Estimating relative renal function.

Estimating relative renal function. Radionuclide measurements of relative renal function have been made using conventional dual-probe renography, computer assisted triple-probe renography, rectilinear kidney scanning and computer assisted gamma camera renography and kidney scanning. The relative area of each kidney from the excretory urogram also has been used to measure relative function. The best correlation between renography and kidney scanning was obtained with the gamma camera computer system. The relative function of each kidney was obtained by outlining regions of interest that corresponded closely to the renal images and subtracting the blood and tissue background activity, using a special background region. Triple-probe renography, using computer assisted blood background subtraction, provides another reliable indicator of relative function, which is considerably more accurate than conventional dual-probe renography. Relative renal function also may be determined, but with less precision, from the relative counts in a rectilinear kidney scan, from the relative scan areas and from the relative areas found on excretory urography. Both relative area methods are less reliable in the presence of outflow tract obstruction, renal tumors and renal cysts.


Outlet obstruction in the transplant patient. Transplantation is now an acceptable mode of therapy for end stage renal disease. Increased survival rates and acceptance of older recipients have resulted in an increased frequency of outlet obstruction in the male recipient. Reviews of urological complications in renal allotraansplantation have failed to emphasize this clinical entity. We present 3 patients, each emphasizing a different facet in the natural history of outlet obstruction in the male recipient of a renal allotransplant. The rationale for aggressive investigation of outlet obstruction is emphasized.


Diagnosis and management of arterial stenosis causing hypertension after successful renal transplantation. Renal artery stenosis causing hypertension has been noted in 11 patients after successful renal transplantations. We believe that all patients with moderate to severe post-transplant hypertension should be evaluated with angiography and selective renin determinations. However, because of definite risk to the graft we believe that operative intervention should be undertaken only if hypertension is uncontrolled or if declining renal function is present and attributable to the stenosis.


Simultaneous surgical management of bilateral hypernephroma: an alternative therapy. Herein are reported 2 cases of bilateral hypernephroma treated by simultaneous bilateral partial hephrectomy. One patient died of a myocardial infarction 3 years postoperatively and the other is well 30 months postoperatively. Bilateral partial nephrectomy is proposed as an alternative to bilateral nephrectomy and homotransplantation.


The pathology of urethral stricture.

The pathology of urethral stricture. In this 3-part study the distribution of the post-gonococcal stricture has been related to the disposition of mucous glands in paraurethral glands by mapping the distribution of these glands in the human male urethra. Experimental study in the rat has indicated the role of extravasation of urine in the pathogenesis of urethral stricture. Lastly, the ultrastructure of urethral stricture tissue has revealed features that suggest why some strictures are fibrous and others resilient.


Free full thickness skin graft urethroplasty for urethral stricture: experience with 66 patients. The free, full thickness skin graft urethroplasty, which has been used successfully for 20 years, was first adopted for anterior urethral strictures at our hospital in 1969. Presently, 66 cases of urethral stricture have been treated, 5 of them for posterior urethral strictures. The free, full thickness tube graft technique is discussed and 3 cases are reported. Of the 66 cases 54 (84 per cent) had good results. When indicated this procedure is advocated with considerable enthusiasm.


Patch graft urethroplasty for urethral stricture disease. The results with 34 cases of patch graft urethroplasties for urethral stricture disease were compared to the results in other series and found to be significantly worse. Various factors that might have influenced the surgical results were analyzed. Patients dilated least frequently had the best results.


Spontaneous renal allograft rupture without rejection: a case report. A case of spontaneous renal allograft rupture is described. Typically, this infrequent transplant complication occurred in the early post-transplant period in an oliguric setting with progressive pain, tenderness and swelling at the transplant site associated with hypotension and a decreasing hematocrit. Prompt surgical exploration and repair of the defect in the convex border of the renal allograft controlled hemorrhage and resulted in graft survival, and a normal blood urea nitrogen and creatinine 10 months after transplantation. There have been no rejection episodes and the renal biopsy demonstrated no evidence of rejection or acute tubular necrosis. Ice preservation for 24 hours and changes secondary thereto may have made the kidney susceptible to rupture when the position of acute flexion was assumed.


Immunologic considerations in renovascular hypertension. For decades certain diseases, such as glomerulonephritis, polyarteritis nodosa, scleroderma and serum sickness, have been linked with autoimmune pathogenesis. During recent years a host of additional diseases traditionally thought to have some genetic predisposition but with obscure etiology have been suspected of being autoimmune in nature. Rheumatoid arthritis, diabetes, myasthenia gravis and thyroiditis are diseases of widely divergent organ systems, yet may well have common pathways of pathology via immune complexing mechanisms. Herein we present evidence supporting the concept that renal artery stenosis (occurring primarily in association with the middle aortic syndrome or after renal transplantation) is of immune etiology. Although the specific antigenic agent is still to be defined there is growing acceptance of the theory that medium and large vessels are subject to autoimmune vasculitis in many aspects similar to the autoimmune affections of small vessels. Several cases are presented. Some of these suggest an immune reaction by the natural history but without evidence of immunochemical reactants in the involved vessels, presumably because active disease was arrested at the time of study. In other cases immunofluorescent preparations demonstrate reactants in the walls of the vessels to document the hypothesis more convincingly.


Intestinal perforation due to fecal impaction after renal transplantation. Three renal allograft recipients suffered major intestinal complications shortly after the operation. Identification of diverticular disease, adequate preoperative bowel preparation, avoidance of excessive amounts of non-absorbable antacids, early ambulation, and periodic laxatives and stool softeners can prevent these complications. Surgical management includes careful inspection for additional perforations, resection and colostomy, and continuous peritoneal lavage.


Bilateral traumatic renal artery thrombosis with survival after hemodialysis and renal transplantation. A case of bilateral thrombosis of the renal arteries following blunt trauma is presented. The patient was a 12-year-old boy who was treated by chronic hemodialysis and subsequently renal transplantation. A review of the literature reveals only 8 such cases reported previously. The condition is unusual and requires early diagnosis because the success of renal vascularization is entirely dependent upon prompt timing of the operation.


Spontaneous rupture of the renal pelvis: complication of renal homotransplantation. The first reported case of rupture of the renal pelvis associated with transplantation is presented. The obstruction was in the ureteral tunnel of the hypertrophic bladder. The cause of the weakness in the pelvic wall could not be determined. Differential diagnosis was acute rejection and lymphocele. Excretory urography was diagnostic. Treatment included revision of the ureteroneocystostomy with repair of the defect and internal stenting. Postoperative morbidity was minimal and satisfactory graft function was maintained.


Bone marrow transplantation from donors with aplastic anemia. A report from the ACS/NIH bone marrow transplant registry. Bone marrow transplantation from HLA-matched allogeneic donors was used to treat two series of patients with severe aplastic anemia. No significant differences were detected in all comparisons made between the Registry series (38 patients) and the Seattle series (24 patients), and pooled data from the two series were used in the analyses. Currently, 55% of the patients who received bone marrow transplants within three months of diagnosis are alive, but only 13% of the patients who received bone marrow transplants more than nine months after diagnosis are alive. The difference between the two groups was significant (P less than .02). Patients less than 21 years of age had a significantly higher survival rate than those patients who were 21 years or older at the time of transplantation (P less than .02). Survival rates were significantly higher for patients who had received 15 or fewer pretransplant transfusions than those who received more (P less than .05).


Liver transplantation of Budd-Chiari syndrome. Orthotopic liver transplantation was accomplished in a 22-year-old woman dying of the Budd-Chiari syndrome. She is well and has normal liver function 16 months postoperatively. In view of the good early result, it will be appropriate to consider liver replacement for this disease in further well-selected cases.


A family outbreak of serious streptococcal infection. A localized outbreak of scarlet fever was caused by an M-nontypable T-1 (NT/1) group A beta-hemolytic Streptococcus. The result was a fatal outcome in a 5-year-old child and a near fatality in his 10-year-old sibling. The outbreak was confined to family units that had members with whom the children were close playmates. Extensive epidemiologic studies in neighborhood schools and local hospital emergency rooms did not demonstrate a disemination of the causative serotype in the community.


Antidiarrheal agents in the treatment of acute diarrhea in children. To evaluate the efficacy of antidiarrheal agents in the treatment of diarrheal illnesses, a study was conducted with children in Guatemala who had an acute diarrheal illness. Eighty patients, aged 3 to 11 years, were hospitalized and treated for two days with one of five agents: kaolin-pectin suspension concentrate (Kao-Con), kaolin suspension, pectin suspension, diphenoxylate-atropine liquid (Lomotil), or placebo. Although the patients receiving kaolin-pectin produced stools that tended to be more formed than those of the placebo-treated group patients, the study did not demonstrate any effect by any of the agents tested in influencing the frequency of bowel movement, the water content of the stools, or the weight of stools. Kaolin-pectin suspension and diphenoxylate-atropine liquid do not appear to be useful in the relief of acute nonspecific diarrhea in children.


Computerized tomography and benign intracranial hypertension. Benign intracranial hypertension (BIH) is a recognized syndrome of unknown origin that conventionally has been diagnosed by excluding an underlying space-occupying lesion using invasive contrast procedures. Computerized tomography (CT) scanning of the head is a safe, accurate method of defining intracranial structures that were previously only discernible by invasive studies. Seven patients with headaches, papilledema, normal mental status, normal brain scan, and normal electroencephalogram had normal CT scans of the head. Patients suspected of BIH can be spared invasive contrast procedures if the CT scan of the head is normal.


Strain differences in the immunogenicity of aggregated human IgG and the adjuvant action of lipopolysaccharide on the low-responder strain of mice. Strain differences in the antibody response to human IgG (HGG) were observed when aggregated HGG was injected intravenously. Lipopolysaccharide (LPS) administered subsequently markedly enhanced the antibody response to HGG in low responder C57BL/6 mice as compared with that in high responder DDD, C3H/He or (C57BL/6 X DDD)F1 mice. Aggregate-free preparation of HGG at a dose of 0.5 mg induced immunological tolerance in all strains of mice tested. LPS injected subsequently converted tolerogenic, aggregate-free HGG into immunogen in DDD mice but not in C57BL/6 mice. To determine the correlation between adjuvanticity and mitogenicity of LPS, spleen cells from normal mice were cultured in the presence of LPS and 3H-thymidine uptake was measured. Spleen cells of DDD mice incorporated three times as much 3H-thymidine as those of C57BL/6 mice. There seems no strong correlation between both activities of LPS. The data obtained are discussed in terms of strain differences in the macrophage function for processing the antigen.


Studies of connections between locus coeruleus and cerebral cortex. Small tracking electrodes were inserted into the cat locus coeruleus (LC), and the effects of LC stimulation were determined on the transcallosal potential (TCP) evoked in cerebral cortex on the same side. LC stimulation at 8 volts inhibited TCP amplitude an average of 11%. Rostral LC placements appeared most effective. LC stimulation, without drugs, did not affect the peak latency of the TCP. dl-Propranolol and FLA-63 blocked LC inhibition of the TCP and also increased TCP amplitude per se. Propranolol first increased the latency of the TCP during LC stimulation, then decreased decreased it, while also prolonging the latency of the TCP per se. Phenoxybenzamine increased rather than blocked the LC inhibitory effect and also increased TCP amplitude. dl-Erythro-DOPS slightly increased the LC inhibitory effect, and substantially increased TCP amplitude. dl-Threo-DOPS produced somnolence in unanesthetized animals, led to increased norepinephrine levels in cortex and brain stem, and caused cortical potentials to fluctuate widely. A midbrain lesion of the dorsal ascending NE bundle blocked the LC inhibitory effect. LC stimulation alone, or in combination with evoked cortical stimulation, did not affect the interstimulus electrocorticogram or the heart rate. In the transcallosal system of the cortical regions studied, the LC appears to play mainly an inhibitory role.


[Change in secretion of somatotropic hormone and insulin in myocardial infarct]. Twenty patients with myocardial infarction and 10 normal individuals were subjected to a carbohydrates tolerance test, and their secretion of insulin and somatotrophic hormone in response to intravenous injections of glucose was studied. The blood serum concentration of insulin and of somatotrophic hormone was determined by way of radio-immuno-assay, while the blood sugar concentration -- by the orthotoluidine technique. It is established that myocardial infarction, like other stress states, is accompanied by disorders in the function of the hypophysis and the adrenal glands, which, in turn, is accompanied by disorders in the secretion of insulin and of somatotrophic hormone.


[Changes in systemic and regional hemodynamics in experimental renal hypertension]. The changes in the cardiac output were studied by the dye-dilution method in rat experiments in different periods of experimentally induced renal hypertension, as well as the distribution of the cardiac output among the tissues and organs. Four days after the procedure a distinct increase of the cardiac output is noted, by the 14th day it returned to the initial level, by the 135th day it clearly tended to decrease. The total peripheral resistance, on the contrary, was steadily growing beginning with the 14th day, thus bringing about an elevation of the arterial pressure. The distribution of the cardiac output among the organs and tissues did not change significantly under hypertensive conditions. The only exception is the cardiac output fraction that is supplied to the spleen.


Experimental pyelonephritis: the effect of chronic active pyelonephritis on renal function. In these experiments, renal function in chronic active pyelonephritis was investigated and the effect of antibiotic treatment and elimination of infection on the gross pathology, histopathology and renal function in animals with chronic pyelonephritis was determined. A severe loss of urine concentrating capacity was demonstrable when the maximum urinary osmolality of a group of animals with pyelonephritis was compared with control animals. Concentrating capacity decreased sharply over the first month but further  loss over an eight-month period was minimal. A compensatory increase in the glomerular filtration rate (GFR) in the control, nonchallenged, group occurred after nephrectomy but no comparable compensation in the infected group was found. Antibiotic therapy had a marked effect on the urinary concentrating capacity and the defect in concentrating ability was significantly less in the treated animals during the first 30 days after challenge. Infection again prevented a compensatory increase in the GFR of pyelonephritic animals which was not reversed by antibiotic therapy. Blood urea concentrations in treated and nontreated animals were not significantly different nor did the eradication of infection affect the gross pathologic and histopathologic changes found at autopsy.


Classical complement pathway activation in membranoproliferative glomerulonephritis. Levels of components of the classical and alternative complement pathways and the activity of the C3 nephritic factor (C3NeF) were measured in serum specimens from patients with type I (subendothelial deposits) and type II (intramembranous dense deposits) membranoproliferative glomerulonephritis (MPGN) and the results compared with the levels in normal subjects. Although C3 and C5 concentrations were comparably depressed in type I and type II, the levels of Clq and C4 were lower in type I and the correlation coefficients between Clq vs. C4 and C4 vs. C3 were higher than in type II. The profile was highly suggestive of classical pathway activation. In contrast, in type II MPGN, factor B levels were lower and C3NeF activity was more frequently detectable and higher. A feature of interest was that type I, as compared to type II, was characterized by significantly lower serum concentrations of properdin, higher and more significant correlation coefficients between serum properdin concentrations and those of Clq, C4 and C3, and consistent glomerular deposition of properdin. The involvement of properdin in type I may reflect recruitment of a pathway resembling the C1 bypass mechanism, said to involve C1, properdin, factor B and C3-9.


A new method for the isolation of ultrastructurally preserved glomeruli. A method is described for the isolation of kidney glomeruli using centrifugation in a discontinuous Ficoll gradient. The method, applied to rats, rabbits, pigs and man, yields a glomerular fraction of high purity with a tubular contamination of normally less than 2%. From observations by light microscopy on epoxy resin-embedded fractions, one-third to one-fourth of the glomeruli had suffered only slight damage during isolation. In the electron microscope these best preserved glomeruli showed a close morphologic similarity to those of the intact tissue and preliminary experiments have indicated that they are well-suited for further studies of the in vitro behavior of isolated, viable glomeruli.


Shape of epithelial cells and intercellular channels in the rabbit proximal nephron. In electron micrographs of proximal convoluted (PCT) and proximal straight tubules (PST), epithelial height was divided into five zones of equal thickness. Morphometric techniques were used to calculate surface area of cell wall bordering intercellular channels in each zone. Surface concentration of total lateral cell surface is 3.85 mu2/mu3 of PCT and 2.90 mu2/mu3 of PST. For tubules normalized to outer diameter = 40mu and inner diameter = 25mu, total lateral area is 29 X 10(5) mu2/mm of PCT and 22 X 10(5) mu2/mm of PST. Zone 5 adjacent to basement membrane has similar area (congruent to 17 X 10(5) mu2/mm) and fine structure in PCT and PST. However, the luminal four-fifths of the two cells differ markedly. Lateral area in PCT zones 1 through 4 increases approximately exponentially (from 1.1 X 10(5) to 6.4 X 10(5) mu2/mm) and constitutes 44% of total area. Respective areas in PST increase at a rate greater than exponential (from 0.7 X 10(5) to 2.6 X 10(5) mu2/mm) but constitute only 23% of total. From these data and the estimated number of cells per millimeter of tubule (825), circumferences of individual cells were estimated and quantitative three-dimensional cell models were constructed. The shape of intercellular channels is similar to that of the space between concentric, truncated and pleated horns.


Treatment of acute allograft rejection with high doses of corticosteroids. Sixty-four rejection crises in 55 kidney transplant patients were treated with high doses of corticosteroids, either 1) prednisone, administered orally in doses ranging between 150 and 600mh/day;2)methylprednisolone, administered i.v. in doses of 0.5 to 1 g/day (total dose: 2 to 8 g); or 3) methylprednisone administered i.v. in the same dosage in combination with heparin 5000 U/day. Acute rejection was reversed successfully in 60% of the crises without any apparent difference between the three treatment groups. Nineteen patients died from steroid-related complications. A total methylprednisolone dosage exceeding 3 to 5 h apparently was not accompanied by a sufficiently improved therapeutic response to warrant the high risk of such treatment.


Effect of vesicoureteral reflux on renal function in children with recurrent urinary tract infection.s. The functional damage caused by vesicoureteral reflux (VUR) has been examined by unilateral clearance studies in 22 children with recurrent urinary tract infection (UTI) and representing 23 kidneys with large VUR. 7 kidneys with small to moderate VUR and 14 kidneys without VUR. Inulin clearance, Na+ excretion and glucose reabsorption were determined. In kidneys without or with small and moderate VUR, UTI had no effect on renal function if treated. In kidneys with large VUR extending into the pelvis and dilating the ureter, there was a gradual deterioration of glomerular filtration rate (GFR) that was accelerated after the age of 6 yr. Before puberty more than 50% of renal function was lost despite strict medical care of the UTI. If this functional loss was unilateral, hyperfunction of the contralateral kidney was generally observed. Maximal glucose reabsorption was depressed in proportion to GFR. In kidneys with unilaterally low GFR, the fractional Na+ excretion was consistently increased as compared to the contralateral kidney with normal GFR. This adaptive increase in Na+ excretion must therefore be of intrarenal origin.


Occurrence of vascular IgA deposits in clinically normal skin of patients with renal disease. Skin and kidney biopsies were performed on 262 patients with various nephropathies. In 45 skin biopsy specimens finely granular  deposits of predominantly IgA and late-acting complement factors were detected in the walls of superficial capillaries, sometimes concomitantly with IgM, IgG, C4 or a combination of these proteins. Twelve of the 45 patients presented with anaphylactoid purpura and the majority of the other 33 patients had either recurrent macroscopic or microscopic hematuria. The renal lesions in 32 of these 45 patients consisted of focal segmental intracapillary proliferation. In 35 the kidney biopsy specimen showed mesangial deposits of IgA; in one case IgA was deposited along the glomerular basement membrane. In only three of the remaining 217 patients without cutaneous IgA deposits were typical mesangial IgA deposits found. The close correlation between IgA deposits in cutaneous vessels and focal segmental intracapillary proliferation with mesangial IgA deposits suggests that immunofluorescence examination of skin biopsy specimens could prove of diagnostic value. The results provide additional evidence for a close pathogenic relationship between IgA-associated glomerulonephritis and anaphylactoid purpura.


Transplantation in mesangiocapillary glomerulonephritis with intramembranous dense "deposits": recurrence of disease. Six patients with mesangiocapillary glomerulonephritis and intramembranous dense "deposits" developed terminal renal failure and were transplanted, three from living and three from cadaver donors. Eight renal biopsy specimens were obtained from five of the grafts, from 1 to 26 months following transplantation. All six biopsy specimens taken later than seven months following the graft showed recurrence of dense intramembranous "deposits" in the basement membranes of glomeruli, and of Bowman's capsule and tubular basement in five. Recurrence of "deposits" was associated with deposition of C3 on immunofluorescent study in all but one specimen; in addition, IgM was found in two specimens, but IgG and early complement components were absent. Only two patients, however, showed glomerular proliferation associated with profuse proteinuria. In the other subjects the recurrence of the "deposit" was not associated with clinical findings. Graft loss, which occurred in two patients, was predominantly from rejection.


[The characterization of clinically healthy hepatitis-b-surface-antigen (HBsAg)-carriers. Clinical, biochemical, histiological and immunological investigations in 129 case of a prospective study (author's transl)]. 129 blood donors found to be HBsAg-positive on routine testing were studied for evidence of hepatic disease. Twelve had already lost the antigen from the serum when histologically examined. None of these has had clinical or histological evidence of inflammatory liver disease. Two of the 129 patients showed mild icteric hepatitis, cleared the antigen during the follow up and became anti-HBs positive. The remaining 115 patients who appeared clinically healthy and who had no history of previous icteric liver disease remained HBsAg positive during a mean follow up period of 17.3 +/- 3.0 months. Forty patients from these had a normal liver histology and 37 mild to distinct steatosis but no signs of inflammatory liver disease. 11 patients a mild nonspecific mesenchymal activity but no focal necrosis, 16 patients had mild infiltration in portal tracts and a few necrotic parenchymal cells with mesenchymal reaction, 6 patients had chronic persistent hepatitis, 4 chronic aggressive hepatitis, and 1 definite posthepatic cirrhosis.


Sanded nuclei in hepatitis B: eosinophilic inclusions in liver cell nuclei due to excess in hepatitis B core antigen formation. In confirmation of earlier descriptions by Huang et al. (Huang S-N, Millman I, O'Connell A, Aronoff A, Gault H, Blumberg BS: Am J Pathol 67: 453, 1972) nuclear eosinophilic inclusions due to excess HBcAg particles have been identified in cases of chronic hepatitis B virus infection. As the euchromatin space of affected nuclei is "sanded" by numerous core particles with concomitant dissolution of the chromatin network, spiky, finely granular, and eosinophilic inclusions without a limiting membrane become visible in hematoxylin and eosin-stained paraffin sections. These HBcAg inclusions stain greyish pink with chromotrope aniline blue and are negative for orcein, the periodic acid-Schiff reaction, and the Feulgen reaction for DNA. Sanded nuclei were detected, although not always and only few in number, exclusively in HBAg-positive patients when a focal (as in chronic aggressive hepatitis) or a generalized core formation (as in immunosuppressed kidney transplant recipients) could be demonstrated by electron microscopy or immunofluorescence. Therefore, the positive finding of sanded nuclei in a persistent hepatitis B virus infection indicates an excessive core formation the extent of which should be verified by specific methods.


The SJL/J mouse: a new model for spontaneous age-associated amyloidosis. I. Morphologic and immunochemical aspects. A high incidence of spontaneous amyloidosis is described in SJL/J mice. Amyloid was detected as early as 30 weeks of age and the incidence rose to 90 per cent by 60 weeks of age. Amyloid deposits were most prominent in the perifollicular zones of the spleen and the lobular areas of the liver. Ultrastructural analysis revealed rigid, nonbranching fibrils indistinguishable from those observed in casein-induced murine amyloidosis. On the other hand, immunochemical studies indicated that amyloid deposits in SJL/J mice differ from those found in casein-treated CBA mice with respect to size, amino acid content, and antigenic properties. Since the SJL/J mouse also develops spontaneous reticulum cell tumors and serum M components, it appears to be a useful model for study of the pathogenesis of amyloidosis and its relationship to aging, neoplasia, and certain B-cell dyscrasias.


Cell-mediated immune response in head and neck cancer patients. The immune reactivity of 100 head and neck cancer patients was studied by means of DNCB, candidine, blastic transformation with PHA, and lymphocyte counts. DNCB reactivity was strong in only 21% of the population and was found impaired in patients with advanced primitive tumors, with more than one primitive tumor, and in patients after radiation. Candidine reactivity was impaired in bigger primitive tumors, positive nodes, and advanced stages, as well as in postradiation patients. Blastic transformation was significantly worse in patients over 70 years and tended to be lower in patients with more than one primitive tumor. Good blastic transformation was also lowered in postradiation patients.


Critique of an earlier study of the Sacramento Medical Care Foundation's Certified Hospital Admission Program (CHAP). The Certified Hospital Admission Program (CHAP), which was originated by the Medical Care Foundation of Sacramento, California, is regarded as a prototype of admission certification programs and the concurrent monitoring of inpatient care. These peer review functions have now been made key elements of provider utilization review requirements and of Professional Standards Review Organizations' program operations for Medicare and Medicaid. The present article questions, on methodological and interpretive grounds,  earlier published findings and conclusions about CHAP's effectiveness. Significant deficiencies in evaluating its impact may mean that the success of CHAP has not yet been demonstrated and, hence, that an adequate basis for formulating certain national peer review policies may not exist.


Effects of Medicare on hospital use: a disease-specific study. This paper presents results of a study to determine 1) the effects of Medicare on the patients of hospital use in specific disease groups, and 2) the sensitivity of length of stay and proportions of admission in specific disease groups to "short-run" changes in hospital occupancy rates. The analysis indicates that Medicare did increase utilization of hospital services by patients 65 and over through increases in both admissions and average length of stay. The largest increases occurred in the lower risk disease categories, although it is pointed out that this result does not necessarily imply a misallocation of hospital resources. The results also indicate significant differences among different socioeconomic groups and a much greater initial impact on the 75 and over age group than on the 65-74 age group.


Barriers to appropriate utilization of an acute facility. Professional Standards Review Organizations (PSROs) have been mandated to assure appropriate utilization of health resources. In order to meet this objective, PSROs must be able to determine when and why health resources are misutilized so that corrective action may be taken. This paper describes a study designed to identify and measure the significance of factors causing the misutilization of beds at one hospital. Using explicit Medicare levels of care criteria, a utilization review nurse coordinator determined the appropriate location (hospital, skilled nursing facility, home health care, home with outpatient or no care) or a sample of hospital patients. When a patient was judged inappropriately located on a particular day the nurse coordinator identified the barrier(s) to appropriate utilization, i.e., the reason(s) the patient remained in the hospital. Approximately 10 per cent of the 1,902 patient days were judged inappropriate at a hospital level of care. The most significant barriers to appropriate utilization were 1) the unavailability of skilled nursing facilities with the necessary amount of nursing services, and 2) the attending physician's conservative medical management of the patient. The implications for reduction of hospital misutilization are discussed.


Immunologic cross-reactivity between antisera to group A, type 12 streptococcal cell membrane and human glomerular basement membrane. The effect of age and carbohydrate content. Antisera to group A, type 12 streptococcal cell membrane and human glomerular basement membrane was evaluated, by indirect immunofluorescence, on adult and neonatal human kidney sections, before and after carbohydrase treatment. Cleavage of GBM carbohydrate potentiated the reactivity of SCM antisera on adult GBM, but not neonatal GBM which in general showed maximal activity without CHOase treatment. Of 22 sera checked 17 showed positive reactivity versus human GBM. Chemical analyses showed that adult GBM contained more carbohydrate than did neonatal GBM, which may explain the observed masking effect.


Immunotherapy of leukemia.

Immunotherapy of leukemia. The data reviewed in this paper indicate that immunotherapy is effective in prolonging remission and survival in acute and chronic leukemia. The acute lymphocytic leukemias may or may not respond to immunotherapy and further work is needed in this area. No studies of immunotherapy in chronic lymphocytic leukemia have been done, but this will be an important area for investigation, since there is often profound immunodeficiency in this disease. The malignant lymphomas are another fertile area for this type of research, since they have a high response rate, tumor-associated immunodeficiency, and at least differentiation antigens if not tumor-specific antigens. The scientific basis for the use of immunotherapy in leukemia includes the demonstration of a relationship of rate and duration of remission and survival to immunocompetence, the demonstration of unique tumor-associated antigens on leukemia cells, and the demonstration of immune responses to these antigens which can be boosted by immunization. At the present time, active nonspecific immunotherapy with BCG and MER and active specific immunotherapy have been proved effective in acute myelogenous leukemia. Careful attention should be given to dose, schedule, route, and so forth. Other types of immunotherapy remain to be explored.


The defibrination syndrome.

The defibrination syndrome. Defibrination is a fairly common clinical entity seen in a wide variety of clinical disorders. With an awareness of the likely clinical settings, a high degree of suspicion, and widely available sensitive laboratory tests, the diagnosis is ordinarily easily made. The best therapy is usually that which is directed at the underlying disease rather than at the defibrination syndrome itself. In certain symptomatic cases, heparin and/or replacement therapy is indicated, especially if the underlying disorder cannot be immediately successfully treated. On occasion, antifibrinolytic therapy will be useful, always with due regard to the danger of renal cortical necrosis. Depending on the clinical setting, it may be advisable to give heparin with the antifibrinolytic therapy to minimize that danger.


Diagnosis and treatment of pure red cell aplasia. Pure red cell aplasia is a selective aplasia of the marrow erythroid cells. Unlike aplastic anemia, the marrow has a normal cellularity and the patients generally have normal leukocyte and platelet blood counts. The congenital form of the disease occurs in the firlst 1 1/2 years of life and is often responsive to corticosteroids. The acquired form may be secondary to infections, drugs, chemicals, or hemolytic anemia (aplastic crisis). In these cases it is often acute and self-limited with cessation of the infection or drug ingestion. It may also be secondary to systemic lupus erythematosus, rheumatoid arthritis, acute severe renal failure, severe nutritional deficiency, or diverse neoplasms, and may remit with treatment of the primary condition. When a thymoma is present, it should be resected since a remission is produced in 29 per cent of these patients. The remaining patients have an acquired primary form of the disease that tends to be chronic and in some cases may have an immune pathogenesis. A cytotoxic immunoglobulin inhibitor of the marrow erythroid cells or erythropoietin has been described and these patients may respond to prednisone and/or to cytotoxic immunosuppressive drugs such as cyclophosphamide and 6-mercaptopurine. Pure red cell aplasia appears to be more common than the literature has revealed and has stimulated much investigation into an immune pathogenesis for marrow failure.


Immunosuppressive therapy of idiopathic thrombocytopenic purpura. The autoimmune nature of idiopathic thrombocytopenic purpura, as currently defined, is well established. Manipulations of the immune apparatus aimed at abating this deviant immunologic state may be one mode of approach  to the therapy of this disease. Several cytotoxic compounds are capable of inhibiting the primary and secondary immune response to experimentally injected antigens in animals and man. Their beneficial role in the treatment of an autoimmune lupus-like syndrome in NZB mice24 is well documented. In human autoimmune disease, efficacy of the drugs is still to be established. The mechanisms by which immunosuppressive agents effect therapeutic response, and, in particular, whether this action is linked to suppression of immune reactivity needs clarification. Although preliminary analysis of the efficacy of immunosuppressive drugs in idiopathic thrombocytopenic purpura is encouraging, their therapeutic role has not superseded that of conventional management with steroids and splenectomy. Carefully controlled randomized clinical trials are now necessary so that more rational use of these agents can be recommended in future reports.


The definitive treatment of children with acute leukemia. Current therapy has resulted in improved prognosis in previously untreated children with acute lymphocytic leukemia less than 16 years of age. The induction phase of chemotherapy should include the use of at least prednisone and vincristine. This combination should result in a hematologic remission in about 90 per cent of the patients. The efficacy of the addition of either L-asparaginase or daunomycin, the consolidation phase or the periodic readministration of induction drugs has not been established. Specific central nervous system treatment, early in the course of therapy, is an integral component of recently reported effective protocols. Several modalities of prophalytic central nervous system therapy have been utilized. These include cranial irradiation plus intrathecal methotrexate, craniospinal irradiation and intrathecal methotrexate alone. An encephalopathy syndrome has been reported as a complication in 10 to 66 per cent of these patients. The most effective form of central nervous system therapy, associated with the least toxicity, has not been established. Maintenance chemotherapy should include a combination of two or more drugs. Complications are numerous, and include hematopoietic depression, immunosuppression, overwhelming infections, and, possibly, the development of secondary primary cancers. In the most successful protocols maintenance chemotherapy has been administered for 3 years. Because of the potential significant toxicity there is a need to define the optimal duration of maintenance therapy. Psychological complications developing in a patient with a disease now considered a potential long term chronic illness, rather than a disease once considered universally fatal, are also discussed. The possibility of an immunologic deficiency allowing for the initial development of acute lymphocytic leukemia and the role of immunotherapy are presented. While the use of intensive combination chemotherapy and specific central nervous system prophylactic therapy have resulted in an improved prognosis in childhood acute lymphocytic leukemia, because of a significant incidence  of failures, a standardized single form of therapy has not been established.


The vascular anatomy of the eustachian tube in the guinea pig. Vascular anatomy of the eustachian tube has received little attention in the world's medical literature. Forty guinea pigs were perfused with Berlin Blue as a contrast medium and the eustachian tube microvascular architecture visualized through surface preparations. A diffuse, dense two-layered capillary network was found which followed the distribution of mucous glands. Five animals suffering from suppurative otitis media showed marked capillary congestion with increased vessel to tissue density. Relationships to gross arterial and venous supply as found in the human are discussed.


The use of steroids in Bell's palsy: a prospective controlled study. A prospective, controlled, double-blind study was designed to evaluate the effect of steroid treatment on the natural history of Bell's palsy. Fifty-one patients were included in the study between 1972 and 1974. The patients were evaluated and started on treatment within two days of onset of Bell's palsy and followed for six months. Treatment was given in randomized double-blind fashion and consisted of either vitamins or a total of 410 mg of prednisone plus vitamins in descending doses over 10 days. The recovery of facial motor function was determined by three physicians who had no knowledge of the treatment received by the patients. They examined photographs of the patients taken six months after onset of paralysis in eight positions of facial function and categorized them as to complete fair, or poor recovery of facial function. These results of this evaluation were submitted to the biostatistician who broke the treatment code. The results of this study demonstrate no statistically significant beneficial effect of steroid therapy upon recovery from Bell's palsy. Factors considered included the patients' age, sex, the presence of pain, ageusia, hyperacusis, diabetes, hypertension, the progression and degree of palsy, the results of nerve excitability and salivary flow tests, and the time at which recovery was first noted or became complete. Bell's palsy remains without a proven efficacious treatment.


"Practical suggestions on facial plastic surgery--how I do it.". For many years, we have used 6-0 catgut for closure of epithelial and superficial dermal wound edges. Only when absolutely necessary do we use deeper dermal or subcutaneous sutures. The superficial suturing is supplemented with antitension skin taping. Details of the technique are presented and reasons why satisfactory results occur are postulated. The recommended techniques have been used in closure of wounds on the face and body. It is emphasized that only certain catgut and antitension taping products work well.


Hunting poisons of the North Pacific Region. The hunting poisons of the North Pacific region are discussed. The most important one used by the Ainu was based on Aconitum species (surku or suruku): on Hokkaido, to some extent A. japonicum Thumb. but probably mainly A. yezoense Nakai and A. sachalinense Fr. Schm.; on southern Sakhalin, perhaps A. fischeri Reichb., A. maximum Pall. ex DC., and/or A. sachalinense Fr. Schm.; and on the Kuril Islands, A. maximum Pall. ex DC. Poison from the Japanese stingray Dasyatis akajei (Müller et Henle) (aikor chiep) was also much used, alone or mixed with aconite, and was believed by some Ainu to be better than aconite. Adjuvants to these poisons were numerous and varied in each locality. Daphne kamtschatica Maxim. var. yezoensis (Maxim.) Ohwi (ketuhas) was used in hunting walrus. The use of Cynanchum caudatum (Miq.) Maxim. (penup) enabled birds to be caught. Juglans ailanthifolia Carr (nesko) was a fish poison. A critical evaluation of the accounts by Krasheninnikov, Steller, Harms, and others, indicates that the inhibitants of the Kamchatka Peninsula, the Kamchadal (Itelmen), hunted with a poison derived from Aconitum maximum Pall. ex DC. This same species was almost certainly used in the Aleutian Islands and the Kodiak Island region, principally for hunting whales. There is some evidence that the inhabitants of the far north-eastern part of Siberia and of the Alaskan coasts opposite may also have used poison in hunting. The chemistry and toxicology of the poisons are briefly considered.


Amylase--its clinical significance: a review of the literature. This review of the English literature on amylase was undertaken because no recent discussion of the subject could be located, no comprehensive list of disorders causing hyperamylasemia or hyperamylasuria is available, and several major advances in the area have been made, notably the amylase isoenzyme determination and Cam/Ccr ratio. Several important concepts have emerged from this review. First, hyperamylasemia and hyperamylasuria are not specific indices of the presence of pancreatic disease or damage. Second, serum and urinary amylase levels can be spuriously normal with hypertriglyceridemia and pancreatitis. Third, the current emphasis on diagnostic methods for measuring serum amylase isoenzymes promises to improve the specificity of this determination. It will also enhance our understanding of the sources, distribution, metabolism, and elmination of amylase. Fourth, the development of the Cam/Ccr ratio may provide a practical diagnostic tool for separating clinically significant hyperamylasemia due to pancreatitis from that caused by other factors. Both the the isoamylase determination and Cam/Ccr ratio clearly require future research to place their clinical application in the proper perspective.


Renal cell carcinoma: unusual systemic manifestations. A series of cases is presented which illustrates unusual aspects in the presentation, diagnosis, and management of renal cell carcinoma. The entire "classic triad" of flank pain, gross hematuria, and palpable mass was not present at the time of diagnosis in any of the patients. Moreover, in only three patients did the initial clinical findings raise the suspicion of renal cell carcinoma. A diagnosis of polycystic kidney disease, cardiac failure, glomerulonephritis, analgesic abuse, and perirenal hemorrhage obscured the primary diagnosis in the other five patients. In four patients the tumor was probably present from 3 to 12 years before detection. These findings emphasize that knowledge of the hematologic, humoral, immunologic and vascular abnormalities induced by this tumor may provide a clue to early diagnosis. The systematic use of excretion urography, nephrotomography, ultrasonography, renal scanning, renal arteriography and cyst puncture then may allow the accuracy of radiologic diagnosis of this tumor to approach 100%. Lastly, the therapy of choice for this tumor is radical nephrectomy. Excision of apparently solitary metastases also may sometimes be feasible. However, partial nephrectomy to remove tumor in a solitary kidney was performed in one patient to avoid the need for end-stage kidney treatment. Where nephrectomy renders the patient anephric, chronic hemodialysis and renal transplantation should be considered as potential measures to sustain life. While hormonal agents, chemotherapy, and radiation therapy sometimes provide palliation, their use generally has been disappointing.


Studies in familial systemic lupus erythematosus. Although many examples of familial SLE have been reported, the relative importance of genetic and environmental factors remains unclear. In an effort to better understand these factors, eight such families were studied. These families, plus one deceased pair and 31 described in the literature consisted of 8 pairs of identical twins, one pair of non-identical twins, and 16 sibling and 15 parent-offspring combinations. Fifty-three cases in 25 families provided sufficient documentation for detailed analysis. Each familial case was compared to his affected relative utilizing 23 clinical and laboratory features of SLE. A control group of non-related SLE patients, each matched to a familial case for age, sex, race and disease duration, was similarly analyzed. Impressive concordance for disease expression was found between pairs of identical twins and between parent and offspring. No such concordance was found between siblings and controls. These findings support genetic influences in the expression of SLE in identical twins and parents and offspring pairs. Comparison of the frequencies of clinical and laboratory attributes in the familial group as opposed to non-familial groups showed no real differences. Thus, familial SLE is probably not a different disease entity from non-familial SLE. The finding of four father-offspring pairs lessens the possibility that SLE is transmitted during the perinatal period. The onset of SLE in each of identical twins occurred within an average of 2 years. In siblings, however, while the average difference in age at onset was 9 years, the average difference in time of onset (actual date) was only 3 years. Comparable figures for parents and offspring were 20 and 8 years, respectively. These data suggest environmental influences in the initiation of SLE, especially in siblings. Studies of 27 unaffected first-degree relatives in our eight families revealed two sisters with thyroid disease, persistent leukopenia and sedimentation rate elevation. They were daughters of a patient with SLE and Hashimoto's thyroiditis and sisters of a patient with SLE. The remaining 25 relatives were clinically, hematologically, biochemically, and serologically normal. While these studies suggest both genetic and environmental influences in the pathogenesis of SLE, further studies are necessary to elucidate the mechanisms.


Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. 1. Among patients with SLE, 71 (51%) had significant neuropsychiatric problems during the course of the disease. In 52 (37%), the nervous system manifestations were secondary to SLE. 2. The most frequent manifestations were psychiatric dysfunction, seizures, long tract signs, cranial neuropathy, and peripheral neuropathy. 3. Psychiatric abnormalities secondary to SLE were characterized by organic features (present in 22 of 24) and by the association of neurologic lesions which were often diffuse or multifocal. 4. An abnormal cerebrospinal fluid was found in 32% of neuropsychiatric episodes in which specimens were obtained. The most frequently abnormal study was the electroencephalogram (71%), and the least frequent was the brain scan (8%). These studies did not correlate with specific clinical patterns. 5. In 63% of the patients, NP manifestations preceded the diagnosis of SLE or occurred within the first year of diagnosed disease, and in most episodes were associated with evidence of clinical and/or serologic activity of the underlying illness. 6. Only two clinical features showed significant and striking correlations with neuropsychiatric involvement, namely vasculitis and thrombocytopenia. The possible pathogenic implications have been discussed. 7. Only 2 of the 140 patients were felt to have steroid-induced psychoses. In approximately one-half of the NP episodes secondary to SLE, patients were receiving no corticosteriods on presentation. Of those developing while patients were on steroids, the majority occurred on low doses or after tapering from higher levels. 8. The immediate prognosis for improvement in neuropsychiatric function was good with 84% of episodes showing complete or partial resolution. Corticosteroids appeared to be of benefit in  a substantial number of patients although their precise role is difficult to quantitate. 9. Five and 10 years survivals for the overall population were 94% and 82%, respectively. There were no significant differences in survival for patients with or without nervous system involvement.


NADPH-forming dehydrogenases in the adipose tissue of obese and nonobese diabetics. The activity of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) of adipose tissue was markedly decreased, both on a protein and on a fat cell number basis, in nonobese diabetics compared to control subjects, but was unchanged in obese diabetics. Average value in the obese diabetics was about fourfold higher than in nonobese diabetics. On the other hand, the activity of malate dehydrogenase (decarboxylating) (NADP) (EC 1.1.1.40) was reduced by about 50% in both groups of diabetics. These findings suggest that in obese diabetics NADPH-generation in the adipose tissue, necessary for several biosynthetic processes, might be less severely depressed than in lean diabetics.


Plasma alpha-cell glucagon in primary hyperparathyroidism. Plasma glucose, insulin, and alpha-cell glucagon profiles were examined in ten adults with uncomplicated primary hyperparathyroidism before and 8-12 week after surgical removal of a single parathyroid adenoma. Treatment restored abnormal serum calcium and phosphorus concentrations to a normal range and reduced serum parathyroid hormone levels from 47 +/- 4 to 16 +/- 4 mu 1 Eq/ml (normal = 0-40). Plasma glucose curves during 100-g oral glucose tolerance, 30 min intravenous glucose (1.5 g/min), or arginine infusions (1.0 g/min) did not differ before and after surgery. However, basal and peak insulin concentrations were higher before treatment during these tests (p less than 0.05). Basal glucagon levels were unaffected by hyperparathyroidism (72 +/- 7 versus 77 +/- 7 pg/ml). Peak 30 min values after arginine provocation were also similar before and after treatment as was maximal suppression of basal glucagon during glucose infusions. Four patients also received 400 g lean beef meals. Glucose and glucagon responses over 240-min periods were nearly identical before and after surgery despite higher insulin levels before treatment. It is concluded that elevated serum parathyroid hormone and plasma insulin concentrations in primary hyperparathyroidism do not relate to abnormalities of plasma alpha-cell glucagon in the basal state or after glucose, arginine, or protein administration.


Lack of central autonomic regulation of substrate during early fasting in man. To determine whether centrally mediated adrenergic tone modulates lipolysis, ketogenesis, or insulinopenia during starvation, four lean male subjects with complete cervical cord transection and six lean healthy male volunteers were fasted for 48 hr. Plasma glucose and insulin levels decreased to comparable levels in both groups. Plasma free fatty acid (FFA) and beta-hydroxybutyrate concentrations rose to peak levels 1.23 +/- 0.08 mmoles/liter and 4.2 +/- 1.0 mmoles/liter at 36 and 48 hr in normals, respectively. Cord-sectioned subjects had similar peak FFA (1.2 "/- 0.12) and beta-hydroxybutyrate (5.6 +/- 0.3) concentrations. Urinary catecholamine excretion in four normal subjects failed to increase during the fast. Since normal glucose, free fatty acid, beta-hydroxybutyrate, and insulin relationships were maintained in sympathectomized subjects, it appears that central adrenergic mechanisms are not essential for initiation of lipolysis, ketonemia, or the hypoinsulinemia of early starvation. These results provide additional evidence that these metabolic events are primarily related to insulinopenia.


The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part I of IV parts: mechanisms of calcium transfer between blood and bone and their cellular basis: morphological and kinetic approaches to bone turnover. The supracellular organization of living bone enables the study of isolated cellular and subcellular systems to be related to the study of the whole organism. Bone is formed by osteoblasts in successive stages, separated in both time and space, of matrix formation and primary mineralization. Osteoblasts are joined by tight junctions and largely cover the osteoid seam which separates them from mineralized bone. Secondary mineralization is not completed for several months and is not regulated by the osteoblast. Bone is resorbed by osteoclasts which simultaneously accomplish mineral dissolution and matrix digestion. Active osteoblasts occupy about 5% of the free bone surface, osteoid seams with less active osteoblasts about 10%, active osteoclasts about 0.5%, and Howship's lacunae at which bone remodeling is either quiescent or arrested about 5%. The remaining 80% of the free bone surface is covered by a leaky envelope of thin flattened cells, termed surface osteocytes. Some osteoblasts become permanently buried in the bone as deep osteocytes, around which a specialized and metabolically active perilacunar bone is formed. This bone is less highly mineralized and can temporarily lose or gain calcium in accordance with homeostatic needs. Deep osteocytes maintain contact with each other and with the surface osteocytes, their cell processes within canaliculi being joined by gap junctions. Remodeling of cortical bone proceeds with the excavation by osteoclasts of a longitudinal tunnel which is refilled by osteoblasts to form a new osteon. The anatomically discrete longitudinally oriented structure consisting of a cutting cone of osteoclasts in front and a closing cone of osteoblasts behind is termed a cortical remodeling unit. The events of centrifugal resorption and centripetal formation which occur in a single cross section is termed a cortical remodeling cycle. Normally each new cycle is slightly out of phase with its predecessor. The quantities which characterize cortical remodeling are the birth rate of new remodeling cycles or activation frequency (mu), and the durations of the resorptive period (sigma r), the quiescent interval (sigma q) and the formation period (sigma f). The average distances traveled by the osteoclast and osteoblast are indicated respectively by the mean cement line diameter and mean wall thickness of completed osteons. These quantities show little interindividual variation. Because of this constancy the magnitude of bone turnover (the bone formation rate) is almost entirely a function of mu, the activation frequency of new remodeling cycles. Variations in the velocity of advance of osteoclasts (the linear resorption rate) or of osteoblasts (the appositional rate) alter inversely both the extent of surface engaged in resorption or formation and the time taken to replace a particular moiety of bone, but in a steady state do not influence the rate of turnover of the skeleton as a whole...


LH and FSH responses to luteinizing-releasing hormone in normal, adult, human males. Time-response and dose-response relationships were established for the LH and FSH response to single intravenous bolus injections of synthetic LRH. Sixteen normal adult human males, ages 19-45 were studied, and 80 individual tests were performed using a broad range of LRH doses from 0-3000 mug. Serum gonadotropins were measured at frequent intervals ranging from -30 to 180 min after LRH injection. The curves describing changes in blood LH and FSH with time were not superimposable at any dose level. The 50% decay time for the LH response showed a significant linear log-dose relationship to LRH. For LH, dose-response relationships existed for both, the peak LH release, and the total LH secretion (area under the time-response curve). No minimal or maximal effective doses were reached for LH within the dose range from 1 to 3000 mug LRH. The smallest dose (measured as peak LH concentration), that produced a response significantly different from saline injections, was 1.58 mug/subject; judged by total LH secretion (area under the time-response curve) the smallest dose producing a significant response was 2.39 mug/subject. No dose-response relationship existed for the peak FSH release. Judged by total FSH secretion (area under the time-response curve), the effects of LRH were dose related; the smallest effective dose was 20 mug LRH. As for LH, no maximal effective dose was reached within the dose range studied. The 95% confidence intervals for the peak responses to an intravenous bolus injection of 100 mug synthetic LRH were 400%-800% of the individual mean base line LH concentration, and 100%-200% of the individual mean base line FSH concentration. Serum testosterone did not change significantly in response to single bolus injections of LRH at any of the dose levels studied. The peak LH responses to any dose of LRH were positively correlated to the individual mean base line LH concentrations. No correlations were observed between the peak LH or FSH responses and age, race, marital status, body weight, or body surface area of the subjects. In a second series of studies, a 2-hr, constant infusion of synthetic LRH was administered at five different infusion rates (doses) to four normal adult human males for a total of 20 infusions. Serum LH and FSH responses were sustained at dose related levels characteristic of each individual during the entire LRH infusion period. In contrast to the lack of testosterone responses to bolus injections of LRH, serum testosterone rose significantly in response to all dose levels of LRH infusion. These are the most extensive pharmacologic studies of LRH-LH and LRH-FSH relations in man yet reported.


[Mutagenesis of synchronous populations of Escherichia coli with normal and defective reparative enzymes under the influence of hydroxylamine]. Bacterial populations of E. coli K12 uvr+ and E. coli K12 uvr- were preliminary synchronized on membrane nitrocellulose filtres and then treated with 1 M hydroxylamine for different times; the frequency of mutants failing to assimilate glucose was estimated. Kinetics of mutagenesis in the cells of both strains was almost the same and indicated that lesions induced by hydroxylamine were not repaired. It is for the first time that the maximum mutation frequency was registered in experiments with hydroxylamine; this suggests that the repair hypothesis of attaining the maximum mutation frequency is not universal.


[Formation of L-asparagine and L-glutamine deamidases by bacterial cultures]. Among studied 40 bacterial cultures, 17 strains catalysed hydroxylaminolysis of I.-asparagine and L-glutamine, and among these cultures seven strains belonged to the Pseudomonas genus. Extracts of the cells of Ps. boreopolis 526 (MGU), Ps. aurantiaca IBFM B-14, and Ps. septica IBFM B-40 had the maximum deamidase activity during the stage of decelerated growth. The activity of L-asparaginase 2 was practically the same upon various ways of disintegration of the cells of Ps. aurantiaca IBFM B-14: ballistic technique, ultrasound, extrusion form the solid state. Production of beta-aspartylhydroxamic acid by L-asparaginase 2 depended on the concentration of hydroxylamine and protein in the reaction mixture and on the duration of the reaction.


Double-blind factorial trial of prindolol and hydrochlorothiazide in hypertension. The antihypertensive actions of the beta-adrenergic blocking agent, prindolol, and of the diuretic, hydrochlorothiazide, were analysed in a double-blind randomized 2 X 2 factorial trial in 16 patients. There were four eight-week phases in which patients received prindolol alone, hydrochlorothiazide alone, prindolol plus hydrochlorothiazide in combination, and no treatment. Both drugs were given in fixed doses: prindolol, 10 mg three times per day; hydrochlorothiazide, 50 mg per day. Blood pressure was measured weekly, alternately at the outpatient clinic and at home. Supine mean arterial pressure (MAP) in resting patients fell from 127 mm Hg in the placebo phase to 117 mm Hg with hydrochlorothiazide alone, 116 mm Hg with prindolol alone, and 111 mm Hg with the combination of prindolol and hydrochlorothiazide. (The standard error of difference between treatments was +/-3-58). A mean factorial effect of -7 mm Hg for hydrochlorothiazide (P less than 0-01) and -8 mm Hg for prindolol (P less than 0-01) was obtained, and the two drugs acted in an additive manner. The effects on standing blood pressure in resting patients were similar. No serious side effects were noted.


[Gastric tolerance of different preparations of acetylsalicylic acid in postoperative prevention of thrombo-embolism (author's transl)]. The necessity for thrombosis-prophylaxis is indisputable. The evaluation of our patients over a period of 2 years revealed results compatible with other authors. Due to its thrombocyte desaggregating action, acetyl-salicylic acid was found to have a definite effect on the thrombophilia by inhibiting the thrombocyte adhesiveness in a beginning thrombosis. It was shown that acetylsalicylic acid in combination with glycocoll is apparently superior to microencapsulated acetylic acid in terms of gastric tolerance. In a small number of patients the therapeutic efficiency was investigated and according to the platelets agglutination test, verified. Further investigations are planned in a major series of patients where acetylsalicylic acid with glycocoll was administered in respect to the treatment of rheumatic fever.


Effects of rifampicin on synthesis and functional activity of DNA-dependent RNA polymerase in Escherichia coli. During the course of kinetic studies on the synthesis of RNA polymerase subunits in Escherichia coli K12, strain Km7 (CP372), certain anomalies were found that seemed to be associated with the system of reversible inhibition of RNA and protein synthesis by rifampicin. To find a possible explanation for these anomalies, effects of rifampicin on RNA chain elongation and on residual synthesis of polymerase subunits were investigated with several strains including Km7. Examination of mRNA synthesis for the tryptophan operon suggested that RNA chain growth as well as RNA chain initiation is inhibited at high drug concentration (500 mug/ml), wheras RNA chain initiation is inhibited specifically at low concentration (20 mug/ml). Analysis of effect of rifampicin concentration on total RNA synthesis gave results that are also consistent with this conclusion. These results emphasize the need for selecting a proper drug concentration whenever rifampicin or other related antibiotic is used as a specific inhibitor of transcription initiation. When rifampicin was added to a culture of these strains absolute rates of synthesis of all subunits of RNA polymerase increased for several minutes and then decreased. The extent of this transient stimulation varied depending on the strain, drug concentration and other conditions, but was most striking  for the beta and sigma subunits with strain Km7 at high drug concentration (500 mug/ml). With a rifampicin-sensitive wild-type strain tested, the maximum stimulation was found at about 50 mug/ml of the drug, with a particularly marked effect for sigma subunit. Streptolydigin, on the other hand, inhibited the synthesis of core subunits much faster than the bulk of protein, but inhibited synthesis of sigma subunit only after a lag. Hence a specific effect of rifampicin but not the inactivation of beta subunit per se appears to be involved in transient stimulation of polymerase synthesis observed. Implications of these findings on the control of RNA polymerase synthesis are discussed.


Mitochondrial genetic damage induced in yeast by a photoactivated furocoumarin in combination with ethidium bromide or ultraviolet light. Ethidium bromide (EB) and ultraviolet light (UV) in combination are known to produce a synergistic induction of "petite" mutants in yeast. Two other agents were combined with EB, 3-Carbethoxypsoralene (3 CPs) activated by 365 nm light or gamma rays. EB in combination with 3 CPs also resulted in an enhanced production of "petite" mutants. After the photoaddition of 3 CPs in exponential phase cells, recovery of the "petite" mutation during dark liquid holding was inhibited by the presence of EB producing an enhanced number of "petite" mutants. The behavior of mitochondrial antibiotic resistance markers after individual and combined treatments with EB and 3 CPs indicates a random loss of markers after EB and a preferential loss of a certain region for the 3 CPs photoaddition. The combination of the two agents leads to an additivity of total drug marker losses rather than a synergistic loss. The combination of EB with gamma rays produced no enhancement in "petite" induction. A combination of UV and 3 CPs showed a synergistic interaction for "petite" induction. These results indicate that the three agents, EB, UV and 3 CPs photoaddition may share a common repair step for mitochondrial lesions.


Replication of small plasmids in extracts of Escherichia coli. Sakakibara and Tomizawa (1974a) have described a soluble in vitro system that can carry the semi-conservative replication of the Co1 E1 plasmid. However, the usefulness of this system is restricted by its rapid inactivation during storage. This paper describes a stable soluble system prepared by freeze-thaw lysis of chloramphenicol-treated E. coli cells which replicates added Co1 E1 and C1o DF13 DNA. It differs from the system employed by Sakakibara and Tomizawa in two important points: (1) Its replicative capacity for Co1 E1 DNA is by an order of magnitude higher and (2) it can be stored in liquid nitrogen for several months without loss of activity Plasmid replication in vitro is dependent of DNA polymerase I and requires de novo RNA synthesis. It is completely inhibited by rifampicin, oxolinic acid, and novobiocin. The DNA synthesized during a 60 min incubation at 30 degrees C consists mostly of monomeric supercoils. If Co1 E1 DNA is used as template, a minor portion of the label is also found in closed dimeric catenanes. Density labelling experiments indicate that plasmid DNA synthesis occurs by a semi-conservative replication process.


Expression of the plasmid pKM101--determined DNA repair system in recA- and lex- strains of Escherichia coli. pKM101, a plasmid R factor of the N compatibility group increases methylmethane sulfonate mutagenesis and diminishes UV-killing in recA+ LEX+ and recA+ lex- strains, , but not in recA-lex+ strains. The induction of a "reclex" dependent colicin is not present in lex- strains carrying the pKM101 factor. These facts indicate that pKM101 acts through an error-prone DNA repair system which is recA+ dependent, but not lex+ dependent.


Peptide analysis of RNA polymerase alpha subunit from Escherichia coli: comparison of free with assembled form. The analysis of tryptic peptides was performed on the unassembled as well as assembled form f alpha subunit of the DNA-dependent RNA polymerase from Escherichia coli. The peptide profiles obtained by Dowex 50 column chromatography of the unassembled alpha subunit prepared from cells, either pulse-labeled or continuously labeled with radioactive lysine or arginine, were essentially identical with those of the alpha subunit from intact RNA polymerase. The results suggest that newly synthesized free alpha subunit is assembled into the polymerase structure without any remarkable modifications. The number of lysine- and arginine-containing peaks were close to the values expected from the amino acid composition of alpha subunit assuming that the two alpha subunits in RNA polymerase core enzyme have identical primary structure.


The influence of mutations upon the synthesis of RNA polymerase subunits in Escherichia coli cells. The influence of mutations in structural genes of beta and beta subunits of RNA polymerase upon the synthesis of these subunits in E. coli cells have been investigated. An amber-mutation ts22 in the beta subunit gene decreases the intracellular concentration of this subunit and the rate of its synthesis. At the same time the concentration and the rate of beta subunit synthesis is increased. These suggest the compensatory activation of the RNA polymerase operon that takes place under the conditions of shortage of one of the subunits. Reversions as well as more effective suppression of ts22 amber mutation, achieved by streptomycin addition, substitution of su2 by sul, or by specific mutations, result in a rise of beta and drop of beta subunit concentration and synthesis in ts22 mutant. TsX missense-mutation in the beta subunit gene alters the properties of the enzyme increasing, at the same time, the concentration and the rate of synthesis of both beta and beta subunits, particularly at a nonpermissive temperature. This points to an inversely proportional relationship between the rate of synthesis of RNA polymerase subunits and the total intracellular activity of the enzyme. Extra subunits are rapidly degraded in ts22 and tsX mutants. The whole complex of our data and those of others suggest that the regulation of the synthesis of RNA polymerase subunits is accomplished by interaction of a negative and a positive mechanisms of regulation which include not only activators and repressors but the enzyme itself as well.


Cis-dominant regulatory mutations affecting the formation of glucose-repressible alcohol dehydrogenase (ADHII) in Saccharomyces cerevisiae. The formation of ADHII in Saccharomyces cerevisiae is regulated by carbon catabolite repression. There are two genes involved in the formation of ADHII: ADR2, the structural gene as identified by electrophoretic variants and ADR1, possibly a regulatory gene. A new genetic element involved in the regulation of ADHII was identified by three allelic mutants insensitive to strong glucose repression. They were called ADR3c (wild type designation ADR3) and found to be tightly linked to the structural gene, ADR2. The alcohol dehydrogenase found in ADR3c mutants could not be distinguished electrophoretically from the ADHII of the glucose-sensitive wild type, ADR3. Dominance relations between ADR3c and ADR3 were established in diploids heterozygous for ADR3 and the two alleles of ADR2 (ADR2-S: slow ADHII, ADR2-F: fast ADHII). During growth on 10% glucose, an ADR3c adr2-F/ADR3 ADR2-Sheterozygous diploid formed only the fast ADHII variant wheras an ADR3c ADR2-S/ADR3 ADR2-F heterozygote produced only the slow form. This was taken as evidence of the cis-dominance of all ADR3c alleles. The cis-effect of ADR3c was also demonstrated in glucose-derepressed diploids. The ADR3c mutations do not only cause glucose-insensitive ADHII frmation, but also reduce the activity of the adjacent structural gene during derepression. Thus ADR3c alleles were considered to be controlling site mutations. No pleiotropic effects were observed on the formation of enzymes related to the function of ADHII. An adr1 ADR2 ADR3 single mutant did not form ADHII. In contrast to this, an adr1 ADR2 ADR3c double mutant formed ADHII at a similar level as double mutant formed ADHII at a similar level as an ADR1 ADR2 ADR3c mutant. This showed that ADR3c was epistatic over adr1 (previously suggested as a positive regulatory gene). From this it was concluded that ADR1 is the fact a positive regulatory gene the function of which is required for the expression of the structural gene for ADHII, ADR2. ADR3 is the controlling site for the structural gene ADR2. Mutations at this site, ADR3c, alleviate the requirement for the ADR2 gene product. Adr3c is discussed as a promotor or operator site.


Kinetic properties of ATP phosphoribosyltransferase of Escherichia coli. The reversible reaction catalyzed by ATP phosphoribosyltransferase favors the pyrophosphorolysis of phosphoribosyl-ATP (PR-ATP). The enzyme is inhibited by PR-ATP. To avoid this problem and measure with confidence initial rates of the transferase, we have purified more than one hundred fold the enzyme PR-ATP pyrophosphohydrolase, which irreversibly converts PR-ATP to PR-AMP. Using this coupled assay, we report on substrate kinetics and histidine inhibition studies of ATP phosphoribosyltransferase of Escherichia coli. 1. In the absence of histidine the variation of initial velocity as a function of ATP or phosphoribosyl pyrophosphate (PRPP) concentration, follows Michaelis-Menten kinetics, with ATP inhibiting at high concentrations. In the presence of histidine a change from hyperbolic to sigmoidal kinetics is observed. 2. Apparently AMP acts as a competitive inhibitor of ATP. 3. The bisubstrate kinetics gives a pattern of parallel lines, suggesting a double displacement mechanism. 4. The inhibition by histidine appears not to be cooperative or perhaps slightly negatively cooperative.


[Combination of CPPB with IPPV (author's transl)]. A combination of CPPB and IPPV has been used successfully in our hospital for therapy of children with IRDS, when their spontaneous breathing under CPAP was not sufficient and to get children progressively used to spontaneous respiration after prolonged periods of controlled ventilation. The Assistor 644 and Servoventilator 900 respirators are not equipped for the combination of CPPB and IPPV. We describe the modifications of both respirators which we introduced to be able to use them for CPPB alone as well as for the combination of CPPB with CPPV.


[Immunofluorescence and immunoelectron microscopic study of changes occurring in secondary reaction of popliteal lymph nodes in young and old rats]. A comparative study of the secondary reaction of popliteal lymph nodes in young and adult rats was carried out. In one group of experiments secondary reaction was induced by bovine serum albumin (BSA), in the other one by peroxidase from horseradish. Antigen was administered with Freund adjuvant. It was established that the index of popliteal lymph nodes in a secondary reaction induced by BSA does not change with the increasing age. The incidence of antibody-producing cells in young and adult rats is the same. In the cytoplasma and mitochondria of the antibody-producing cells of the adult animals degenerative changes were observed. In the secondary reaction brought about by peroxidase intracytoplasmatic localization of the antibody in the young and adult animals did not reveal any differences.


[Block-impregnation technic for the histological demonstration of chloride ions]. Authors worked out a new method for the histological demonstration of chloride ions by modifying old techniques. Unfixed, fresh tissue pieces are treated with silver nitrat, then embedded in paraffin. Chloride ions present in the tissue react with silvernitrate, thus forming silver chloride. Silver salts of other anions present in the tissue can be eliminated with weak solution of nitric acid, thus silver precipitate formed by reduction of silver chloride indicate only the localization of chloride ions. This method seems to be suitable for the demonstration of chlorid ions in the parietal cells of the stomach and for the lokalization of reabsorbed chloride ions in the renal tubules.


Formaldehyde induced DNA-protein crosslinks in Escherichia Coli. Exposure of Escherichia coli to low doses of formaldehyde induces interstrand cross-links in the cellular DNA, at least 50% of which involve protein "bridges" between the DNA strands. The biological importance of these cross-links is suggested by both the high yield of formation and by the inability of some sensitive repair deficient mutants to completely remove cross-links and bound protein from the DNA during post treatment incubation.


Partial suppression of the LexA phenotype by mutations (rnm) which restore ultraviolet resistance but not ultraviolet mutability to Escherichia coli B/r uvr A lexA. In Escherichia coli, lexA mutations eliminate expression of UV-inducible functions, causing pleiotropic effects which include sensitivity to ultraviolet (UV) light and loss of UV mutability. Selection for UV resistance, after 5-bromouracil (BU) treatment of E. coli B/r uvrA lexA-102, has yielded derivatives more resistant than lexA but still refractory to UV mutagenesis. The mutation responsible for the UV-resistant UV-nonmutable phenotype (rnm) is cotransducible with malB to about the same extent as is lexA-102 and is tightly linked to lexA-102 in at least one strain. The rnm mutation may therefore be an intragenic partial suppressor of the LexA phenotype. In addition to increased UV resistance and lack of UV mutability, rnm strains show improved ability to perform postreplication repair and to control postirradiation DNA degration compared to the lexA parent. We ascribe the properties of rnm mutants to their having reacquired control of Exonuclease V activity without having reacquired UV-inducible error-prone postreplication repair. We relate our results to current interpretations of UV mutagenesis and to models of coordinate regulation of UV-inducible functions.


The detection of monosomic colonies produced by mitotic chromosome non-disjunction in the yeast Saccharomyces cerevisiae. A diploid yeast strain, D6 is described which monitors mitotic non-disjunction by the phenotypic expression of a set of coupled and recessive markers flanking the centromere of chromosome VII. These markers are not expressed in the heterozygous condition prevailing in D6. The left arm of chromosome VII carries a tightly centromere linked marker, leu1 (leucine requirement), distal to leu1 in this order: trp5 (tryptophan requirement), cyh2 (recessive resistance to cycloheximide) and met 13 (requirement for methionine). The right arm is marked with ade3 (simultaneous requirement for adenine and histidine). D6 is homozygous for ade2 and consequently, forms red rather than the normally white colonies. It shows no requirement for the above amino acids and it is sensitive to cycloheximide. Unmasking of all the markers on chromosome VII leads to colonies that are white because ade3 sets a block preceding the ade2 block (which causes the accumulation of a precursor of the red pigment), they require leucine, tryptophan and methionine, and grow on media with cycloheximide. Cells are plated on a cycloheximide medium where red and white colonies are formed. Colonies of spontaneous origin were tested. The majority of the white colonies expressed all the recessive markers whereas only few of the red colonies expressed all the markers on the left arm of chromosome VII. Basically expression of recessive markers on both sides of the centromere can be explained as a result of two coincident events of mitotic crossing over. However, the frequency of colonies expressing centromere linked leu1 was 14 times higher among the white types than the red ones. This suggested that the white, cycloheximide resistant, leucine requiring colonies arose by mitotic non-disjunction and not only by two coincident mitotic crossing over events. Presumptive spontaneous monosomic segregants were placed on sporulation medium. Only 8 out of 30 isolates sporulated, which showed that these eight segregants were diploid at the time of sporulation. They could have arisen by two coincident crossover events or through restoration of a normal disomic condition after non-disjunction had occurred. The genetic data thus leaves us with only its statistical argument in favour of non-disjunction. Further confirmation of monosomic nature of the white cycloheximide resistant colonies was provided by the estimates of their DNA contents. Compared to the stock wild type diploids the presumptive monosomics showed a reduction in DNA content. We have utilized D6 to investigate the possible induction of mitotic non-disjunction after treatment with gamma rays, heat shock at 52 degrees C and ultraviolet irradiation. In all cases white, cycloheximide resistant colonies were produced at levels significantly higher than that found in untreated cultures. In order to detect the production of monosomic cells, treated cultures were grown for 48 h in non-selective medium after exposure to allow for "expression" of the monosomic condition.


[Conditions for specific oligoribonucleotide binding with E. coli RNA-polymerase]. RNA polymerase of E. coli (EC 2.7.7.6) is able to bind certain oligoribonucleotides with the length greater than or equal to 5 from the corresponding isoplith mixtures (Knorre V.L., Vasilenko S.V., Salganik R.I., FEBS Letters 30, 229, 1973). It has been shown in this study that all pentaribonucleotides able to be bound by RNA polymerase can be extracted from the random mixture by the enzyme saturation procedure. Loosely and tightly bound pentaribonucleotides subfractions were isolated and each was separated by chromatography into 3-4 isopliths. Blocking of the enzyme SH groups by p-chloromercurium benzoate (10(-3) M) and denaturation by urea (6.3 M) prevent formation of the enzyme-pentaribonucleotides complexes. Complexes are destroyed by heat denaturation. Removal of sigma-subunit does not influence the enzyme capacity for pentaribonucleotides binding.


On the lack of host-cell reactivation of UV-irradiated phage T5. I. Interference of T5 infection with the host-cell reactivation of phage T1. UV-irradiated phage T5, in contrast to T1, T3 and T7, fail to display host-cell reactivation (HCR) when infecting excision-repair proficient Escherichia coli cells. Possible causes of this lack of HCR (which T5 shares with the T-even phages) have been investigated by studying HCR of T1 under conditions of superinfection by T5. Repair-proficient B/r cells were infected at low multiplicity with UV-irradiated phage T1 in the presence of 1.8 mg/ml caffeine and were superinfected after 15 min with heavily UV-irradiated T5 amber mutants at highly multiplicity. The caffeine, which is later diluted out, prevents any T1 repair prior to T5 superinfection, and UV (254 nm) irradiation of T5 with 144 J/m2 reduces the ability of this phage to exclude T1, thus permitting a reasonable fraction of the mixedly infected complexes to produce T1 progeny. Under these conditions, T5 superinfection causes loss of HCR in about 90% of the T1-producing complexes. Superinfection with unirradiated T5 likewise inhibits HCR of T1, but superinfection with irradiated T3 (a host-cell reactivable phage) does not. This indicates that the observed HCR inhibition of T1 results from T5 infection rather than from competition of irradiated foreign DNA for the excision-repair enzymes of the bacterial host. Employment of appropriate T5 amber mutants has shown that "first-step transfer" (FST) of T5 DNA (involving only 8% of the T5 genome) is sufficient for HCR inhibition, but that transfer of the remainder DNA in addition inhibits a previously described minor T1 recovery process. HCR inhibition of T1, and thus presumably lack of HCR in T5 itself, is ascribed to a substance which is produced either post infection by a gene located in the FST segment of the T5 genome, or which is transferred from extracellular T5 together with the FST DNA.


On the lack of host-cell reactivation of UV-irradiated phage T5 II. Further characterization of the repair inhibition exerted by T5 infection. Experiments reported in the preceding paper [4] had shown that host-cell reactivation (HCR) of UV-irradiated phage T1 in excision-repair proficient Escherichia coli cells is inhibited by superinfection with phage T5. Theoretical considerations have led to predictions concerning the dependence of repair inhibition on the multiplicity of superinfecting T5 phage and on the UV fluence to which they were exposed. These predicitions have been supported by experimental results described in this paper. The fluence dependence permitted calculation of the relative UV sensitivity of the gene function responsible for repair inhibition; it was found to be about 2.3% that of the plaque-forming ability of phage T5. The T5-inhibitable step in excision repair occurs early in the infective cycle of T1. Furthermore, experiments involving the presence of 400 mug/ml chloramphenicol showed that HCR inhibition of T1 is caused by a protein produced after the FST segment of T5 (i.e. the first 8% of the T5 genome) has entered the host cell. A previously described minor T1 recovery process, occurring in both excision-repair-proficient and -deficient host cells, is inhibited by T5 infection due to a different substance, which is most likely associated with the "second-step-transfer" region of T5 DNA (involving the remainder of the genome). Superinfection with T4v1 phage resulted in HCR inhibition of T1, resembling that observed after T5 superinfection. The discussion of these results suggests that inhibition of the bacterial excision repair system by T5 or T4 infection occurs at the level of UV-endonucleolytic incision, and that lack of HCR both in T-even phages and in T5 can be explained in the same manner.


Intragenic mutational spectra and hot spots. In this review we outline the various factors which may contribute to the non-randomness of intragenic mutational spectra and the occurrence of hot spots. These factors include sample size limitation, particularly for sites of low mutability, and possible regions of low recombination potential. In addition, the nature of the gene product places great restraint on the detectability of either frameshift and premature chain-terminating mutations on one hand, or of the majority of missense mutations on the other. The nature of the Genetic Code itself also limits the mutational spectrum in so far as specific base pair substitutions lead only to a limited number of detectable amino acid replacements. Mutational hot spots may be a special example of the influence of neighbouring base pairs in the mutability of any given base pair. This is apparently true for frameshift mutations which tend to occur in runs of repeated base pairs or base pair doublets. Neighbouring base effects could operate not only at the level of initial reactivity with a mutagen, but also subsequently at the levels of DNA repair, recombination or replication. In some cases rare or modified bases may be responsible for neighbour effects. We suggest specific experimental approaches which seem likely to aid in the elucidation of these problems.


UV-induced lethal sectoring and pure mutant clones in yeast. The induction of lethal sectoring and pure mutant clones by ultraviolet light has been studied in a homogeneous G1 population of Saccharomyces cerevisiae grown in a normal growth medium. At the lowest UV dose of 250 ergs, which corresponds to a shoulder in the survival curve, all mutants appeared as pure clones. At higher doses the frequency of mosaic mutants progressively increased. These results indicate a relationship between the highest frequency of complete mutants and the maximum repair activity. In addition, the frequency of lethal sectoring at all doses tested was too low to account for the origin of pure mutant clones.


Enhancement of base pair substitution induced by alkylating mutagens in simulated hyperbaric diving environments. The effect of simulated saturated diving environments on mutagenicity was investigated using two histidine auxotrophs (hisG46 and hisTA1950 derived by Ames from Salmonella typhimurium LT2) exposed to several chemical mutagens. In agar diffusion tests with impregnated paper discs, 68 atm of normoxic supporting gases (containing 0.2 atm O2) reduced the number of histidine revertants of auxotrophs exposed to N-methyl-N'-nitro-N-nitrosoguanidine (NTG) and two other alkylating agents. The effect was induced in increasing order by helium, a mixture of neon and helium, nitrogen and argon. The effect of the gases on the growth of the two strains was small and did not explain the reduction of revertant recovery. On the other hand, it was shown that NTG in concentrations of 0.6 to 250 mug/ml was significantly more lethal for the hisG46 strain under 68 and 136 atm than at 1 atm. Revertant recovery was similarly related in both conditions. The maximal number of revertants, approx. 2.6 X 10(4), was obtained at 136 atm when the concentration of NTG was 0.6--1.25 mug/ml and at 1 atm when the concentration of NTG was 5--10 mug/ml. A comparable hydrostatic environment did not affect revertant recovery. The most plausible interpretation of these results is that hyperbaric environments accelerate the rate of intracellular accumulation of NTG, which is manifest in greater mutagenicity at the lower concentrations and greater lethality at all concentrations.


Mutagenicity of atrazine: a maize-microbe bioassay. A water-soluble extract from maize plants grown in the presence of atrazine contained a mutagenic agent(s) when tested on strains of yeast. Atrazine alone or control plants not treated with atrazine did not express mutagenic properties. The reversion frequency at the waxy locus in pollen grains from plants grown in atrazine was higher than in control plants. We suggest that atrazine may be degraded by the plant into environmental mutagenic agents.


Pathology of goats and sheep experimentally infected with Mycoplasma mycoides var. capri. Twenty goats and four sheep were experimentally infected with Mycoplasma mycoides var. capri and examined histopathologically. Death occurred or a moribund state developed in most of them within a week after parenteral inoculation with mycoplasmas. Histopathological examination revealed severe serofibrinous inflammation on the serosa and interstitial connective tissue at the site of inoculation. Marked inflammatory edema with infiltrating polymorphs was found in the early stage of infection. As the infection progressed, the lesion became a cellulitis; necrosis, sometimes with focal liquefaction, was a constant feature. Organization with infiltration by lymphocytes and histiocytes had begun in some tissues. Acutely infected organs had evidence of systemic involvement. Lesions included splenitis, lymphadenitis, meningitis, metastatic foci in the intestine and urinary bladder, and parenchymatous degeneration in the liver, heart, and kidneys. Mycoplasmas were isolated from many tissues of critically ill animals. Other goats which had received mycoplasmas by instillation escaped severe illness. Even so, mycoplasmas were isolated from one or two of their tissues at necropsy. The great variation in clinical and pathological response was apparently dependent upon the route of inoculation. Recovery of mycoplasmas from two contact control goats which remained healthy is suggestive of the clinically undectable carrier state. As other workers have reported, the clinical and pathological changes in sheep were similar to those in parenterally inoculated goats.


Competition of some biogenic amines for uptake into synaptic vesicles of the striatum. Synaptic vesicles were isolated from the caudate nucleus of the pigs by differential centrifugation and incubated with labelled monoamines in the absence or in the presence of ATP-Mg(2+). Addition of ATP-Mg(2+) enhanced the uptake of (14)C-dopamine into the vesicles. Serotonin competitively inhibited the ATP-Mg(2+)-dependent uptake of (14)C-dopamine without influencing the uptake which took place in the absence of ATP-Mg(2+). Likewise, dopamine caused a dose-dependent inhibition of the ATP-Mg(2+)-dependent uptake of (14)C-serotonin without inhibiting the uptake in the absence of ATP-Mg(2+). Incubation of the vesicles with equal concentrations of(3)-dopamine and (14)C-serotonin revealed that the presence of the one amine competitively inhibited the ATP-Mg(2+)-dependent uptake of the other. Tyranimine competitively inhibited the ATP-Mg(2+)-dependent uptake of (14)C-dine, (14)C-serotonin and (14)C-noradrenaline into the vesicles; the uptake of the amines which took place in the absence of ATP-Mg(2+) was not impairedby tyramine. Analysis of the amine uptake by the ABC test showed that a mutual inhibition exists between dopamine and serotonin for the uptake into the synaptic vesicles. GABA did not influence the uptake of (14)C-dopamine either in the absence, or in the presence of ATP-Mg(2+)...


Intractable renovascular hypertension in an adult recipient of a pediatric cadaveric renal transplant. Renovascular hypertension developed in an anephric 37-year-old patient after he received a cadaveric renal transplant from a 2-year-old donor. Despite adequate homograft function, a transplant nephrectomy was perfomed because of intractable, lifethreatening hypertension. There was relative stenosis throughout the course of the transplanted renal artery. Pathologic examination of the kidney did not demonstrate evidence of technical failure or immunological or hypertensive damage. Atrophic changes in the media of the renal artery may have resulted from radiation damage. The hypertension appears to have been caused by disproportionate growth between the parenchyma in the hypertrophying pediatric homograft and its renal artery.