PERSISTENCE OF STREPTOCOCCAL GROUP A ANTIBODY IN PATIENTS WITH RHEUMATIC VALVULAR DISEASE

Antibody levels to streptococcal Group A and A-variant carbohydrates were determined using a radioactive immune precipitation technique on patients with rheumatic fever, with and without valvular disease, on patients with post-streptococcal acute glomerulonephritis, and on age-matched controls. During the acute phase of the above illness, the means of the antibody levels to both carbohydrate antigens were equally elevated and were significantly higher than the normal controls. When Group A antibody levels were determined on sera obtained at intervals of 5–12 months and 1–5 yr after the acute illness) it was found that the antibody levels declined within the normal range at the 5–12 month interval in patients with glomerulonephritis as well as in patients with rheumatic fever in whom no valvular involvement had complicated the disease, i.e., patients with pure Sydenham's chorea. However, in patients with rheumatic valvulitis, who had been on penicillin prophylaxis after the last acute episode, the A antibody level showed little decline from the level obtained during the acute illness. The elevated antibody level in patients with rheumatic valvulitis, including patients with Sydenham's chorea with valvulitis, persisted for periods of at least 1 yr and up to 20 yr after the last acute attack. The pattern of the decline of the antibody levels to the A-variant carbohydrate as well as of the antibody titers to the other streptococcal antigens tested, ASO and anti-DNase B, was similar in all patients studied regardless of the presence of valvular disease. These findings suggest that prolonged persistence of the Group A antibody is a phenomenon peculiar to patients with rheumatic valvular disease. Whether this persistence is involved in the pathogenesis or is an outcome of the valvular disease remains to be determined.     

PATHOGENESIS OF CHRONIC DISEASE ASSOCIATED WITH PERSISTENT LYMPHOCYTIC CHORIOMENINGITIS VIRAL INFECTION : I. RELATIONSHIP OF ANTIBODY PRODUCTION TO DISEASE IN NEONATALLY INFECTED MICE

Mice infected shortly after birth with lymphocytic choriomeningitis (LCM) virus are not immunologically tolerant, although they carry the virus throughout life. These LCM carrier mice make anti-LCM antibody, which apparently complexes with viral antigen in the circulation and these complexes accumulate in the glomeruli. LCM carrier mice of different strains vary significantly as to concentration of detectable infectious virus in their tissue, amount and time of appearance of anti-LCM antibody, and development of an associated chronic disease. The chronic disease consists primarily of glomerulonephritis, focal hepatic necrosis, and disseminated lymphoid infiltrations. LCM carriers of the SWR/J strain contain high tissue concentrations of virus, considerable anti-LCM antibody detectable in the glomeruli by 3 wk to 2 months of age and develop chronic disease within the first 2–3 months of life. In contrast, C₃H strain LCM carriers contain 1/1000 as much infectious virus, less detectable anti-LCM antibody, and have not, over a 24 month observation period, developed any detectable disease. B10D2 old and new carrier mice with intermediate amounts of virus develop chronic disease during the latter half of the first year of life. The pathogenesis of the glomerulonephritis of chronic LCM disease is apparently related to the formation of circulating virus-antibody complexes which are trapped in the glomerular filter. There is no evidence for direct glomerular injury by the virus nor for any autoimmune response by the host.     

PERIOD OF INFECTIVITY OF PATIENTS WITH HOMOLOGOUS SERUM JAUNDICE AND ROUTES OF INFECTION IN THIS DISEASE

1. Pooled specimens of serum obtained from 3 human volunteers three-fourths through their respective 56, 66, and 70 day incubation periods of homologous serum jaundice produced the disease in 1 out of 4 human volunteers following parenteral inoculation. 2. Serum specimens obtained from these same 3 patients during the acute, pre-icteric phase of their homologous serum jaundice produced the disease in 3 out of 4 human volunteers following parenteral inoculation. 3. These same sera, proven to be infectious by parenteral inoculation, failed to produce disease when ingested by 10 other human volunteers. 4. Pooled specimens of serum obtained in the convalescent phase (28 to 32 days after onset) of these 3 patients failed to produce apparent infection when inoculated parenterally into 5 human volunteers. 5. Pooled specimens of feces of 3 patients obtained in the acute phase of homologous serum jaundice, when virus was proven to be in the serum, were not demonstrably infectious when fed to 6 volunteers. 6. These findings are slightly different from those encountered in a similar study with infectious material from cases of infectious hepatitis.     

INFECTIOUS MYXOMATOSIS OF RABBITS : STUDIES OF A SOLUBLE ANTIGEN ASSOCIATED WITH THE DISEASE

The soluble antigen of myxoma is a heat-labile protein which has an isoelectric point near pH 4.5 and is precipitated from half saturated solutions of ammonium sulfate. It can be partially purified by methods of differential precipitation based on variations in the pH and electrolyte concentration. Rabbits receiving the labile, soluble substance of myxoma develop homologous precipitins and their serum agglutinates elementary bodies of myxoma, provided the dermal pulp from which the bodies are obtained contains the soluble substance; neutralizing antibodies do not appear, however, and the animals are not resistant to infection with the virus of myxoma. Elementary bodies of myxoma appear to have a heat-stable agglutinogen that operates when brought in contact with serum from animals recovered from myxoma, but little, if at all, when in contact with anti-soluble substance serum.     

A GENERALIZED VISCERAL DISEASE OF GUINEA PIGS,ASSOCIATED WITH INTRANUCLEAR INCLUSIONS

A spontaneous generalized visceral disease of guinea pigs, characterized by the presence of intranuclear inclusion bodies of the herpes type, is described. The possible relation of this disease to the salivary gland virus infection of guinea pigs is discussed.     

THE DEVELOPMENT OF A DRUG DOSAGE ADJUSTMENT SERVICE FOR PATIENTS WITH RENAL IMPAIRMENT

The dosage of nephrotoxic drugs such as gentamicin should ideally be adjusted when they are administered to patients with varying degrees of renal impairment. Such an adjustment of dosage should be estimated with a knowledge of the plasma levels of the drug. Until regular monitoring of drug levels in plasma is routinely available, the use of nomograms which utilize pharmacokinetic data quoted in the literature would provide dosage regimens tailored to suit the individual need of the renal patients. A service for dosage adjustment of nephrotoxic drugs has been provided in the Macclesfield Health District since December 1977 and has been well received by prescribers in the hospitals. The use of a flow chart scheme for the adjustment of individual dosage for routine use is described. About 80% of the requests were for dosage adjustments of gentamicin in renal failure. It is advocated that such a service can be provided by hospital pharmacists without difficulty and should be encouraged as part of the patient services.     

THE RENAL LESION ASSOCIATED WITH HEMOGLOBINEMIA : II. ITS STRUCTURAL CHARACTERISTICS IN THE RAT

Histological studies have been performed on experimental acute renal failure induced by intravenous injection of hemoglobin in rats. These have been correlated with alterations in renal excretory function, assessed by the measurement of inulin clearance, at various stages of the lesion. The most prominent morphological changes during the first 24 hr after hemoglobin injection, when inulin clearance is most markedly suppressed, are: the presence of hemoglobin within the lumen of small intrarenal vessels, particularly the vasa recta; hemoglobin cast formation involving predominantly the thick ascending limbs of the loops of Henle; and evidence of injury of the epithelium of the proximal tubules and thick ascending limbs. Notably absent during this stage of the lesion are marked tubular dilatation, interstitial edema, and cast formation in the distal collecting ducts. The considerable recovery of function which occurs at 72 hr is accompanied by a marked reduction in involvement of the vasa recta. Standard sections and microdissection reveal many markedly dilated proximal tubules at this stage of the lesion, suggesting obstruction of filtering nephrons. These data have led to a tentative hypothesis regarding the pathogenesis of renal failure in this experimental lesion. It is suggested that renal ischemia and failure of glomerular filtration are the primary factors responsible for the early and severe impairment of renal function, and that these are related to intravascular aggregation of hemoglobin pigment. As this defect recedes, tubular obstruction by hemoglobin casts prevents restitution of excretory function in a variable fraction of the nephrons. The latter accounts for the relatively prolonged, moderate reduction in inulin clearance associated with the late stages of this lesion. These hypotheses form the basis for a continuing study of this renal lesion.     

POPULATION PHARMACOKINETIC STUDY OF GENTAMICIN AND A BAYESIAN APPROACH IN PATIENTS WITH RENAL IMPAIRMENT

A population pharmacokinetic study was conducted on a total of 70 patients receiving gentamicin therapy. The patients included those with normal renal function and those with varying degrees of renal impairment. The parameters studied were the apparent volume of distribution and the plasma clearance of gentamicin. The interindividual variability and the residual variability of those parameters in the different subpopulations were studied according to a statistical model that assumed log normal distribution. Use of the one-way ANOVA test revealed statistically significant differences (P = 0.004) in the population plasma clearance of gentamicin in patients below and above 50 years of age. A linear relationship was established between the plasma clearance of gentamicin and the creatinine clearance in those patients. At the same time, the coefficient of variation of the Clp increased progressively in patients with renal impairment, varying between 28.98% in patients with a ClCR greater than 100 ml/min and 76.53% in patients with a ClCR between 20 and 60 ml/min. The results obtained in the population study were later applied to drug monitoring in 23 patients with varying degrees of renal function and who received gentamicin therapy with different doses. The residual variability of the population allowed us to calculate a weighting factor (FF) between the experimental and the population data using Bayesian fitting. The weighting factor was 0.89 in patients with normal renal function and 0.80 in patients with renal impairment. Statistical comparison of the pharmacokinetic parameters obtained from the populational data, non-linear regression and the Bayesian method using revealed differences in the values for the apparent volume of distribution obtained with the two methods.(ABSTRACT TRUNCATED AT 250 WORDS)     

INFECTIOUS MYXOMATOSIS OF RABBITS : II. DEMONSTRATION OF A SECOND SOLUBLE ANTIGEN ASSOCIATED WITH THE DISEASE

A second soluble antigen, separable from the virus, occurs in extracts of infected skin and in the serum of rabbits acutely ill with infectious myxomatosis. Like the first antigen (A), the second (B) is heat labile and has certain characteristics of a globulin. The two antigens precipitate in different concentrations of ammonium sulfate and can be separated by this method. Neither of the antigens after being heated at 56°C. precipitates in the presence of specific antibody but each is capable of inhibiting the activity of its antibody.     

EXPERIMENTAL STUDIES IN ACUTE RENAL FAILURE : II. FINE STRUCTURE CHANGES IN TUBULES ASSOCIATED WITH RENAL FAILURE INDUCED BY GLOBIN

When purified human globin is injected intravenously into rats it produces acute renal failure characterized by tubular casts and oliguria. The globin is identifiable within vesicles and channels in the cytoplasm of the proximal tubules, through which it passes from lumen to basal side with no apparent serious effect on the cells. When a very minimal amount of globin is taken up by cells of the distal limb of Henle's loop or distal tubules (lower nephron), a markedly deleterious effect is apparent and the cells die within a short time. The mixture of cell debris and precipitated globin forms plugs within the confines of the basement membranes of the former distal limbs and distal tubules. After a number of lower nephrons are plugged a disruption of proximal tubules is found, which apparently results from the effect of back pressure in the obstructed nephrons. We suggest that any amount in excess of a low threshold of globin, either alone or combined with heme or related material, has a toxic effect on lower nephron cells. Once initiated, the toxic effect is not reversible and the resulting plug of debris and precipitate will occlude the lumen. If a sufficient number of nephrons are made non-functional the animal becomes anuric; otherwise it is oliguric. A high rate of urine flow will protect against the excess absorption of material and thus against acute renal failure.     

Infection and Immunosuppression: A STUDY OF THE INFECTIVE COMPLICATIONS OF 75 PATIENTS WITH IMMUNOLOGICALLY-MEDIATED DISEASE

We have studied the infective complications in a group of 75patients with immunologically-mediated disease who requiredhigh dose immunosuppression. There were 22 patients with anti-glomerularbasement membrane antibody disease, 19 patients with systemiclupus erythematosus, 18 with Wegener's granulomatosis and 16patients with other forms of systemic vasculitis. The infection rate was 3.69 infections/patient, or 0.74 infections/patient/weekof immunosuppression. Bacteria were the commonest infectingorganisms (76.1 per cent); serious opportunist viral and fungalinfections were less frequent (10.7 per cent) but opportunistpneumonias were an important cause of death. Sixteen patientsdied (21 per cent) and in 10 of these (62.5 per cent) deathwas considered to be primarily due to infection. Analysis of six aspects of host susceptibility to infection(age, renal function, dose of prednisolone, cyclophosphamideand azathioprine, and number of plasma exchanges) revealed nosingle factor as predisposing to infection in the whole group,but in 23 patients who suffered severe infective complications,renal impairment and increasing doses of prednisolone were associatedsignificantly, particularly in combination (p = 0.06). Cyclophosphamidewas associated with infection only in the presence of neutropenia,which was rare (13 infections in nine patients). The durationof plasma exchange was not related to the frequency of infection. Fifty patients needed an arteriovenous shunt to provide vascularaccess for haemodialysis or plasma exchange, and septicaemiaoccurred in 13; only two episodes of septicaemia were seen inpatients without a shunt.     

冠心病运动前后血液流变学指标变化的研究

本文观察了３８例冠心病患者运动前后血液流变学习指标的变化，并与３０例正常人进行对照，结果表明：冠心病组在运动前后血液流变学指标改变具有高度显著性，特别是全血比粘度和纤维蛋白原．而对照组运动前后血液流变学指标改变无显著性。两组间运动前血液流变学指标差异无显著性，运动后的差异具有显著性．提示运动前后测定血液流变学指标有助于冠心病的早期诊断．     

THE RENAL LESION ASSOCIATED WITH HEMOGLOBINEMIA : I. ITS PRODUCTION AND FUNCTIONAL EVOLUTION IN THE RAT

A method is presented for the production of a reproducible and reversible renal lesion in the rat by the intravenous injection of a relatively small amount of homologous hemoglobin (40 mg/100 g body weight). Production of the lesion is dependent on prior water deprivation and its severity is related to the degree of dehydration. Ether anesthesia, at the time of hemoglobin injection, predisposes to a severe and reproducible functional defect in the dehydrated rat. In contrast, injection of hemoglobin during pentobarbital anesthesia results in a significant lesion only sporadically. The functional evolution of the lesion has been characterized by inulin clearance measurements. Functional impairment occurs abruptly, within 1 hr after hemoglobin injection, and persists unchanged over the ensuing several hours. Some increase in inulin clearance rate is usually observed at 24 hr after injection, but severe functional impairment persists. Between 24 and 72 hr, a considerable increase in inulin clearance rate occurs, so that only moderate restriction of excretory function is present at the latter time. A further moderate increase in inulin clearance rate is apparent at 7 days after hemoglobin injection, but some reduction in function. persisted in all rats studied at this time. Hemoglobinuria is slight or inapparent in animals manifesting the most marked depression of excretory function, indicating that a severe renal lesion may exist in the absence of visible urinary pigment. Hemoglobinemia is evanescent at the dosage used in this study. These observations suggest that clinical acute renal failure secondary to hemoglobinemia may readily go unrecognized and that this may be a more frequent association than is now appreciated.