Drug protein binding and the nephrotic syndrome. A reduction in plasma albumin concentration, as seen in patients with the nephrotic syndrome, is usually associated with a decrease in plasma protein binding of highly bound drugs. Therefore, the fraction of the unbound drug increases, but the absolute free concentration remains essentially unchanged due to a compensatory reduction in the steady state total plasma concentration. With phenytoin, protein binding and plasma albumin concentration are closely related, so that the degree of binding can be estimated without specific binding techniques. To be able to correctly interprete plasma levels the degree of protein binding should be known, since a reduced total concentration may be fully effective, if the free drug fraction is increased in hypoalbuminaemic patients. Although the mean steady state plasma concentration of highly bound drugs is not affected in the nephrotic syndrome, a greater fluctuation of the unbound level is observed between doses, offering a possible explanation for the increased incidence of toxicity in hypoalbuminaemic patients. As a consequence, shorter dosing intervals of these drugs seems to be advisable, rather than a reduction in the total daily dose. Reduced protein binding is accompanied by an increase in the total plasma clearance which is a function of the elimination rate constant and the volume of distribution.


Bioavailability of drugs: the digoxin dilemma. The absorption of oral digoxin preparations has been a topic of much concern during the last 5 years. The completeness of digoxin absorption is proportional to the area under the serum concentration time curve and to the urinary excretion of digoxin after single doses. During chronic therapy the completeness of absorption is proportional to these values and also to the steady state serum concentration. Determination of absolute bioavailability of a given digoxin preparation requires a comparative study using intravenous digoxin as a standard. Oral digoxin solutions are incompletely absorbed, but have biological availability greater than or equal to that of tablets. The absorption of digoxin tablets depends upon their dissolution rate which in turn is related to drug particle size. Digoxin tablets with small drug particles have rapid rates of dissolution and can be absorbed as completely as oral solutions. The bioavailability of digoxin from tablets can be influenced by changes in gastro-intestinal motility, malabsorption syndromes, and by co-administration of food or other drugs. New regulations now insure that all marketed digoxin tablet preparations have satisfactory bioavailability. Problems with biological availability at present are unlikely to account for unexpected clinical results during digoxin therapy.


Plasma level monitoring of anticonvulsants. The plasma concentrations of anticonvulsant drugs, and of certain of their biologically active metabolites, tend to be proportionate to the antiepileptic effects of these drugs. Consequently, anticonvulsant drug levels in plasma are monitored to help guide the clinician in managing his patients' epilepsies. In making use of the measurements, the clinician needs to know the relation between plasma level and biological effect for the various drugs. He also needs to have some awareness of simple pharmacokinetic principles. These are important in deciding when plasma levels should be monitored in relation to the patients' clinical state, to the dosage interval, and to change in the dosage of anticonvulsant or other drug. The clinician also requires pharmacokinetic knowledge in altering anticonvulsant drug dosage in his patients, and in interpreting plasma anticonvulsant level data, particularly when the patient is concurrently suffering from non-neurological disease. The ability to monitor plasma anticonvulsant levels has appreciably improved the treatment of epilepsy, but to obtain maximum benefits from the method, both pharmacokinetic insight and clinical wisdom are required.


Computer assisted prescribing of drugs.

Computer assisted prescribing of drugs. Computer programs for drug dosage adjustment may be fixed, adaptive or empirical. The aminoglycoside antibiotic dosage requirements of individual patients are relatively predictable, and it seems to be adequate to assume that volume of distribution is a fixed proportion of body weight and that renal clearance is a fixed proportion of creatinine clearance. This approach has been less successful with digoxin because patient compliance, the proportion absorbed and liver clearance are not yet predictable. Accordingly, adaptive programs have been developed which use feedback from drug concentration measurements to predict the future dosage needs of the patient. When individual needs are known for a large patient group it becomes possible to predict the dosage requirements of a new patient from the same population by empirical methods. Computer programs for dosage adjustment will not be widely used until their scope is increased and objective evidence of clinical benefit is obtained.


The binding of drugs to plasma proteins from patients with poor renal function. Plasma from patients with renal failure has decreased binding of many drugs. The decreased binding of anionic drugs is pronounced and is apparently due to occupation of protein binding sites by non-dialysable endogenous acidic compounds. Organic bases seem to bind normally, particularly if hypoproteinaemia or hypoalbuminaemia are not present. This modification of drug binding to plasma proteind from uraemic patients must be considered when plasma concentrations of acidic drugs are measured.


Drug dosage in renal disease.

Drug dosage in renal disease. Based on the well known linear relationship between the overall drug elimination rate constant and the endogenous creatinine clearance, it is shown how individual drug elimination parameters in patients with renal disease can be estimated from the patient's creatinine clearance or serum creatinine concentration. By means of a simple nomogram the elimination rate fraction is determined which describes the elimination rate of the drug as a fraction of its normal elimination rate constant. Based on the estimated elimination rate fraction the dosage regimen in the patient with renal disease is individually modified according to pharmacokinetic principles. At present the described method can be used with 45 different drugs.


Clinical pharmacokinetics of anticonvulsants. Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended. Primidone may have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone. Ethosuximide. The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended. Diazepam exerts a repid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man. Clonazepam. The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested...


Drugs, diseases and altered gastric emptying. Drugs are usually given orally. They are not absorbed to any extent from the stomach but may be absorbed very rapidly from the small intestine. Thus factors influencing the rate of gastric emptying may alter the rate of absorption of most if not all orally administered drugs. Food, hormones, posture, peritoneal irritation, severe pain, gastric ulcer, diabetes and other metabolic diseases, as well as drugs such as alcohol, anticholinergics, narcotic analgesics, ganglion blocking drugs, antacids and metoclopramide all influence the rate of gastric emptying and they will, in turn, change the rate of absorption of another drug. In most instances, increasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavin, increased gastrointestinal motility is associated with a decrease in the rate of absorption. Delayed drug absorption due to altered gastric emptying usually results in therapeutic failure, especially if the drug has a short biological half-life. At present it is not possible to predict accurately the magnitude and clinical relevance of all drug absorption interactions.


Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. The volume of distribution of a drug (Vd) is a useful pharmacokinetic parameter for relating drug concentration in the plasma to the total amount of drug in the body. Disease-induced changes in Vd may well result in a change in the therapeutic or toxic significance of a given plasma level. For the different factors under consideration, especially plasma protein binding, the weight and the age of the patient plays an important role. Plasma binding of many drugs is lower in patients with renal or liver disease and binding capacity can be decreased in neonates and elderly individuals. Since the heart, liver and kidney are the major organs determining the distribution and elimination of drugs, it is not surprising that alterations in their function will influence the pharmacokinetic properties of drugs. When comparing the Vd in different groups of patients one should use Vd(ss), since this is the only meaningful term as it is independent from elimination processes. Drugs which are strongly bound to plasma constituents (e.g. phenytoin, diazepam) demonstrate an increased Vd in patients with liver or kidney disease, since plasma binding is lowered. A reduced Vd seems to be a general phenomenon associated with renal failure and pronounced changes are most likely for drugs that are eliminated by a renal excretory mechanism (e.g. digoxin). From these disease-induced changes in Vd it follows, that plasma level monitoring should be done more extensively in patients with kidney, liver or heart disease and that arbitrary dosing regimens are only of limited value in these patients. It is also recommended that dosage should be adjusted according to the severity of the disease.


Propranolol disposition in chronic liver disease: a physiological approach. The pharmacokinetics of propranolol can be quantitatively explained on a physiological basis from a knowledge of the effects of four biological determinants: (1) the activity of the drug metabolising enzymes (intrinsic clearance); (2) hepatic blood flow; (3) drug binding, and (4) the anatomical arrangement of the hepatic circulation. Distrubances of all these determinants can occur in chronic liver disease and result in predictable changes in propranolol disposition. These changes, as well as those occurring with other drugs in chronic liver may be explained by 'intact hepatocyte theory' which postulates that the major pathophysiological change occurring in compensated chronic liver disease is a reduction in relatively normally perfused and functioning cell mass with the development of intrahepatic portasystemic vascular shunts.


Pharmacokinetics in the elderly.

Pharmacokinetics in the elderly. The elderly are generally considered to be different from young people in terms of drug response and this applies particularly to quantitative differences. While altered drug handling is a major potential source of difference in responsiveness to drugs, the relative contribution of pharmacokinetics and pharmacodynamics to this difference is not clear. In the present review we have examined the available data on pharmacokinetics in the elderly. In the past, data pertaining to animal models have been extrapolated to man and in the absence of human experimentation these assumptions have tended to hold sway. This is best exemplified by studies on drug absorption. The absorption of actively transported substance may in fact be diminished in the elderly. However, most drugs are absorbed by passive diffusion and the recently available evidence in man indicates that there is no age-dependent change. While definitive data on the effect of old age on drug metabolising ability in animals is available, no direct assessments have been made in man. Many of the studies carried out using drug plasma half-life and clearance assessments are complicated by changes in distribution. This is best illustrated by a definitive study with diazepam, in which marked prolongation of plasma half-life was accompained by an increase in apparent volume of distribution in the elderly. This latter change influences plasma drug clearance and, possibly, drug concentration at its site of action. Thus, the implications for drug effect  of such changes in volume of distribution remain to be clarified. In theory, the rate of elimination of antipyrine should provide a good index of drug metabolising ability. Both plasma half-life and clearance values suggest a decreased in metabolism in the elderly. No other drug has been studied as intensively and the evidence for a diminished metabolism of other drug in the elderly is less definite. Thus, while it is likely that the metabolism of some drugs is imparied in old age, it is not possible at this time to generalise with regard to the effect of age on drug metabolising ability in man. It is also difficult to generalise about age-related changes in plasma protein binding of drugs. With some drugs, binding to plasma protein does not appear to be altered and for two drugs-warfarin and phenytoin, the findings of different investigators conflict. Diminution of glomerular filtration rate, renal plasma flow and associated tubular function with age have been well documented. Drug clearance comparisons between old and young have been carried out for only three renally excreted drugs-digoxin, propicillin and sulphamethizole. With digoxine and sulphamethizole, the evidence is that renal excretion is diminished in the elderly. With propicillin, changes in volume of distribution predominate, resulting in higher plasma levels in the elderly but similar percent recovery in urine...


Pharmacokinetics of the penicillins in man. The purpose of this article is to review and summarise those aspects of the pharmacokinetic behaviour of the penicillins that may be of particular interest to the clinician. While these antibiotics differ markedly in their acid stability and oral absorption, misleading inferences may be drawn from simple inspection of the maximal serum concentrations produced by a given dose administered orally. A more accurate picture emerges when serum protein binding and intrinsic activity of the drugs are taken into account. All of the penicillins are readily and actively secreted by the renal tubles and most are eliminated, almost completely unchanged, in the urine. The majority are excreted in small quantities in the bile, but this is a major route for elimination of nafcillin from the body. Distribution of the penicillins in 'non-specialised' sites is excellent. In contrast, penetration of the central nevous system and eye are poor, and of the prostate, minimal. Inflammation reduces the barries to penetration of these areas. However, quantitative data related to this phenomenon in man are few. Probenecid actively competes with the 'export' pump of the meninges and renal tubular cells. This results in an increase in concentrations of the penicillins in the blood and cerebrospinal fluid. The effect of this agent on active secretion of these antibiotics from the eye and biliary tract is minimal. While elimination of the penicillins from the body takes place largely via renal excretion, penicillin V and oxacillin are extensively degraded as well. In contrast to the situation with respect to 'natural' and 'broad-spectrum' penicillins, the serum half-life of the isoxazolyl congeners and nafcillin is only minimally prolonged in the presence of renal failure. These agents are only weakly haemodialyzable, while the other penicillins are rapidly removed from the circulation by this procedure.


Drug metabolism in thyroid disease.

Drug metabolism in thyroid disease. Thyroid dysfunction can influence the physiological disposition of drugs. Depending on the pharmacokinetic properties of the individual drug, changes in the rate of metabolism ranging from profound to moderate or negligible have been observed. Since renal function is also influenced by thyroid disease, changes in renal elimination of drugs which are excreted in the urine mainly as unchanged drugs have to be considered as another reason for altered drugs disposition in thyroid disease. In patients with thyrotoxicosis lower, and in patients with myxoedema, higher, digitalis plasma levels have been observed. The altered disposition of cardiac glycosides in thyroid dysfunction can be attributed to changes in renal elimination and metabolism. These findings may be the kinetic correlate for the clinical observation that larger than the usual dose of digitalis is required in thyrotoxic patients and lower in hypothyroid patients. Antipyrene half-lives are very much shortened during hyperthyroidism and prolonged appreciably during hypothyroidism. The alterations in the disposition of these drugs seen during thyroid dysfunction can be ascribed to changes in its rate of metabolism which is controlled by the levels of circulating thyroid hormones. N-demethylation of aminopyrine is depressed both in hyper- and hypothyroid patients as compared with euthyroid subjects. Changes in the half-life of this drug were observed only during hypothyroidism. The physiological disposition of the antithyroid drug propylthiouracil is not changed during thyrotoxicosis. A decrease in plasma half-life of methimazole is however, observed during hyperthyroidism, whereas in hypothyroid patients half-life is increased. The few data available so far do not allow general prediction of how thyroid disease could alter drug metabolism in man.


Clinical pharmacokinetics of levodopa in parkinson's disease. Although levodopa has provided a major advance in the treatment of parkinsonism, its maximum benefits have not yet been realised, in part because of its complicated pharmacokinetics. This review summarises that available pharmacokinetic data involving levodopa, especially as it relates to therapeutic response of parkinsonian patients. A large number of factors, including protein intake, gastric emptying time, pyridoxine ingestion, and dopa decarboxylase activity, affect plasma levels of levodopa attained following oral administration of this drug. Other variables influence the rate of brain uptake of levodopa from the blood. Even so, plasma levodopa concentration correlates significantly with dosage size in a large parkinsonian population and also coincides with therapeutic response in many, but not all, patients. Therefore, in certain instances, valuable information may be derived by correlating clinical response with plasma levodopa concentration. Cerebrospinal fluid levels of homovanillic acid, a major metabolite of dopamine, may have some value in predicting clinical response to levodopa. This relationship, however, has not been firmly established. Concentration of homovanillic acid or levodopa in body fluids may also be closely related to certain adverse side-effects, including abnormal involuntary movements, gastric discomfort and psychiatric disturbances. Evidence indicates that a clearer understanding of levodopa pharmacokinetics may improve the clinical management of parkinsonism.


Drug interactions and clinical pharmacokinetics. Some drugs influence the gastro-intestinal absorption, distribution , metabolism or renal excretion of other drugs, i.e., processes involved in pharmacokinetic interactions. The clinical consequences of pharmacokinetic drug-drug interactions will be either an increase or a decrease in known therapeutic or toxic effects of the interacting drug. In order to evaluate the importance of drug interaction affecting gastro-intestinal absorption, it is necessary to distinguish between interactions which alter the rate of absorption of another drug and those which alter the amount of drug absorbed. Many drugs displace other drugs from their protein binding sites in vitro. This may cause an increase in the pharmacological effect of the displaced drug. However, much discrepancy exists between in vitro findings. In some cases, the enhanced effect only seems to be a temporary phenomenon. The degree of protein binding and the size of apparent volume of distribution (Vd) must also be taken into consideration. Perhaps the importance of interaction involving protein binding has been overemphasized. Barbiturates, glutethimide, rifampicin and phenytoin increase the rate of drug metabolism in man. The most important interactions reported are between oral anti-coagulants and barbiturates. After withdrawal of these hepatic microsomal enzyme inducing drugs, it takes 2 to 3 weeks before the rate of drug metabolism reaches the pretreatment level. In this period, risk of haemorrhage exists. Induction seems to be dose-dependent, but not all persons are inducible. Many drugs compete for the drug metabolising enzyme system in the liver and consequently some drugs inhibit the biotransformation of other drugs. The time course of these interactions depends on the pharmacokinetic properties of the drug involved, and these interactions also seem to be dose-dependent. The most important of such interactions, clinically involved the oral sulphonylurea hypoglycaemic drugs and the antiepilepic drug phenytoin. Drugs are eliminated by urinary excretion through three mechanisms: glomerular filtration, tubular reabsorption, and active tubular secretion. The most important interactions seem to be those involving competition for tubular secretion.


External and internal exposure to the antigen in the hand eczema of nickel allergy. A provocation study was performed in twelve female patients with contact allergy to nickel and hand eczema of the pompholyx type. Intense handling of nickle-contaminated metal objects did not induce any visible eczematous activity. Oral administration of nickle in a double-blind test provoked an aggravation of the hand eczema in nine of the twelve patients, and in seven of the patients this was accompanied by secondary eruptions including outbreaks of earlier, healed eczema. The nickle dose given is probably in the upper limit of the presently known daily intake of the metal, but should be considered to be within the physiologic range. It is concluded that ingestion of small amounts of nickel may be of greater importance in maintaining the hand eczema than external contacts with the metal.


Clinical significance of fibrinuria with fibrinogen split-product E following kidney allotransplantation. Typical findings of disseminated intravascular coagulation were found in patients following kidney allotransplantation where quantitative determinations revealed fibrin degradation products in the urine. Split-product E, which was quantitatively determined in urine samples, contributes to this fibrinuria. Elevated levels of fibrinogen split products in serum as well as in urine are detectable several days prior to clinical signs of rejections and serve as an early indicator of impending rejection in patients with renal allografts.


Studies on glomerular permeability using inert polymers. Dextrans and other macromolecular inert polymers such as polyvinyl pyrrolidone fulfil all the criteria of an ideal test material for measuring glomerular permeability. Following a single intravenous injection of radioactively labelled polydisperse material serial plasma and urine samples can be analysed by gel filtration chromatography and the polymer fractionated into its constituent molecular sizes. Polymer of molecular size 24 A is capable of passing through the glomerulus as readily as water while material larger than 60 A is affectively excluded from the glomerular filtrate and one can determine the clearance of 20--30 intermediate molecular sized fractions. The accumulated data can be analysed by a number of different theoretical mathematical models; furthermore the technique can be employed in the study of proteinuria induced by vasoactive amines such as renin or angiotensin.


Glomerular protein filtration in normal and nephritic rats. A micropuncture study. The acute heterologous phase of anti-basement membrane glomerulonephritis in rats was studied morphologically and functionally at the single nephron level. In samples drawn from Bowman's space or from the very early segment of the proximal tubule the protein content was measured by ultra micro-disc-electrophoresis. Morphologically, in rats which were treated with anti-glomerular basement-membrane serum (AGBM) no significant changes could be seen in light microscopy whereas in immunohistology the typical, linear, subendothelial fluorescent staining for IgG could be seen. In controls, small amounts of albumin were filtered (7.57 +/- 0.66 mug/min X 100 g body weight, n = 14) but in nephritic animals the filtered load of albumin increased significantly to 58.33 +/- 4.10 mug/min X 100 g body weight, (n = 8). Besides this increased albumin filtration also several serum globulins could be detected, whereas in controls they were missing. Total GFR and proximal passage time did not change significantly. It is concluded that the glomerulus is an effective barrier for protein under control conditions and that it becomes permeable for albumin and higher molecular weight serum proteins following the antigen antibody reaction at the glomerular basement membrane in the AGBM-treated animals.


Nephritogenic glycoprotein. VI. Induction of proliferative glomerulonephritis with the immunofluorescent 'mesangial pattern' in rats by a single injection of soluble glycoprotein isolated from human urine. Proliferative glomerulonephritis was induced in rats by a single injection in the hind footpads of the urinary glycoprotein or more purified urinary glycopeptide with Freund's incomplete adjuvant. Although the urinary (water-soluble and non-dialyzable) glycoprotein and glycopeptide were prepared from heterologous urines (human urines), the immunofluorescent pattern of the kidneys was not 'granular' but 'mesangial', as in rats given a single injection of homologous or heterologous renal glycoprotein with nephritogenicity. The pathogenesis of proliferative glomerulonephritis in the present experiments may be explained by the same mechanism as that of rats given a single injection of renal glycoprotein, i.e. by any mechanism other than antigen (heterologous protein)-antibody immune complex and anti-GBM antibody mechanisms.


IgA glomerulonephritis in Japan.

IgA glomerulonephritis in Japan. A clinicopathological study was done on 85 Japanese patients with IgA glomerulonephritis. Of patients with glomerulonephritis whose clinical course is of slow progression, the presence of IgA glomerulonephritis was demonstrated immunohistologically. The majority of such patients presented with a mild degree of proteinuria and/or persistent microscopic hematuria. In 15% of the patients, recurrent gross hematuria was noted. These findings suggest that immunohistological study is important in dealing with adult patients with so-called idiopathic renal hematuria. Light-microscopic findings of IgA glomerulonephritis were divided into 4 groups. In 56% of the patients, diffuse stalk thickening of the mesangium was noted and in one third of them, small crescent formations were present. In 22% of the patients, focal segmental proliferation was noted. Diffuse mesangial deposition of IgA noted by immunofluorescence was considered to correspond to the characteristic nodular deposition detected by light microscopy and to the relatively large globular hemispheric deposits detected by electron microscopy.


Classification of chronic glomerulonephritis based on prognostic considerations. Based on the correlation of LM, EM and IF findings of kidney biopsy tissues with the clinical and laboratory findings as well as renal function, classification of primary GN is proposed with special reference to the smouldering and progressive forms of chronic GN. The two forms of chronic GN should be differentiated because their prognoses are different.


The identification of staphylococci in clinical and food microbiology laboratories. A comprehensive review of the methods which have been utilized for the identification of staphylococci is presented. Biochemical characteristics which have assisted in the primary isolation of staphylococci, such as pigmentation, hemolytic activity, the egg yolk phenomenon, and deoxyribonuclease and coagulase production, are also analyzed. The potential applicability of advanced techniques to identify staphylococci, such as the detection of enterotoxin production, base ratio analysis, cell wall analysis, phage typing, and serology, is discussed. The following procedures are recommended for routine use: Idnetification of Staphylococcus sp. (clinical laboratories): microscopic observation, catalase activity, coagulase production, lysostaphin sensitivity, and (optional) facultative growth in thioglycolate medium. Identification of Staphylococcus aureus (food laboratories): microscopic observation, catalase activity, coagulase production, thermonuclease production, and (optional) lysostaphin sensitivity.


The tunnel graft procedure for attachment of a hairpiece. A new procedure for attaching a hairpiece to the scalp is described. Two skin-lined tunnels in the anterior and posterior scalp are built, using a strip of free full-thickness donor skin fron the postauricular area. Silicone-coated metal clips, suitably fashioned from .062'' Kirschner's wire, are then attached to the hairpiece. The metal clips are inserted into the skin-lined tunnels and thereby anchor the hairpiece to the scalp.


Sweet's syndrome: unique local response to streptococcal antigen. Although hypersensitivity has been postulated, the etiology of Sweet's syndrome has never been elucidated. In the present case intradermal tesing with viridans streptococcus led to an immediate reaction and reproduced a lesion clinically and histologically identical to that of the primary disease. Other bacterial and fungal antigens failed to elicit any response. These findings provide further support for the role of hypersensitivity in the pathogenesis of this disorder. It would appear that immediate or humoral immunit


Clotrimazole troches: a new therapeutic approach to oral candidiasis. To ascertain the topical effectiveness of clotrimazole in oral candidiasis, a troche form was administered to 12 patients suffering from longstanding infection. One-half of the patients took one 10 mg troche and the other half of the patients one 50 mg troche, ten times a day. The troches were not chewed, but were retained in the mouth until completely dissolved. The impressive clinical and mycological response to this treatment as well as the lack of toxicity strongly indicate that further trials are warranted.


The use of multicartilage composite grafts to repair wounds of the lower third of the nose. The use of multicartilage composite grafts to repair surgical wounds of the lower third of the nose (ala nasi and tip) is described. These differ from the classic composite ear graft in three respects: First, the skin portion of the graft is removed separately from the cartilage permitting the operator to select the donor site that matches the nose best. Second, the cartilage, instead of being a single piece, is divided into small units allowing for more uniform reconstruction of cartilaginous portions of the nose. Third, larger composite grafts can be constructed safely by this technique than heretofore considered possible by the conventional method. The results of the multicartilage composite graft in eight patients is assessed. The implications for their healing by the bridging phenomenon is discussed.


Psoriasis: treatment with a new topical corticosteroid. A total of 60 patients was treated for psoriasis in a double-blind, paired comparison study of 0.1% halcinonide with an active corticosteroid comparison drug as topical creams. An overall evaluation of comparative responses clearly demonstrated the superiority of halcinonide in a greater number of patients. Separate evaluation of the overall therapeutic responses also favored halcinonide, with a good to excellent response in 80% of patients compared to 65% with the control drug.


Pseudopelade of Brocq secondary to lichen planus. Immunofluorescence studies as as the underlying cause of pseudopelade of Brocq (PPOB) in a middle-aged woman. The routine use of immunofluorescent studies in clinical cases of pseudopelade of Brocq might make more specific diagnoses possible.


Psoriasis: topical corticosteroid therapy. Fifty-nine patients with bilateral psoriatic lesions were subjects in a double-blind paired comparison of halcinonide cream and fluocinonide cream. They applied the corticosteroid creams twice a day for 14 days without occlusive dressings. Objective and subjective assessment of response to therapy was made four or five days, one week, and two weeks after starting treatment. The results were analyzed by statistical methods. At the second visit (day 4 or 5), there was little difference between the two compounds, but at visits three and four, reduction of inflammation was significantly better with halcinonide than with fluocinonide.


Cutaneous signs of diabetes mellitus.

Cutaneous signs of diabetes mellitus. Cutaneous signs of diabetes mellitus are extremely valuable to both the clinician and the researcher. Lesions such as necrobiosis lipoidica diabeticorum, diabetic dermopathy, carotenemia idiopathic bullous eruptions of granuloma anulare alert the physician to consider the diagnosis of diabetes mellitus. Xanthomas reflect the status of glucose and lipid metabolism. Diabetic dermopathy might be a useful monitor of angiopathic changes in the heart, kidney and brain. Finally, the accessibility of the skin makes it an ideal organ for studying the pathogenesis of diabetes and the effect of medications on the vascular and neurological complications of diabetes.


Clinical comparison of desonide cream with fluocinonide cream in steroid-responsive dermatologic disorders. Desonide, a nonfluorinated topical corticosteriod, was compared with fluocinonide, a potent fluorinated steroid, in identical concentrations, in the treatment of various steroid-responsive dermatologic disorders. In treatment comparisons, the group treated with desonide showed significantly (p less than 0.05) better erythema and scaling scores after the first week than did those in the fluocinonide group, but the two week scores were not significantly different. Although 5 percent of patients treated with fluocinonide had adverse reactions, no such reactions were observed in the desonide-treated group.


Heavy alcohol consumption and physical health problems: a review of the epidemiological evidence. A review of morbidity and mortality studies bearing on the hazards to physical health of chronic heavy alchol use indicates that such use carries a risk of premature death greatly exceeding normal expectancy. While the life style typical of many heavy drinker contributes to this risk, the effects of alcohol per se account for a substantial part of the excess mortality. The lowest level of consumption at which there is a significant increase in the death rate has yet to be determined. It is certainly below 120 g/day- the lower limit of consumption of most clinical alcoholics-and quite possibly below 35-60g: levels which appear to carry an increased likelihood of cirrhosis and certain cancers. On the other hand, the mortality experience of drinkers commonly identified as 'moderate' in the literature does not seem to differ notably from that of life-long abstainers. The relationship between heavy drinking and elevated mortality is exhibited in populations at large by the generally close covariation of cirrhosis death rates and per capita alcohol sales. There are also indications of co-variation between the latter and the excess of male over female general mortality in the middle age range.


[Alcoholism in women].

[Alcoholism in women]. The present survey of empirical studies of female alcholism considers firstly questions concerning the prevalence of female alcoholism. Empirical findings on the psychopathology, the development and course of female alcoholism, partner relationships and problems in female identification of these patients are described and discussed with regard to their informative value. It is shown that most of the present empirical results contribute little to a more refined understanding of female alcoholism and that they also have little relevance to the development of special therapeutic approaches. Finally basic reasons for this state of affairs are discussed together with suggestions for further research.


A morphological comparison of the regional distribution of methadone in human and rat brain as demonstrated by immunofluorescence. The brains of ten narcotic addicts who had died from an overdose of methadone, and the brains of ten rats, given methadone for one month, were examined by the immunofluorescent technic. Positive neuronal fluorescence was seen primarily in the limbic systems of both species as well as in closely associated areas. In the human, Purkinje cell fluorescence was seen in the cerebellum, whereas only stellate cell staining was observed in rat cerebellum. Neurons of the hippocampal denate gyrus often fluoresced in man while only pyramidal cell staining was seen in this region of rat brain. The method should prove to be of value in the detection and tracing of narcotic drugs and may be helpful in investigations of drug tolerance and dependence.


Generation and characterization of aerosols and vapors for inhalation experiments. Control of aerosol and vapor characteristics that affect the toxicity of inhaled contaminants often determines the methods of generating exposure atmospheres. Generation methods for aerosols and vapors are presented. The characteristics of the resulting exposure atmosphere and the limitations of the various generation methods are discussed. Methods and instruments for measuring the airborne contaminant with respect to various charcteristics are also described.


Normal and pathologic biochemistry of the lung. The lung is an important metabolic organ. Glucose provides the major source of substrate. Oxidative pathways are active and are required to maintain normal tissue energy stores. Synthetic activity in the lung is extensive and related mainly to synthesis of dipalmitoyl lecithin and other components of the lung surfactant system. The lung plays an important role in the metabolism of xenobiotics and endogenous hormones leading to degradation as well as activation of important biologic properties.


Chronopharmacokinetics of ethanol. I. Review of the literature and theoretical considerations. Pharmacokinetic parameters are generally assumed to be invariate with the time of day, although circadian variation of drug metabolism and drug response is known. As proposed, chronopharmacokinetics considers the implications of the chronovariability of pharmacokinetic parameters. In order to investigate chronovariation in the rate of disappearance of a substance from the approximate a linear course until very low blood levels are attained. As a background for such studies, the literature on the chronopharmacologyof ethanol and the pharmacokinetics of ethanolemia is reviewed. Theoretical considerations are presented for chronovariation of elimination constants for hypothetical drugs following exponential and zero-order models. In describing these cases, the substitution of a sinusoidal function for the rate-constants in pharmacokinetic differential equations is proposed and graphed herin for the first  time. It is concluded that: 1)rhythmicity within elimination curves can only be determined by repetion of the experiment at different times of the diel period; 2)the expectation that a rate-constant estimated at one time of the day may be valid for another part of the day carries with it an unknown risk. No pharmacokinetic analysis can be considered definitive unless chronopharmacokinetic variation of parameters is considered.


Deposition and clearance of inhaled particles. Theoretical models of respiratory tract deposition of inhaled particles are compared to experimental studies of deposition patterns in humans and animals, as determined principally by particle size, density, respiratory rate and flow parameters. Various models of inhaled particle deposition make use of convenient approximations of the respiratory tract to predict tractional deposition according to fundamental physical processes of impaction, sedimentation, and diffusion. These theoretical models for both total deposition  and regional (nasopharyngeal, tracheobronchial, and pulmonary) deposition are compared with experimental studies of inhaled dusts in humans or experimental animals that have been performed in many laboratories over several decades. Reasonable correlation has been obtained between theoretical and experimental studies, but the behavior of very fine (less than 0.01 mum) particles requires further refinement. Properties of particle shape, charge, and hygroscopicity as well as the degree of respiratory tract pathology also influence deposition patterns and further experimental work is urgently needed in these areas. The influence upon deposition patterns of dynamic alterations in inspiratory flow profiles caused by a variety of breathing patterns also requires further study, and the use of such techniques with selected inhaled particle size holds promise in possible diagnostic aid in diagnosis of normal versus disease conditions. Mechanisms of conducting airway and alveolar clearance processes involving mucociliary clearance, dissolution, transport to systemic circulation, and translocation via regional lymphatic clearance are discussed. The roles of the pulmonary macrophage in airway and alveolar clearance are described, and the applicability of recent solubility models for translocation or deposited materials to liver, skeleton, or other systemic organs is discussed.


The pulmonary macrophage.

The pulmonary macrophage. An overview of the pulmonary macrophage is provided, with particular emphasis on the origin of this cell and the adaptive mechanisms whereby the macrophagic system is able to respond to increased inhalant loads of organic and inorganic pollutants. Evidence is presented which favors an hematopoietic origin for the alveolar macrophage with a monocytic transportation compartment in the blood and an interstitial cell compartment in the lung in which cellular division and maturation may occur. Through the simple mechanism of increased cellular turnover this system of mononuclear phagocytes rapidly adapts to most inhalant challenges. In addition to its primary tasks phagocyte and destroyer of microorganisms the macrophage plays a pivotal role in the genesis of silicotic fibrosis, and it is possible that similar mechanisms may hold for a variety of cryptogenic fibroses. Paradoxically, destruction of collagen by the dual mechanisms of phagocytosis and the secretion of lytic enzymes may also occur. The relevance of this secretory function of the macrophage to the pathogenesis of destructive diseases of the lung such as emphysema remains to be determined.


Isolation of cells that retain differentiated functions in vitro: properties of clonally isolated type II alveolar pneymonocytes. We have isolated byclonal culture techniques a diploid cell strain (L-2) from adult rat lung. These cells appear to retain differentiated functions that are present in type II alveolar epithelial cells of intact lung. The L-2 cells are diploid, epithelial cells, they contain osmiophilic lamellar bodies in their cytoplasm and they synthesize lecithin by the same de novo pathways as whole lung.


Preservation of dog kidneys by hypothermic perfusion with glucose-free and glucose-rich perfusates. Dog kidneys were perfused for 48 h at 8-10 degrees C with two different perfusion fluids: one fluid rich in glucose, and another in which mannitol was a substitute for glucose. Immediately after reimplantation of the perfused kidneys, contralateral nephrectomy was performed. Kidney function, estimated by serum creatinine, was the same in both groups of animals, and 2 weeks after implantation it was identical to that of dogs with a single normal kidney. In a second series of experiments the renal utilization of glucose and glycogen was studied. Although small amounts of perfusate glucose were metabolized to lactate and CO2, the results of this study indicate that the kidney is not dependent upon glucose for its metabolic needs in order to retain function during 48 h hypothermic preservation.


Mucinous secretion from canine Heidenhain pouch after stimulation with food, pentagastrin and histamine. Principal glycoproteins and amino acids were determined in gastric juice obtained from Heidenhain pouches of Labrador pure-bred dogs. Secretions were stimulated by food, pentagastrin or histamine. Non-stimulated fasting secretions served as controls. All samples showed the presence of galactose, glucosamine, galactosamine, fucose, glucose, mannose and sulfate. Galactose and glucosamine were found in equimolar amount and the galactose to galactosamine ratio was 2:1. Concentrations of most carbohydrate components studied were higher in fasting than in stimulated secretions. Outputs of some of these components were lower in fasting than in stimulated secretions. Modes of stimulation used did not significantly affect the outputs of principal glycoproteins studied. Compared with human gastric secretions studied by others, using similar methods, certain differences were found particularly in the relationship between some carbohydrate components and between amino acids.


Effects of age on learning ability: contributions from the animal literature. For both ethical and practical reasons, animal subjects are becoming increasingly important tools for life span developmental researchers. Selected studies from the animal literature which have important implications for the study of learning in a life span context are reviewed. Specific issues discussed include task difficulty, genotype effects on life span learning processes, perseveration, and early versus later experience. It was concluded that 1) the hypothesis that task difficulty has a greater effect on senescent animals relative to younger animals generally is supported by the current literature, 2) genotype is a highly relevant variable for life span developmental research, but little work has been dirrected toward how genotype affects behavior within specific environmental contexts, 3) perseveration is very likely an important factor in poorer performance among aged subjects, but it has not been adequately studied in relation to physiological correlates, earlier precursors, or genotype, 4) the issue of the importance of early versus later experience has not been resolved, but research in this area promises much information with regard to potential modifiers of a decline in learning ability with increasing age.


[Participation of the stomach and small intestine in the mechanism of insulin secretion following oral glucose administration]. In chronic experiments on 22 dogs, four of them having fistulas of oesophagus, stomach, and duodenum combined with artificial dissociation of stomach from duodenum, the per os and intraduodenal administration of glucose increased concentration of glucose and immunoreactive insulin in the peripheral blood, while intrastomach administration of glucose increased the immunoreactive insulin concentration alone. The data obtained suggest three phases of insulin mobilization: the first is due to neural mechanisms and occurs at the moment of contact between glucose and mucosa of the mouth, stomach, and duodenum; the second phase seems to be due to enterohormones and is activated by the contact between glucose and mucosa of the mouth, stomach, and duodenum; the third phase is associated with resorptive hyperglycemia which directly activates the B-cells.


[Effect of oral contraceptive on the pituitary and plasma L.H. levels and on the hypothalamic LH-RH level (author's transl)]. The effects of the oral contraceptive on the pituitary content and plasma level of LH and the hypothalamic LH-RH level were investigated in 16 adult female rabbits. The oral contraceptive preparation, Sophia-C (Norethindrone 2mg + Mestranol 0.1 mg), as administered orally by a stomach tube each day for 7 days in 8 adult female rabbits. At the end of the treatment, the rabbits were bled from the abdominal aorta into heparinized syringes and the plasma was separated. The stalk median eminences were excised. All the materials were stored in -80 degrees C until assayed. Plasma level and the pituitary content of LH and the hypothalamic LH-RH were measured by radioimmunoassay. All the dose response curved were drawn using logitlog transformation. Radioimmunoassay procedures for LH was described in detail elsewhere. Purified rabbit LH for iodination (125-I) and strandard were prepared by T. Makino and R.O. Greep, at Research Laboratories for Human Reproduction, Harvard Medical School, Boston, U.S.A. The starting B/T was 25% at the final dilution of the antibody of 1/20,000. Minimal detectable quantity was about 40 pg/tube. The 50% intercepts were approximately 460 pg/tube. Radioimmunoassay procedures for LH-RH were performed according to the method described by Arimura et al. Antiserum against synthetic LH-RH was kindly supplied to us by Drs. A. Arimura and A.V. Schally, New Orleans, U'S.A. The synthetic LH-RH was kindly supplied to us by Dr. N. Yanaihara. The starting B/T ratio was 29% at the final dilution of the antibody of I/17,500. Minimal detectable quantity was about 40pg/tube and the 50% intercepts were 150pg/tube. It has been assumed that oral contraceptive drugs exert their action by blocking the hypothalamic LH-RH, resulting in a depression of the plasma level of LH, because plasma level of LH returned to the normal level when LH-RH was administered intravenously even while oral contraceptive steroids were given continuously. However, these findings concerning the site of action of the drugs furnished only indirect evidences. The possibility of a direct inhibitary effect of these steroids on the anterior pituitary cannot be ruled out. Administration of 2mg of Norethindrone and 0.1mg of Mestranol significantly depressed both the pituitary content and the plasma level of LH. On the other hand, they significantly increased the hypothalamic LH-RH level. Those findings strongly suggested the direct action of this drug on the anterior pituitary in the female adult rabbits. Detailed mechanisms on how the hypothalamic LH-RH was increased were not known in this experiment, further investigations are now in progress.


An evaluation of betamethasone dipropionate (Diprosone) versus Locacorten 0.02% cream. A double-blind randomized evaluation of betamethasone dipropionate cream (Diprosone) compared with Locacorten 0.02% cream flumethason privalate in 60 patients over 3 consecutive weeks showed the betamethasone dipropionate cream to be significantly more effective in the treatment of psoriasis and other steroid-responsive dermatoses.


A double-blind study comparing Daktacort, miconazole and hydrocortisone in inflammatory skin infections. In a 4-week double-blind trial, Daktacort cream was compared with each of its constituents (i.e. miconazole 2% and hydrocortisone 1%) in a total of 63 patients (aged 12-60 years) with inflamed skin infections of bacterial or mycotic origin. Daktacort treatment induced a significant improvement of all symptoms within 1 week and was superior to both miconazole and hydrocortisone in suppressing the inflammation. This tendency persisted throughout the trial but at the end miconazole treatment proved also superior to hydrocortisone.


Effects of somatostatin on the biosynthesis and release of insulin from isolated pancreatic islets. The glucose-stimulated insulin release of pancreatic islets isolated either from normal mice or from mice with the obese-hyperglycemic syndrome (genotype ob/ob) was inhibited by somatostatin in the concentration range 10(-2) - 10(-4) mM. Islets prepared from the obese-hyperglycemic mice appeared most sensitive and there was a strong inhibitory action on the insulin release irrespective of whether the islets were exposed to somatostatin directly after isolation or after five days in tissue culture. There was, however, no effect of somatostatin on the glucose-stimulated insulin biosynthesis of the mouse islets. Neither was there an effect on the insulin biosynthesis of isolated islets from three days old rats, despite a previous report to the contrary. It is concluded that somatostatin does not affect the insulin biosynthesis of isolated islets at concentrations which inhibit insulin release.


The management of deformities of the foot in children with spina bifida. A simple photographic technique is described which measures the weight-bearing and non-weight-bearing areas of the feet in the standing child. The child stands on a rectangular sheet of thick glass which is set into the floor. Beneath the floor is a cellar, from which the soles of the feet may be observed and photographed. A transparent grid placed over the photographic print enables the weight-bearing and non-weight-bearing areas of the foot to be measured, and thus to express the weight-bearing areas as a percentage of the total area of the sole of the foot. The procedure was used to assess 55 spina-bifida children who had had surgical correction of deformities of the feet. The findings are discussed.


Surgery of the knee in children with spina bifida. The achievement of independent mobility by children with spina bifida is often hampered by deformities of the knee joints. This report reviews the results of surgical treatment in 34 spina-bifida children with knee deformities. The surgical procedures are described and it is concluded that surgery is justified in a proportion of cases with fixed-knee deformities.


Prevention and treatment of knee problems in children with spina bifida. The outcome of surgical treatment of flexion, valgus or extension knee deformities is reviewed in 114 spina-bifida children (164 knees) who received such treatment over the period 1968 to 1975. Eggers' procedure for 26 knees produced very good results in 21 cases and good results in four; supracondylar osteotomy in 128 knees produced very good results in 104 cases and good results in 16; and quadriceps Z-plasty with anterior capsulotomy in 10 knees produced very good results in nine cases.


Basic physiotherapy of spina bifida.

Basic physiotherapy of spina bifida. Physiotherapy for children with spina bifida uses very basic techniques which include prophylactic and therapeutic 'stretching', training to walk, supervision of calipers, and instruction to the parents. Success or failure of treatment very largely depends on the ability of the physiotherapist to teach and encourage the parents to help the child become as independent as possible in all aspects of daily living.


The effects of admission to hospital and surgery on children with spina bifida. Up to the age of nine years, 43 actively-treated cases of myelomeningocele had had an average stay of 28 weeks in hospital, one-fifth having spent between one and two years in hospital, and each child having had an average of six operations. After the age of two years there was a tendency to withhold surgery in more hopeless cases. The number of hospital admissions and surgical procedures declined appreciably after the children's admission to school. Girls spent longer periods in hospital than boys. Children with IQs of less than 80 spent twice as long in hospital compared with intellectually competitive children, probably because of the greater frequency of hydrocephalus and other physical handicaps. Admission to hospital in itself seemed to have little effect on intellectual status. Parents' comments showed that hospital admission held few fears for their children, except when orthopaedic procedures were involved. It is concluded that because of their familiarity with hospital, the emotional hazards associated with frequent admission to hospital seems to have little effect upon the behaviour of these children.


Myelomeningocele: a progressive intra-uterine disease. A series of cats were made hydrocephalic by intracisternal injection of kaolin, and four weeks later ventriculography confirmed the presence of hydromyelia. Ten days later, laminectomy in the lower thoracic region was performed. Several days later ventriculography revealed a markedly dilated central canal beneath the entire laminectomy, and pathological examination confirmed the presence of a focal bulge confined to the same region. On sectioning, it was evident that the central canal was massively enlarged to fill the entire spinal cord beneath the bulging region. The conclusion from these findings is that myelomeningocele is the result of progressive intra-uterine disease which begins with pathological hydromyelia and culminates in rupture of the unsupported spinal cord as a result of maldevelopment of associated dermal tissue.


Assessing the development of daily living skills in patients with spina bifida. The development of independence in daily living skills of 256 patients with spina bifida was assessed by means of a new Functional Activities scoring system. The score was derived from nine categories of activity; five are to do with self-care, three with locomotion and one with social interaction. The reasons for the variation in achievement between individuals with the same degree of paralysis are discussed, as are the differences in learning curves for single activities. The scoring system enables a quantitative assessment to be made of the current status of an individual patient, and enables more realistic therapeutic goals to be set.


The reliability of prediction of outcome in spina bifida. The clinical findings in 85 neonates with spina bifida were given to two neurosurgeons and two paediatricians, who were asked to predict from them the length of survival and quality of survival with regard to intellect, locomotion and continence, without their knowing the actual outcome. All four clinicians correctly predicted the survival of infants with meningocele, closed myelocele and encephalocele. The paediatricians correctly predicted the survival of all infants with open myelocele who actually survived, but also included some who had died. The surgeons correctly predicted the deaths of all those with open myelocele who actually died, but expected a considerable number to die who in fact survived. All four clinicians were similar in their predictions of intellect: they underestimated the outcome in patients with successfully shunted hydrocephalus, they overestimated the intellect in patients who had developed intracranial infection and shunt blockage, and they largely underestimated the outcome in the patients who did not require shunts. They made correct predictions for limb and sphincter function in nearly all the survivors. This investigation underlines the problem of selection for treatment caused by the inability to predict the complications of hydrocephalus and infection. Reasons for the differences between the expectations of the paediatricians and surgeons, and the implications of the results of this study for selection for surgery are discussed. It is suggested that limb paralysis and incontinence ought not to be considered as factors excluding infants from treatment.


The effectiveness of genetic counselling for neural-tube malformations. A total of 160 couples who, between 1967 and 1974, had had genetic counselling because of neural-tube malformations in a previous pregnancy were later interviewed in their homes to assess the effectiveness of the counselling. In the earlier years, few couples in which the husband was in a manual occupation came for counselling, but latterly the proportion increased. Most couples seen together for counselling acted appropriately on the risks given, but only when very high or low risks were given were these remembered accurately. Both accurate recall and appropriate action tended to be compromised by poor preparation of the couple for counselling, by too early a consultation after the birth of an abnormal child, by survival of the child, or by psychiatric illness. Before prenatal diagnostic tests became available, few couples embarked on further pregnancies, but more recently half the couples started a further pregnancy within one year and only one in five couples decided against having more children. It is concluded that couples at risk should be persuaded to seek counselling, and be better prepared for it beforehand, that counselling should not take place too soon after the birth, and that there should be later follow-up. Couples should be seen together, and a non-directive approach usually should be adapted. More public education would help to bring the service to more of the families most in need of it.


Heterotopic dorsal-root ganglion cells around the spinal cord in children with spina bifida aperta. Sixty-three of 95 cords from children with spina bifida aperta had associated heterotopic ganglion cells, usually located in dorsal nerve roots posterior or lateral to the cord. Heterotopic cells were more common in cords with complete or partial diplomyelia, and the largest number was found in the upper sacral region. It is proposed that the heterotopic position of the cells is due to abnormal and delayed migration of neural crest cells during primary neurogenesis. The findings lend support to the concept that in children with myelomeningocele the cord lesion is not due to secondary rupture.


Orthopaedic management of children with myelomeningocele: a plea for realistic goals. The aims and principles of orthopaedic management of children with a myelomeningocele are discussed. The primary aim is to establish stable posture, and details are given of the various operative procedures used to bring about stable posture. The management described has resulted in reductions in the number of operations for each child, in the incidence of post-immobilisation fractures, in the number of hospital admissions and in the number of bed-days spent in hospital.


Intra-operative evoked potential studies of newborn infants with myelomeningocele. Somatosensory evoked potentials were studied in seven infants during surgery for repair of thoraco-lumbar myelomeningocele. All were operated on during the first 24 hours of life. Because anaesthetics were known to suppress somatosensory evoked potentials, narcotics and muscle relaxants were used for anesthesia. Before surgical dissection, stimulation of median nerves evoked cortical responses in five of the seven patients. After dissection, evoked potentials could be retrieved from the neural plaque with peroneal nerve stimulation in five of the seven infants. Stimulation of the neural plaque produced cortical responses in five of the seven but cortical responses with long latencies could be obtained from peroneal nerve stimulation in only two of the seven patients. In two patients lumbar-root stimulation distal to the plaque produced low-amplitude and delayed-latency cortical responses. These findings indicate that the distal nerves and neural plaque may have intact afferent connections with the cortex: therefore at surgical repair the neural plaque has been meticulously preserved.


Normal pressure hydrocephalus in patients with myelomeningocele. Although the syndrome of normal pressure hydrocephalus (NPH) was described in the adult as early as 1964, it has only recently been recognized in the child. In this preliminary report, eight myelomeningocele patients with presumed NPH were evaluated before and after ventricular shunting procedures. Cranial computed tomography and serial psychological testing have proved to be particularly valuable both in the pre-operative and post-operative assessment of these patients and have the distinct advantage of being simple, non-invasive diagnostic measures. Continuous intra-ventricular pressure monitoring has shown what promises to be characteristic elevated pressure plateaux imposed on normal baseline cerebrospinal fluid (CSF) pressures in so-called NPH but is a more difficult clinical procedure, necessarily associated with potential complications. Although decreasing response to growth-stimulating hormone can be demonstrated in patients with long-standing hydrocephalus, this endocrine malfunction cannot be considered an early indicator of intracranial pathology. Single IQ scores are inadequate measures of intellectural function in children with NPH and serial examinations should be carried out. Detailed neuropsychological testing will document performance IQ scores well below verbal IQ scores and will generally show failure of psychomotor development to keep pace with chronological ageing. Initial studies indicate that improved performance scores can be expected within 1 1/2 to 3 months following successful ventricular shunting operations, and that any downward trend in pre-operative test scoring can at least be reversed. Statistically significant improvements in full-scale IQ scores have not been seen, however, before the end of the first post-operative year. Clinically, improved attentiveness and sociability, and decreased spasticity (if present prior to surgery) can be expected following shunting. Over-all, ventriculomegaly, normal CSF pressure, stable head size, and non-progressive neurological symptoms cannot be regarded as sufficient criteria for the diagnosis of an arrested state of hydrocephalus, and should suggest NPH, especially in those children who demonstrate a discrepancy between performance and verbal IQ scores and who fail to exhibit continuing psychomotor development with advancing age.


Prophylactic long-term anticoagulant treatment of hydrocephalic patients with ventriculo-atrial shunts. Thrombosis of the superior vena cava is a frequent cause of death among patients with ventriculo-atrial shunts. In this study, one group of spina-bifida children with such shunts was treated with prophylactic anticoagulant therapy and a second group was not. While there was no significant difference between the two groups in the number of shunt revisions required over a six-year period, distal catheter complications were twice as frequent in the group not receiving anticoagulant therapy. There was little difference between the groups in the rate of proximal catheter revisions. It is suggested that the benefit of anticoagulant therapy is in transferring shunt problems from the distal to the proximal catheter, obstruction of which is less dangerous and more easily treated.


Preliminary evaluation of alpha-adrenergic blocking agents in children with neurogenic bladder due to myelomeningocele. Twenty children with myelomeningocele and neurogenic bladder dysfunction were treated with alpha-adrenergic blocking agents. The results were satisfactory and are considered to justify the use of these drugs, especially for children who have weak or absent detrusor activity and urethral outflow resistance not of the dyssynergic type. There are indications that urinary diversion in such cases may be able to be postponed when alpha-adrenergic blocking agents are used more routinely.


Long-term results of obstructive neurogenic bladder in children with myelomeningocele. A total of 91 children with myelomeningocele and neurogenic bladder were followed up for periods of between five and 10 years. The results of investigations of the upper and lower urinary tracts at the ages of three months, five years and 10 years showed that subvesical obstruction was rare in the infant period but that it increased year by year as the children grew older. By the age of five years 50 per cent of the children in this sample had severe obstructive changes. The study shows that children with neurogenic bladder who reach five or six years of age without developing severe symptoms of progressive subvesical obstruction will stand a good chance of being able to be treated conservatively.


Types of neurogenic bladder in children with spina bifida, and response to treatment with phenoxybenzamine. Seventeen children with spina bifida and neurogenic bladder were treated with phenoxybenzamine, an alpha-blocking agent, and in 15 cases the treatment was successful. It is suggested that in certain types of neurogenic bladder the need for urinary diversion can be avoided by treatment with phenoxybenzamine; only if this treatment fails does urinary diversion become necessary.


Orthotic management of the myelomeningocele spine. The appropriate use of spinal orthosis is an important adjunct in the rehabilitation of spinal deformity in children with myelomeningocele. The Newington developmental programme described here employs a series of orthotic devices, used at different stages of development, with the aim of achieving a developmental sequence as close as possible to the usual age for normal development.


Isolation and fractionation of cell-free extract from streptolysin-S-forming streptococci. A series of procedures have been developed for obtaining a partially purified fractions possessing anticancer activity using live streptolysin S-forming streptococci (Su strain) harvested from their yeast extract-culture fluid. These procedures consist principally of (1) preparing cell-free extract (CFE) from homogenized streptococci, (2) streptomycin-treatment of CFE (S-CFE) to remove nucleic acids, and (3) stepwise fractionations of S-CFE with 0.4, 0.5, 0.6, and 1.0 saturated solutions of ammonium sulfate, each fraction being dialyzed against distilled water followed by lyophilization. The 60-F product, which was precipitated by the 0.6-saturated solution, was found to be the most potent among six products obtained and to be about 4 times more effective than the original CFE in depriving the invasiveness of Ehrlich carcinoma cells in mice. Data on physical and biochemical properties of 60-F product are also presented.


Successful treatment of the patients with malignant pleural effusion with BCG cell-wall skeleton. The usefulness of the cell-wall skeleton of Mycobacterium bovis BCG (BCG-CWS) to the management of malignant pleural effusion is demonstrated in this report. In two patients with malignant pleurisy the oil-attached BCG-CWS reduced the pleural effusion in volume when injected intrapleurally. The following intradermal injections of BCG-CWS into the bilateral upper arms repeated monthly prevented the reaccumulation of the effusion and improved other clinical conditions of the patients. The possible mechanism responsible for this effect is discussed in relation to previous experimental and clinical studies.


Adjuvant and antitumor activities of Nocardia cell-wall skeletons. The adjuvant activity of the cell-wall skeletons prepared from eight species (ten strains) of Nocardia was determined by Brunner's method using allogeneic cell-mediated cytotoxicity test. The antitumor activity of the cell-wall skeleton of N. rubra, which showed the most potent adjuvant activity, was examined using EL-4 leukemia and MH-134 hepatoma cells in syngeneic mice. Its results suggest that the cell-wall skeleton of N. rubra is more potent than BCG cell-wall skeleton as the immunotherapeutic agent for cancer immunotherapy in man. The chemical properties of the cell-wall skeleton of N. rubra were also described.


Experimental immunotherapy of neoplastic pleural effusion with oil-attached BCG cell-wall skeleton in mice. An experimental model for neoplastic pleural effusion was made using a transplantable pleural fibrosarcoma MC-106 in ddO mice, and a local immunotherapy of neoplastic pleural effusion with oil-attached BCG cell-wall skeleton was attempted. Viable cells (3 X 10(5)) of MC-106 were injected into the right pleural cavity of the mice on day 0 with a tuberculin syringe which was joined to a two-way tap attached to a capillary manometer. All of the mice in the control group, which received intrapleurally saline solution 24 hr after the injection of tumor cells, died within 24 days and the mean survival time was 16.9 +/- 3.4 (SD) days. Macroscopically massive blooded pleural effusion in both pleural cavities and multiple tumor nodules on the surface of parietal and visceral pleura were observed. On the other hand, the mice which received intrapleurally 100 mug of oil-attached BCG cell-wall skeleton 24 hr after the injection of tumor cells survived much longer. About 50% of the mice remained alive and were killed on day 95. They revealed histologically no malignant lesion of the pleura except for residual changes of inflammatory reactions.


Two-step mechanism of macrophage-mediated tumor lysis in vitro. Normal peritoneal macrophages from C3H/He mice could not lyse syngeneic MM46 tumor cells in co-operation with syngeneic antitumor antibody. Thus, normal macrophages could not effectively participate in the antibody-dependent macrophage-mediated tumor lysis in vitro. However, after activation in vivo by stimuli, such as lipopolysaccharide, BCG, or glycogen, macrophages could co-operate with antitumor antibody in cytolysis of target cells. In the cytolysis nonspecific activation of normal macrophages was an essential first step, followed by specific tumor lysis in the presence of an antitumor antibody (second step). Immune macrophages from resistant mice were apparently equal in functional state to activated macrophages. A two-step mechanism of tumor lysis in vitro in a syngeneic mammary tumor system is proposed.


Serotonin containing and histamine containing cells in human stomach. Identification of these cells by fluorescent microscope and electron microscope. Paraformaldehyde (PF) treatment of epithelial cells of human stomach revealed intense yellow fluorescent granules within the cells. These granules were identified as serotonin on microspectrofluorometry. Serotonin containing cells were also identified as enterochromaffin cells (EC cells) under electron microscope and by the histochemical analysis. O-phthalaldehyde treatment (OPT) of epithelial cells in human stomach demonstrated whitish blue intracellular granules under fluorescence microscope. The cells containing these granules were identified as histamine containing cells on microspectrofluorometry, because of accordance in excitation and emission spectra with authentic histamine. Histamine-containing cells were considered to be identical to the mast cells, because of metachromatic property on toluidine blue staining and of close structural similarities under electron microscope.


Von Willebrand's syndrome. Studies on a variant factor VIII. A girl with symptoms of von Willebrand's disease was found to have a slightly reduced or normal FVIII procoagulant activity, normal FVIII-related antigen (VIIIR:AG) and virtually absent von Willebrand's factor. The electrophoretic mobility of the VIIIR:AG in this patient's plasma and plasma fractions was increased and has been compared with that of two reported patients with FVIII variants. Her lysed platelets contained increased amounts of VIIIR:AG which had an increased anodal migration identical to her plasma VIIIR:AG. Experiments involving the selective absorption of a rabbit antiserum with the patient's plasma provide evidence that VIIIR:AG and von Willebrand's factor are immunologically distinct.


Nonsuppressible insulin-like activity in rat organs as detected by fluorescent antibody and radioimmunoassay techniques. NSILA-S was localized by immunofluorescent antibody staining in the exocrine part of the pancreas and the submaxillary salivary gland of the rat, where part of the cells give positive reactions. To a lesser degree it was demonstrated in the kidney, where some--probably the actually functioning--nephrons give positive staining reactions within their tubular cells. Radioimmunoassayable NSILA-S was found in extracts of the pancreas (120-550 ng/g), of the submaxillary salivary gland (220-330 ng/g) and of the kidney (45 ng/g), whereas liver (and some other organs) contain practically no NSILA-S.


Effect of neonatal androgen on the activity of peptidases in the rat brain inactivating luteinizing hormone-releasing hormone. The activity of peptidase enzymes in different brain areas inactivating luteinizing hormone-releasing hormone (LH-RH) was investigated in normal male and female rats treated neonatally with androgen. Of the two fractions containing peptidase activity, changes were found only in the supernatant (soluble/cytoplasmic) fraction and were restricted to the hypothalamus and cortex. In both these brain areas, peptidase activity was considerably higher in androgen-treated than in normal female rats; there was no significant difference between activity in male rats and the androgen-treated female rats. These findings indicate that neonatal androgen produces masculinization of the mechanisms responsible for LH-RH inactivation in the hypothalamus which may reflect changes observed elsewhere in gonadotropin secretion in androgen-treated female rats. The changes in peptidase activity in the cortex may infer that sexual differentiation of the brain under the influence of androgen is not limited to the hypothalamus and can be manifested at extrahypothalamic sites within the central nervous system.


Effect of rat stalk median eminence extracts on rat GH secretion in vivo. Estradiol (0.2 mug), injected subcutaneously for 10 days to adult male rats, increased plasma growth hormone (GH) levels as compared with oil-treated controls. In estradiol-pretreated (10 days), urethane-anesthetized rats, the first as well as the second of two successive intracarotid injections, at 1-hour intervals, of one rat stalk median eminence equivalent evoked a significant rise in plasma radioimmunoassayable GH. Under the same conditions, cerebral cortex extracts (1 equivalent) induced a slight elevation whereas vasopressin (30 mU) or serotonin (200 ng) were ineffective. These results indicate that estrogen-primed, urethane-anesthetized rats can be used to demonstrate GH-releasing activity in rat SME extracts.


Primary structure of protein L10 from the large subunit of Escherichia coli ribosomes. The complete primary structure of protein L10 from the large subunit of the Escherichia coli ribosome has been determined. L10 is composed of 165 residues and has the amino acid composition: Asp6, Asn3, Thr9, Ser6, Glu14, Gln4, Pro5, Gly9, Ala33, Val15, Met5, Ile5, Leu15, Tyr3, Phe6, His1, Lys12, Arg13 and Cys1. The molecular weight of L10 is 17 738. The amino acid sequence was determined by a combination of automated Edman degradation of the intact protein in a modified Beckman sequentor and sequencing peptides obtained from digestions with trypsin, themolysin, Staphylococcus aureus protease and chymotrypsin. Further information was obtained from cyanogen bromide fragments and peptides resulting from digestion with trypsin after protection of the epsilon-amino groups of the lysine residues with exo-cis-3,6-endoxo-delta4-tetrahydrophthalic anhydride (ETPA).


[Chemotherapy of acute malaria attacks in patients returning from tropical and subtropical countries (author's transl)]. The number of primary malaria attacks caused by imported infections notified in the Federal Republic of Germany during the period of 1963 through 1975 has increased five fold from 30 to 154 per year. The total number of deaths in the same period was 55. This gave rise to outline again the established methods of chemotherapy and their parasitological basis. The chloroquine resistance of P. falciparum strains is discussed. No causal relationship exists between drug resistance and the fatalities by imported malaria. The need for early diagnosis and treatment in falciparum malaria is emphasized. In order to avoid diagnostic difficulties in medical practice it is suggested to have blood films for parasitological diagnosis sent to a specialized laboratory, and to start chloroquine treatment immediately without awaiting confirmation or rejection of the diagnosis. This procedure would minimize the risk for the patient and would cause no harm if malaria should not be confirmed.


[Experimental study of the effect of a broad-spectrum disinfectant containing iodine on bacteria and dermatophytes (author's transl)]. The effect of a broad-spectrum disinfectant containing iodine on four bacterial species and five dermatophytes was investigated. Both the solution and the ointment demonstrated good disinfection of the skin surface with regard to these bacteria and dermatophytes.


Immunosuppressive effect in mycobacterial adjuvant emulsions of mineral oils containing low molecular weight hydrocarbons. Bayol F preparations from different commercial sources were incorporated into water-in-oil emulsions containing mycobacterial fractions and a protein antigen. It was found that an adjuvant effect was obtained with some mineral oils and a toxic immunosuppressive effect with others.


Immunoglobulins, complement and foreign antigens in human tumor cells. Fluorescein-labeled antibodies (FA) to human immunoglobulins, complement, fetal proteins and other antigens were used to search for these immunologic reactants in malignant and benign neoplasia as well as in control tissues. The FA reacted with five or more target antigens in 42 of 59 (70%) malignant tumors and 21 of 23 (40%) benign tumors. The remaining neoplasia and normal tissues showed positive staining with fewer than five specific antibodies. IgM, IgA, B1C, fetal proteins and HSV were the antigens found most frequently. This indicates that neoplasia exhibits immunologic activity more frequently than normal tissue.


Structure and biological functions of human IgD. VII. IgD antinuclear antibodies in sera of patients with autoimmune disorders. Indirect immunofluorescent tests were employed to study antinuclear antibodies (ANA) of the IgD class in sera from patients with autoimmune disease. In sera containing IgG-ANA, IgD-ANA was detected in 48% of patients with systemic lupus erythematosus, 37% with rheumatoid arthritis, 30% with Raynaud's disease, 23% with systemic scleroderma and 20% with discoid lupus erythematosus. Quantitative comparison of serum IgG, IgA, IgM and IgD between IgG-ANA-positive sera with and without IgD-ANA revealed that patients with IgD-ANA also had elevated serum IgA levels. The detection of IgD-ANA in over 36% of the patient population suggests that IgD may play a role in autoimmune disorders.


A RAST neutralization test for detection of blocking antibodies in serum after hyposensitization. The RAST, originally developed for the assay of reaginic IgE antibodies, was applied for the detection of blocking antibodies. Sera taken ante- or post-hyposensitization were incubated with solid phase coupled allergen which neutralized reaginic IgE antibodies in the serum. The remaining activity of the reaginic IgE antibodies was measured by the RAST. When blocking antibodies were present in the serum they competed with the reaginic IgE antibodies and the amount of reaginic antibodies that was neutralized by the solid phase coupled allergen was decreased. The blocking antibodies were found in the IgG fraction of the serum taken post-hyposensitization. Blocking antibodies to various allergens were detected in 25 out of 26 tests on sera taken post-hyposensitization. The results were compared with those of Prusnitz-Küstner neutralization tests and/or patient self-neutralization tests. There was no correlation between semi-quantitative results of these in vivo tests and those of the RAST neutralization tests. However, cases with subjectively a strong improvement had a significantly higher mean value for RAST neutralization index than those with subjectively a weak improvement. The method is suggested as a supplement to clinical tests for evaluation of hyposensitization treatments.


Improved compatibility of ALG therapy by application of aggregate free globulin. Horse anti-human lymphocyte globulin (ALG) solutions contain, like human gamma-globulin preparations, a varying amount of IgG aggregates, which increase during longer periods of storage. Aggregate formation does not impair the immunosuppressive potency of ALG, as has been shown by prolongation of skin allograft survival time in primates. Deaggregated ALG, which can be obtained by ultracentrifugation at 100,000 g over 2 h, is less immunogenic than aggregate containing ALG. The clinical compatibility of ALG was significantly improved by ultracentrifugal deaggregation.


Studies on immune responses to parasite antigens in mice. IV. Inhibition of an anti-DNP antibody response with the antigen, DNP-Ficoll containing phosphorylcholine. Several nematode parasites contain phosphorylcholine (PC), and mice infected with Ascaris suum and Nippostrongylus brasiliensis produce IgM anti-PC antibodies. PC is a hapten which usually induces highly restricted antibody responses in mice and the conjugate DNP-Ficoll-PC inhibits an adoptive secondary anti DNP antibody response to DNP-flagellin whereas comparable doses of DNP-Ficoll and Ficoll-PC do not. The finding suggests that the restricted anti-PC responses to PC-containing antigens described in the literature may involve a degree of inhibition within the B-cell population (partial tolerance induction), that uni- and multi-cellular parasites of various types may 'utilize' molecules such as PC to induce a state of selective tolerance to parasite antigens, and that such a mechanism may be one means of facilitating survival of the parasites in their hosts and the production of antigenic variants of the parasite.


Effect of vinblastine on the early events in the humoral immune response of mice to SRBC. The effect of vinblastine (VLB), a mitotic blocking agent, on the number of plaque-forming cells (PFC) and on the metabolic activities of spleen cells of mice reimmunized with SRBC was studied. When VLB (75 mug/mouse) and antigen were administered simultaneously, the number of pfc, on the 4th day after immunization, was reduced to 40% of control levels. However, when the same amount of VLB was administered to mice 24 h after immunization, it reduced the number of PFC to 10% of control levels. The possibility that VLB exerts a specific cytotoxic effect on preformed PFC either in vivo or in vitro was ruled out. A direct profound effect of VLB on antigen-stimulated cells was observed when VLB was injected 24 h after reimmunization, and the incorporation rates of radioactive precursors into macromolecules by spleen cells were measured at 4-hour intervals. VLB suppressed completely the antigen-induced peak of 3H-thymiding incorporation, while it had no effect on the incorporation rate of 3H-uridine and only a slight effect on the incorporation rate of 3H-amino-acids by the same cells. The results suggest that the decrease in number of PFC caused by injection of VLB 24 h after immunization is due to prevention by VLB, of precursor cells from going through a critical cell division, which takes place later than 24 h after immunization. Thus, at least one cell division is required for an immune response in vivo.


Enhancement of humoral immune responses. I. Potentiating influence of purified protein derivative on the invitro immune response of spleen cells sensitized to Mycobacterium bovis and Mycobacterium avium. Addition of purified protein derivate (PPD) to suspension cultures of spleen cells from swine sensitized to Mycobacterium bovis and Mycobacterium avium resulted in marked enhancement of antisheep erythrocyte plaque-forming cells after stimulation with sheep erythrocytes. The enhancing effect appeared early in the response and was specific for the sensitizing antigen. The enhancing effect was dependent upon the presence of both sheep erythrocytes and PPD in the culture system. PPD had no effect in the absence of sheep erythrocytes. Addition of PPD to cells from nonsensitized animals did not produce any enhancing effect.


An immunological investigation of a family with chronic mucocutaneous candidiasis. Chronic mucocutaneous candidiasis in two siblings of consanguineous parents suggested an autosomal recessive transmission of the disease. We evaluated the two affected persons and 21 members of their kindred for an inherited immunological defect. Six members of the kindred, including both patients, had negative skin-delayed hypersensitivity to Candida. The lymphocytes of both patients and three asymptomatic relatives had diminished in vitro blastogenic response when cultured with Candida albicans. Because the defect occurred in clinically unaffected relatives, we concluded that the lack of blastogenic response to C. albicans was not the only determinant for or may be unrelated to the clinical manifestations of the disease.


Immune mechanisms affecting bovine leucocytes during suppression of tuberculin skin sensitivity in cattle. Complete desensitization to tuberculin skin-testing (anergy) was produced in cattle by repeated intravenous injections of living BCG organisms into animals sensitized by a prior subcutaneous dose of BCG. Two levels of desensitization were produced; complete desensitization following 10 i.v. doses and partial desensitization following 5 i.v. doses of 100 mg BCG. Intradermal tuberculin testing at the end of the experiment stimulated the appearance of reactive blood lymphocytes in sensitized cattle as measured by in vitro 3H-thymidine uptake. The cattle which were partially desensitized showed this response but the completely desensitized cattle did not. Reactivity of blood lymphocytes in vitro to PHA and Brucella abortus antigen was not depressed in the anergic cattle. Serum antibody titres to BCG polysaccharide, PPD, or whole BCG organisms showed remarkably little change during the i.v. desensitizing injections of BCG. Differential blood leucocyte counts also remained within normal limits during this period. The production of MIF by blood lymphocytes from the anergic cattle appeared to be unimpaired. Using 3H-thymidine uptake by lymphocytes from sensitized cattle did not inhibit lymphocyte stimulation with tuberculin. It was concluded that the lack of tuberculin sensitized lymphocytes in the blood of anergic cattle may have been due to their removal from the recirculating pool and their continued suppression in lymphoid tissue.


Organ distribution of immunocompetent cells in guinea pigs. II. Spleen, lymph node, bone marrow, or thymus cells in the restoration of the splenic plaque-forming cell response to sheep erythrocytes after irradiation. The splenic plaque-forming cell response of inbred guinea pigs to sheep erythrocytes was abolished by whole-body X-irradiation with 600 rad. The minimum doses of various cell types from normal syngeneic donors to restore the response significantly were 100 X 10(6) spleen or lymph node cells or 500 X 10(6) bone marrow or thymus cells. The combination of 100 X 10(6) thymus and 100 X 10(6) bone marrow cells provided statistically significant restoration, but not much more than 100 X 10(6) bone marrow cells alone. The lack of thymus-marrow synergism suggests that in guinea pigs the antigen-reactive cells and antibody-forming cell precursors are not in the same way enriched in the thymus and bone marrow as in mice.


Production of migration inhibitory factor in inbred rats. Strains of genetically inbred rats representative of the known Ag-B groups produced migration inhibitory factor in response to immunization with live bacillus Calmette-Guerin bacilli and intracardiac challenge with old tuberculin; the assays were performed by both in vitro and in vivo methods. None of the strains immunized in this fashion developed delayed hypersensitivity skin reactions to purified protein derivative.


Characteristics of hyperacute rejection of swine kidney xenografts perfused with canine blood. Twenty-five swine kidney xenografts previously flushed with Collins-4 solution were perfused with canine blood and the functional and morphological changes resulting from xenoperfusion were studied. Blood flow of the kidneys practically ceased by the end of 8 minutes parallel with progressive swelling and cyanosis of the organ. Microscopic study of the kidneys revealed gross destruction of the glomerular and tubular apparatus, marked by extensive oedema, interstitial haemorrhages, diffuse capillary thrombosis and damage to the cell membrane.


Prophylactic central nervous system therapy in childhood acute lymphatic leukemia. Effect of poor-risk patients on the results. The results of treatment in a group of 50 children with acute lymphatic leukemia are summarized. A comparison was made between those who received prophylactic central nervous systen (CNS) therapy on attaining complete remission and those who did not. Although none of the prophylactically treated children developed CNS leukemia, the expected prolongation of median complete remission time was not achieved. It was found that there was a high percentage of poor-risk patients in the CNS-treated group, and these patients relapsed early in the course of the disease. The prevention of CNS leukemia, a late complication of the disease, did not change the natural course of the disease in poor-risk patients. A need exists for new treatment protocols aimed at better control of the disease in these poor-risk cases.


[Sugar consumption and prenatal acceleration. I. Studies in the history of medicine on the coincidence and connection of these 2 secular phenomenon]. A comparative historic evaluation reveals an astonishing world-wide relationship between prenatal acceleration, i.e. secular changes of birth-weight and percentage of "large babies", of distinct population groups, and their sugar consumption. They seem to be "connected" as they are regularly "conjoined" (HUME [46]). A statistically highly significant correlation between these two phenomena was established for Switzerland and Germany. The assumption of a causal relationship was confirmed by the abrupt development of growth acceleration together with the rapid increase in the per capita sugar consumption observed in an experiment-like situation in certain Canadian Eskimo populations in recent years.


Immunofluorescent antibodies against gliadin: a screening test for coeliac disease. A sensitive and simple immunofluorescence test for gliadin antibodies is described, which may be suitable as a screening method for coeliac disease especially in cases with no clear-cut indication for performing a biopsy. In serum samples of 19 from 23 patients (83%) with coeliac disease proved by biopsy antibodies against gliadin could be detected. In a control group of 71 children in whom the clinical diagnosis of another malabsorptive disorder was made gliadin-IF-antibodies were found in only 3 children (4%). With better timing of blood sampling (first sample during a period with gluten containing food and in case of a negative result a second sample after 4-8 days of gluten withdrawal) the sensitivity of the screening test will be improved. The described gliadin-IF-test permits the classification of the antibodies into the different immunoglobulin classes. In each child with a positive result IgG antibodies against gliadin were detected. In 9 respectively 4 of the 19 patients with IgG antibodies IgA- respectively IgM-antibodies against gliadin were also found. Antibodies against at least one cow milk protein were identified in nearly all (91%) coeliac patients and in half (49%) of the patients with other malabsorptive disorders.


Nature of Escherichia coli mutants deficient in detergent-resistant and/or detergent-sensitive phospholipase A. 1. Escherichia coli K-12 mutants deficient in detergent-resistant (DR) and detergent-sensitive (DS) phospholipases A and deficient in DS phospholipase A were isolated. 2. The growth, compositions of phospholipids and fatty acids and turnover of phospholipids of three mutants (DR-, DS-, DR-DS-) were compared with those of their parent (DR- was isolated in a previous study). 3. Autodegradations of membrane phospholipids of 18,000 X g supernatants and precipitates of the homogenates of these three mutants were also compared with those of the parent, and the effects of various detergents and organic solvents on these activities were examined. 4. We could not identify any significant physiological role for DR or DS phospholipase A.