated abdominal lymphatic system, severe hypovolemic shock and death.The pathogenesis and relation of two rare disorders of the lymphatic system, contamination of the lymph with blood (hemochylia) and intestinal lymphangiectasia are discussed.     

Granulocytopenia in hospitalized patients: II. A prospective comparison of two antibiotic regimens in the empiric therapy of febrile patients

The results of empiric antibiotic therapy in 126 hospitalized patients with fever during 192 episodes of granulocytopenia were studied. Febrile granulocytopenic patients were randomly allocated to receive either carbenicillin, methicillin and gentamicin, or carbenicillin and cephalothin. The response rate for the two antibiotic regimens was similar, 49 (60 per cent) of 81 responded to the former and 42 (54 per cent) of 78 to the latter. The response rate in patients receiving other antibiotics because of specific indications or counterindications was 19 (58 per cent) of 33. Thirty-nine (35 per cent) of 110 patients who responded to initial antibiotic therapy had an increase in circulating granulocytes of one log₁₀ or more compared to only 10 (12 per cent) of 79 nonresponders with such an increase. The mortality rate in adult patients receiving carbenicillin, methicillin and gentamicin was eight (16 per cent) of 51, compared to 18 (37 per cent) of 49 in those receiving cephalothin and carbenicillin (P < 0.05). The significance of this difference in mortality rate is uncertain, as there was no difference in the initial response rate or mortality rate between patients treated with the two antibiotic regimens when only patients with documented bacterial infection were considered. Patients who responded to their initial antibiotic regimen, and patients for whose fever no explanation was found, had the best prognosis.     

Immunodeficiency, malabsorption and secretory diarrhea. A new syndrome.

Described here is a patient with severe watery diarrhea associated with common variable immunodeficiency. Malabsorption for fat, bile acids, vitamin B12 and xylose was demonstrated, but the patient failed to respond to all the usual therapeutic maneuvers. The diarrhea responded only to high dose steroid therapy. Intestinal perfusion studies showed a hitherto undescribed, presumably acquired, glucose-stimulated water, sodium and chloride secretion in the jejunum and ileum, whereas normal fluid and electrolyte transport occurred from bicarbonate and mannitol solutions. Glucose absorption itself was normal and no hormonal, morphologic or biochemical defect was demonstrated to account for the phenomenon. The patient was also interesting when compared with other patients with common variable immunodeficiency in having normal plasma cells in the intestinal mucosa and an extensive family involvement.     

Effects of alternating phosphorus and calcium infusions on osteoporosis

The osteoblastic effect of inorganic phosphorus and the inhibitory action of calcium on parathyroid hormone secretion formed the basis for a therapeutic trial in which both elements were given intravenously in an alternating sequence for one year to five patients with severe osteoporosis. During treatment, calcium and phosphorus balances were positive, and serum phosphorus concentrations decreased. Iliac crest bone biopsy specimens obtained one year after beginning treatment demonstrated an increase in the thickness of cortical bone. All patients experienced lasting relief of bone pain, and the rate of spontaneous fractures decreased from at least one fracture per year to none following the beginning of treatment. These findings suggest that long-term treatment with alternating phosphorus and calcium infusions may result in lasting relief of symptomatic osteoporosis. It is proposed that the observed improvement reflects an increase in bone mass resulting from enhanced bone formation.     

Familial nephrotic syndrome

Systematic pedigree information was obtained from 70 patients with idiopathic nephrotic syndrome; 16 patients were found to have familial nephrotic syndrome including 1 pair of affected monozygotic twins, 5 affected sibling pairs, 2 affected first cousins from a consanguineous family and 2 patients with sporadic cases from consanguineous families.Patients with familial and sporadic forms of the disease were compared by applying both clinical and histopathologic criteria. No significant differences were found between these groups, but both had a preponderance of males.In contrast to previous reports, the clinical course in the affected monozygotic twins was quite different, providing evidence for the importance of environmental influences on the course of this disease. Furthermore, in affected relatives neither the clinical course nor histopathologic classification was necessarily similar.The recurrence risk for siblings of patients with idiopathic nephrotic syndrome was 0.06. Several possible modes of inheritance were considered. Segregation analysis permitted the exclusion of simple recessive inheritance. The invariable concordance for the occurrence of nephrotic syndrome in both members of monozygotic twinships as well as the sex ratio renders a mixed model, with a small proportion of high risk recessive cases, equally unlikely. The available data are most consistent with a polygenic model which assumes a continuous distribution of disease liability with a discreet threshold effect.     

Evidence of multicentric origin of the multiple endocrine neoplasia syndrome type 2a (Sipple's syndrome) in a large family in the Netherlands. Diagnostic and therapeutic implications

The occurrence of simultaneous tumors in different organs and the multicentric localization of the tumors in each of these organs are discussed on the basis of the findings in six patients belonging to a large kindred with Sipple's syndrome and in patients with Sipple's syndrome not belonging to this kindred, as well as the data in the literature. The high number of accessory pheochromocytomas in this family and in the other patients with Sipple's syndrome was striking. Both the pheochromocytomas and the accessories were found in the form of both cortical nodules and complete adrenal glands with hyperplastic medullary tissue.The invariable occurrence of pheochromocytoma changes in accessory adrenal tissue in this family and in other cases supports and demonstrates the multicentricity of tumor development in Sipple's syndrome. The aim of surgical treatment should be to remove all the pheochromocytoma tissue identified in the adrenal glands, the celiac plexus and side chain regions, thereby reducing the chance of recurrence of the symptoms in these patients and the need for repeated surgical intervention. However, more extensive exploration of the chest, cervical area, etc., to attempt curative surgery, is too destructive to be justifiable. The medullary thyroid carcinoma, which is also multicentric in origin, is, on the contrary, a dangerous tumor for which total thyroidectomy with extensive neck exploration is obligatory, preferably in an early phase. A modified short calcium test which is especially sensitive in this early phase, is described for screening for medullary thyroid carcinoma.     

The reflex sympathetic dystrophy syndrome. II. Roentgenographic and scintigraphic evidence of bilaterality and of periarticular accentuation.

Patchy osteoporosis is the primary roentgenologic manifestation of the reflex sympathetic dystrophy syndrome (RSDS). As recent clinical and histologic data suggested articular changes in RSDS, fine-detail roentgenograms were obtained in eight consecutive patients. Juxta-articular and soft-tissue swelling, osteoporosis and erosions of the subchondral bone were found. 99mTcO4 and 99mTc-EHDP scintigraphy showed localization of nuclide predominantly in the juxta-articular tissues. Serial roentgenographic, scintigraphic and quantitative bone densitometric measurements showed changes that reflected the clinical course of the disease.     

Bronchial component in chronic obstructive lung disease

Possible changes in the responsiveness of the airway to nebulized isoproterenol were studied in 69 patients evaluated retrospectively over an average period of 29 months and in 65 additional patients evaluated prospectively over a period of 6 months. Airway resistance (R_aw) decreased more than 15 per cent in 91 per cent of the patients studied retrospectively and in 97 per cent of the patients studied prospectively. Approximately 25 per cent of the group showed significant increases in vital capacity (VC) and maximum expiratory flow rate (EFR_max). Evidence of airway refractoriness was not observed. The variable physiologic response to isoproterenol suggests separation of patients into resistance-reactive, flow-reactive and vital capacity-reactive groups indicating differential response of the functional segments of the airway in chronic obstructive lung disease. Failure of EFR_max to increase after the inhalation of isoproterenol should not be taken as evidence of an unresponsive airway.     

Asbestos exposure and related neoplasia: The 28 year experience of a major urban hospital

In a retrospective study of 49 cases of asbestosis, a steady increase in the frequency of diagnosis of asbestosis and asbestos-related neoplasia is documented from a major urban hospital since 1960. Although in the majority of cases the subjects were exposed to asbestos in a neighboring shipyard, In 20 per cent of the cases, asbestos exposure was in industries not related to shipbuilding, reflecting its widespread use. This selective population of patients with asbestosis more often than not had an associated neoplasm. The most likely accompanying tumor was pleural mesothelioma, and among cell types of lung cancer, adenocarcinoma was notably frequent.     

Whipple's disease presenting as pleuropericarditis

A diagnosis of Whipple's disease was made by peroral jejunal biopsy in a 48 year old woman with pleuropericarditis of unknown etiology who had been followed for 4 years prior to the onset of clinical and laboratory signs of malabsorption. Pretreatment immunologic investigations revealed lymphopenia, decreased immunoglobulin G (IgG) with normal immunoglobulin A (IgA) and M (IgM) serum levels, and marked impairment of delayed hypersensitivity. Following successful treatment, the total lymphocyte count and serum IgG level returned to normal, and there was no demonstrable impairment in delayed hypersensitivity. This latter observation is in contrast with recent reports of immunologic investigations in patients with Whipple's disease which demonstrate that most patients continue to manifest significant deficits in delayed hypersensitivity despite successful therapy.     

Federal efforts to influence physician education, specialization distribution projections and options

I have tried to indicate the changes in the spectrum of medical education and practice, and have outlined in some detail the federal government's expanding role in this process.The deepening federal commitment to medical education is not the result of a drive for power or control. It is a response to public pressure as expressed through congressional legislation. Federal involvement represents the growing importance of the consumer in decision-making on matters of health.Growing cooperation between government and society is the pattern of the future in health matters. Changes will result more and more from decisions by all affected parties and less and less from random events and unilateral actions.Only through the participation of all significant interests can we achieve a health care system that will work as well for the medical profession as it does for the general public.