Operational characteristics of liquid-conditioned suits. The data from several studies of liquid-conditioned suits carried out over the last 12 years at the RAF Institute of Aviation Medicine have been collated, collectively reanalysed, and used to describe the characteristics of personal liquid-conditioning systems in terms of interactions between the conditioning and the conditioned system. Heat exchange across a liquid-conditioned suit (LCS) is shown to be proportional to the inlet temperature (Tin) of the conditioning liquid. Choice of Tin is determined, for resting subjects, primarily by the environmental temperature, by the length of the heat exchange tubing, and by the insulation value of the clothing worn over the LCS. Mean skin temperature (Tsk), but not core temperature (Tc) is directly related to Tin. However, certainly in exercising subjects, steady-state values for Tc can be increased by selecting very low values for Tin, which reduce Tsk below 29 degrees C. It is suggested that mean Tsk should not fall below 30 degrees C when the LCS is used for personal cooling. When the LCS is used for personal heating, sweating should be minimised, or prevented, by not allowing Tsk to rise to levels sufficient to cause an increase in Tc.


Criminal justice system behavior.

Criminal justice system behavior. Much has been written recently about the underlying motivation of criminals and about the behavior of the criminal justice system itself. Typically, such studies have shown negative correlations between crime rate, probability of apprehension and probability of conviction. However, in addressing the behavior of the system, the present study examines measures of workload for the criminal justice system rather than performance indicators such as those above. Preliminary evidence is examined over several provinces of Canada and is used to investigate the hypothesis that there is adaptation by different subsystems in the criminal justice system to changing workloads in other parts. The initial findings show that present upstream, i.e., toward the beginning of the system, workload affects future behavior of the system downstream, i.e., toward the end, rather than the reverse, especially for the more serious crime types.


Evidence for the presence of two sympatric species of mice (genus Mus L.) in southern France based on biochemical genetics. Populations of mice established outdoors as well as indoors have been investigated at 24 loci using starch gel electrophoresis. Two reproductively isolated groups are recognized, one of which is referable to a house mouse subspecies, Mus musculus brevirostris, and the other to a different species. Mus spretus, contrary to the view of Schwarz and Schwarz that only one species of Mus is present in the Mediterranean Basin. The genetic distance between these two groups is larger than between any pair of investigated subspecies of M. musculus. M. m. brevirostris is biochemically almost indistinguishable from M. m. domesticus. On the other hand, M. spretus exhibits several allelic variants unknown or at most very infrequent in M. musculus, as for instance at the lactate dehydrogenase B-chain locus.


An acid phosphatase locus expressed in mouse kidney (Apk) and its genetic location on chromosome 10. A genetic locus controlling the electrophoretic mobility of an acid phosphatase in mouse kidney is described. This locus, called acid phosphatase-kidney (Apk), is not expressed in erythrocytes, liver, spleen, heart, lung, brain, skeletal muscle, stomach, or testes. The product of Apk hydrolyzes the substrate naphthol AS-MX phosphoric acid but is not active on alpha-naphthylphosphate or 4-methylumbelliferylphosphate. It is not inactivated by 50 C for 1 hr, nor is its electrophoretic mobility altered by incubation with neuraminidase. The locus is invariant among 31 inbred strains (Apka), with a variant allele (Apkm) observed only in Mus musculus molossinus. Codominant expression was observed in F1 hybrids of M. m. molossinus and inbred strains. Apk was mapped on Chr 10, near the neurological mutant waltzer (v).


A second gene affecting the sialylation of lysosomal alpha-mannosidase in mouse liver. We have previously reported on a mouse liver-specific genetic polymorphism associated with altered sialylation of lysosomal alpha-mannosidase. A second electrophoretic polymorphism for liver lysosomal alpha-mannosidase has now been found and characterized. This variation, between SWR/J and SM/JCv inbred mice, is determined by a single genetic locus (Map-2) on chromosome 17 and appears to be the result of further differences in sialylation of the lysosomal enzyme. The Map-2 gene appears to affect the processing of liver, spleen, and lung lysosomal alpha-mannosidase, whereas the Map-1 gene appears to be specific to the processing of liver lysosomal alpha-mannosidase (Dizik and Elliott, 1977). The more negatively charged electrophoretic liver phenotype (MA-A) characteristic of the SM/JCv strain is recessive to the phenotype (MA-B) characteristic of the SWR/J strain. In contrast, at the Map-1 locus, the more negatively charged phenotype is dominant. The electrophoretic pattern of development of the liver enzyme from SM/JCv mice is described.


Autosomal inheritance of phosphoglycerate kinase in the domestic chicken (Gallus domesticus). Electrophoretic variants of the glycolytic enzyme phosphoglycerate kinase (PGK) in the domestic chicken, Gallus domesticus, were found to be inherited in an autosomal manner. No sperm-specific isozyme of PGK exists in the chicken. This is in direct contrast to previous results from therian (placental and marsupial) mammals in which there are two isozymes of PGK, an autosomal form largely or wholly confined to sperm and a sex-linked form found in most other tissues. The implications of these and other results for the question of homology between the avian Z chromosome and the mammalian X chromosome are discussed. It is concluded that there is no evidence of homology between the X chromosome and the Z chromosome.


Genetic and biochemical analysis of cycloheximide resistance in the fungus Podospora anserina. Genetic analysis of cycloheximide-resistant mutants has shown that at least three genes control the resistance to cycloheximide in Podospora anserina and that the antibiotic resistance is recessive to sensitivity. In vitro and in vivo studies of protein synthesis indicated that for two mutants cycloheximide resistance is associated with the ribosomes. For one of these mutants, the elongation step in protein biosynthesis is insensitive to cycloheximide over a wide range of concentration. In this mutant the resistance to cycloheximide is a property of the 60S subunit.


Estimating total genic diversity in the house mouse. In a survey of variation in both electrophoretic charge and thermostability at 14 structural loci in 40 strains of Mus musculus, 27 electromorphs (polypeptides differing in electrophoretic charge) and 20 thermomorphs (polypeptides differing in thermostability) were found. Electrophoresis detected 11 new variants within thermomorphs, and the heat denaturation technique detected four new variants within electromorphs. From these data, and making the assumption that both techniques are independent of each other, it is estimated that the actual total number of alleles at the 14 loci is 53, or an average of 3.79 per locus (1.96 per electromorph), and that electrophoresis apparently detects one-third of the variants, thus describing about 50% of the alleles at structural gene loci in the house mouse.


Inheritance and linkage analysis of five enzyme loci in interspecific hybrids of toadlets, genus Bombina. Progeny produced from Bombina bombina, B. variegata, and field-collected interspecific hybrids have been analyzed for the inheritance of five enzyme loci, which are fixed for alternate alleles in the parental species. Lactate dehydrogenase (Ldh-1), NAD-dependent malate dehydrogenase (Mdh-1), creatine kinase (Ck), adenylate kinase (Ak), and glucosephosphate isomerase (Gpi) are all inherited in a Mendelian manner as codominant alleles at nuclear loci. Both parental alleles are equally functional in artificial F1 hybrids (female B. bombina x male B. variegata) at each of the loci studied. No linkage between any pair of loci was observed. Discovery of this inherited biochemical variation combined with a technique for assaying individual genotypes without killing the animals makes feasible studies of hybrid population structure heretofore impossible.


Messenger RNA for the insect storage protein calliphorin: in vitro translation and chromosomal hybridization analyses of a 20 S poly(A)-RNA fraction. A major poly(A)-containing RNA fraction of the approximate size expected of a monocistronic mRNA for the storage protein calliphorin has been isolated from the larval fat bodies of Calliphora vicina during early instar 3. This 20 S RNA fraction programs the synthesis by cell-free wheat embryo extracts of polypeptides of 86,000 daltons identified by tryptic peptide fingerprinting as precursors of the authentic calliphorin subunits of 83,000 daltons. Complementary DNA synthesized by AMV reverse transcriptase using the same 20 S RNA as template hybridized in situ to a single segment of one or two bands in the salivary polytene chromosomes of C. vicina.


Carbon monoxide-induced arterial wall hypoxia and atherosclerosis. The elevated carbon monoxide level found in tobacco smokers has been suggested as one etiologic factor linking it with atherosclerosis. Unquestionably carbon monoxide does induce some arterial wall hypoxia, which has been established as an atherogenic factor, but without knowing the extent and location of this hypoxia the importance of this mechanism could not previously be assessed. Carbon monoxide acts both by inducing hypoxemia and shifting the oxyhemoglobin equilibrium curve, with these effects acting on the oxygen transport system from both the luminal blood and the vasa vasorum. We have studied this system using a computer simulation of the human arterial wall and found significant, mid-medial hypoxia with blood carbon monoxide levels routinely found in smokers. Because these levels fluctuate, the hypoxia they induce would be expected to be uncompensated by increased vascularization and therefore potentially represent a much more significant factor in atherogenesis than chronic hypoxia alone.


Platelet factors and the human vascular wall: variations in growth response between endothelial and medial smooth muscle cells. In the present investigations, the effects of platelet factors on DNA-synthesis by human arterial and venous smooth muscle and venous endothelial cells were compared. Also studied was the role of such factors in restimulating quiescent endothelial cultures and in endothelial reaction to injury. Aortic smooth muscle cells grown in medium containing 10% human serum prepared from plasma poor in platelets (PPPS) reached 9.7%+/-SE 0.65 labelling index when continuously exposed to [3H] thymidine (1 muCi/ml). When lysate from gel-filtered platelets was added, the index was 19.4% +/- SE 1.13 (P less than 0.01) and in the presence of serum derived from platelet rich plasma (PRPS) it reached 24.6% +/- SE 1.22 (P less than 0.01). Similar results were obtained with smooth muscle cells from umbilical veins. In constrast, platelet factors did not significantly affect DNA-synthesis in endothelial cultures. They reached 25.6% +/- SE 1.97 when grown in medium containing PPPS as compared to 21.9% +/- Se 2.53 (P greater than 0.05), when exposed to PRPS. The ability of sera to stimulate DNA-synthesis in endothelial cultures rendered quiescent by 24 h exposure to medium containing 1.4% serum albumin (labelling index 1.83% +/- SE 0.14) was not affected by platelet factors. Platelet lysates alone were not sufficient to restimulate the quiescent  cells (labelling index 3.03% +/- SE 1.06) (P greater than 0.05). Platelet factors did not affect the proliferative response following experimental mechanical injury to endothelial monolayers in vitro. We conclude that while platelet factors are essential for human vascular smooth muscle cells to achieve optimal growth, they are not indispensable for endothelial cell proliferation. It is suggested that these cellular differences in growth requirements may play an important role in human atherogenesis.


Lipoprotein-lipase activity in human skeletal muscle and adipose tissue in the fasting and the fed states. Sixteen healthy subjects, 7 females and 9 males, with a mean age of 25 years (range 22--29 years), were studied in the fasting state in the morning and 8 h later after partaking of breakfast, lunch and two small meals. The lipoprotein-lipase activity in the adipose tissue increased significantly from 80 +/- 32 to 117 +/- 61 nmol fatty acid released per gram and minute (nmol FA/g/min), whereas in skeletal-muscle tissue it decreased significantly from 25 +/- 11 to 17 +/- 9 nmol FA/g/min. The concentration of serum triglycerides increased significantly from 0.93 +/- 0.18 mmol/l (mean +/- SD) in the fasting state to 1.57 +/- 0.64 mmol/l in the fed state. In the fasting state the lipoprotein-lipase activity of skeletal muscle was inversely related to the ratio between the concentrations of insulin and glucagon.


Effect of THD-341, a new hypocholesterolemic agent, on experimental atherosclerosis in rabbits. The influence of THD-341, N-(2,6-dimethylphenyl)-delta8-dihydroabietamide, upon the formation and regression of atherosclerosis and on serum and liver lipid levels has been studied. When rabbits were fed a 1% cholesterol diet for 7 weeks, THD-341 added at a dietary level of 0.01% during the last 4 weeks almost completely prevented the formation of atherosclerotic lesions and the elevation of serum and liver cholesterol levels. When the drug was fed for 10 weeks, either in the normal or cholesterol diet, to rabbits with pre-established atherosclerosis induced by cholesterol feeding for 11 weeks, it did not affect the extent or severity of the lesions but inhibited the progression of lipid deposition in the aorta in a group fed the cholesterol diet during the final 10-weeks period. The reduction of serum and liver cholesterol levels was greater in the drug-treated groups than in the normal rabbit chow-fed group.


Cholesteryl ester metabolism in fat- and cholesterol/fat-fed guinea pigs. Guinea pigs were fed a semisynthetic diet containing 10% (by weight) cottonseed oil with or without 1% cholesterol. In response to cholesterol/fat feeding there was a significant accumulation of cholesteryl ester (CE), particularly in the liver, but also in the kidney, spleen and suprarenal glands. The hepatic acyl-CoA:cholesterol acyltransferase (ACAT) increased 5-10 times when the animals were fed cholesterol fat during 11 weeks while the acid cholesterol esterase (CE-ase) was similar in the two dietary groups. Intestinal lymph showed the highest content of cholesterol (both free and esterified) in guinea pigs fed cholesterol/fat. A low activity of lecithin:cholesterol acyltransferase (LCAT) was present in the intestinal lymph, irrespective of dietary composition. Triglyceride-rich lipoproteins seem to inhibit LCAT activity in the intestinal lymph. Plasma cholesterol levels in animals fed cholesterol/fat increased markedly while LCAT remained unaffected by the diets. Activity of ACAT and CE-ase in kidney and spleen was low compared to liver tissue and the enzyme activities were not affected by the cholesterol/fat feeding.


Hypertension-induced cerebral atherosclerosis in the cholesterol-fed rabbit. Foam cell lesions were found in cholesterol-fed rabbits with induced hypertension, particularly in intimal cushions at branching sites, where permeability to horseradish peroxidase was enhanced. Permeability to horseradish peroxidase was enhanced at the edge of intimal cushions without foam cell accumulation. This finding suggests that permeability is increased before foam cell infiltration. No foam cell lesions were observed in the intima of cerebral arteries distant from branching sites, but insudation of plasma constituents here caused endothelial cells to separate from the subendothelial matrices. Foam cell lesions were absent from the cerebral arteries in normotensive cholesterol-fed rabbits.


Mode of action of the lipid-lowering agents, clofibrate and BM 15075, on cholesterol biosynthesis in rat liver. When rats were fed a diet containing 0.3% clofibrate or a derivative of this drug, BM 15075, serum cholesterol was lowered within 3-7 days by 26-38%. Both drugs diminished the activity of hydroxymethylglutaryl CoA reductase, the regulatory enzyme of hepatic cholesterol biosynthesis, in rat liver microsomes by about 60% under the same conditions. The decrease in the activity of the enzyme obviously is due to changes in the amount of enzyme protein. Under in vitro conditions microsomal hydroxymethylglutaryl CoA reductase was inhibited competitively by (1.35 mM) clofibric acid (sodium salt) and by BM 15075 (1 mM) with respect to its substrate. These results give evidence that these drugs can affect both, the rate of synthesis and the substrate affinity of hydroxymethylglutaryl CoA reductase.


Effect of metformin on lipid metabolism in the rabbit aortic wall. The aim of the present study was to investigate whether metformin was capable of altering aortic lipid metabolism. Pretreatment of rabbits for 8 days with 120 mg/kg per os metformin reduced by 50--70% the incorporation of a 20 muCi tracer doseof [4(-14)C]cholesterol (given orally 24 h before) into various segments of aorta, plasma, liver, intestine and lung, as compared with control animals. However, as intestinal absorption of cholesterol was also diminished in the same proportion, it was then decided to inject the labelled cholesterol directly into the blood. Under these conditions, metformin induced the same reduction in [4(-14)C]cholesterol specific activity in the aorta, but not in other tissues. Three hours after intravenous injection of a 200 muCi tracer dose of [2(-14)C]-acetate, metformin strongly diminished the radioactivity of total lipids of the aorta, both in fed-rabbits and in rabbits on a 24 h fast, independently of the plasma radioactivity level. The inhibition of acetate incorporation into arterial lipids was observed in all lipid fractions (i.e. free and esterified cholesterol, free fatty acids, phospholipids and especially triglycerides) and the effect persisted unaltered over periods of increasing length after the injection of precursor (1/4, 1/2, 1, 3, 5, 8, 12 h). Metformin also significantly inhibited lipid biosynthesis in the liver and intestine. These properties, added to others previously described, can to a large extent explain the preventive effect of metformin on experimental atherosclerosis.


The dissolution of cholesterol monohydrate crystals in atherosclerotic plaque lipids. Uncomplicated human atherosclerotic plaques often contain large amounts of cholesterol esters and solid cholesterol monohydrate crystals. If such plaques are to regress the crystalline cholesterol would have to dissolve and be transported out of the arterial wall. Since cholesterol is quite insoluble in water, dissolution of plaque crystals might occur through lipids in the plaque, specifically, the cholesterol esters. As part of a study on feasibility of plaque reversal we have studied a specific step involving the dissolution of cholesterol monohydrate into cholesterol ester oil. With specific considerations of the composition and physical state of the cholesterol ester solvent, the size and form of cholesterol monohydrate crystals, the agitation rate, the temperature and the presence of water, we have found that cholesterol esters are an efficient solvent for cholesterol monohydrate crystals. The rate of dissolution was fast reaching 90% of saturation in 1 h. We conclude dissolution of cholesterol monohydrate into cholesterol ester oil is not a rate-limiting step in reversal of the atherosclerotic plaque. We suggest that transport of dissolved cholesterol from cholesterol ester oil may limit the removal. If transport of dissolved cholesterol could be enhanced, cholesterol monohydrate crystals could be rapidly dissolved and facilitate reversal of atherosclerotic lesions.


Comparison of absorption and metabolism of beta-sitosterol and beta-sitostanol in rats. The fates of [4-14C]beta-sitosterol ([14C]S) and [4-14C]beta-sitostanol ([14C]HS) were compared after after oral or intravenous administration to rats. Excretion into feces of oral [14C]HS was significantly higher than that of [14C]S. More than 97% of [14C]HS and 88% of [14CS]S were recovered in the feces within 7 days. Thus, deposition of [14C]HS was negligible in the tissues that were examined. Turnover in serum of [14C]HS which was injected intravenously appeared to be more rapid than that of [14C]S; [14C]HS was excreted as neutral steroids at a rate more than twice that of [14C]S. The rate of excretion of [3H]cholesterol was slightly greater when HS was administered simultaneously. The liver contained significantly less radioactivity after [14C]HS than after [14C]S administration. More [14C]HS than [14C]S was present in esterified form in serum and liver. The ratio of sterol in very low density lipoprotein to that in high density lipoprotein was less for HS or S than for endogenous cholesterol; this was particularly marked with HS. These results suggest that HS would be a more effective hypocholesterolemic agent than S.


A language for computer generation of medical data forms. In this paper we describe the main features of a small-scale plotting language used to produce medical data forms. It requires no previous knowledge of computers and is easily learned and used. Its use at the Statistical Laboratory at the State University of New York at Buffalo has resulted in considerable time savings, a greater unification of data items and data forms, and an increase in the quality of data collected.


Chemical modifications of tyrosyl residue(s) and action of human-fibroblast interferon. Partially purified and purified human fibroblastoid interferon were iodinated and nitrated under experimental conditions in which the most likely amino acyl residue modified was tyrosine(s). The modification resulted in a loss of human interferon activity suggesting that tyrosyl residue(s) is associated with the antiviral action of human interferon.


Growth cones of cultured sympathetic neurons contain adrenergic vesicles. The growth cones of dissociated rat sympathetic neurons developing in culture were fixed with potassium permanganate to visualize vesicular stores of norepinephrine through the formation of granular precipitates. It was found that growth cones contain numerous small granular vesicles (SGV) 40-60 nm in diameter. The majority of the SGV was present in the varicosity of the growth cone but SGV also occurred in filopodia. The SGV appeared in clusters or scattered throughout the varicosity. Treatment of the cultured neurons, before fixation, with reserpine, which depletes catecholamine stores by blocking uptake into vesicles, resulted in the presence of small clear vesicles. In contrast, growth cones of nonadrenergic sensory neurons dissociated from dorsal root ganglia and fixed with permanganate lacked SGV and possessed small clear vesicles. These observations indicate that the growth cones of cultured sympathetic neurons contain norepinephrine, suggest that the norepinephrine is stored in synaptic vesicles, and raise the question whether this transmitter plays a role in early axon-target cell interactions during synapse formation.


Inheritance of low serum immunoglobulin D. Previous studies have shown that log IgD levels in normal individuals are distributed in a nonunimodal manner. Therefore, in this study we tested whether inheritance might play a role in determination of IgD levels. IgD levels were measured in serum or plasma from 301 randomly selected children aged 6-18 yr, 245 consecutive adult blood donors, and 134 first-degree relatives of subjects with low IgD levels. Comparison of serum and plasma from five individuals revealed no difference, so the two were used interchangeably. The distributions of log IgD levels in randomly selected populations of both adults and children were nonunimodal with nadirs at 2.15 IU/ml. In both of these randomly selected populations, 13-14% of the subjects had low IgD values (<2.15 IU/ml). In addition, there was a significant sibling-sibling correlation of log IgD values (r = 0.56, n = 72, P <0.01). Because of the nonunimodality of the frequency distribution histogram for IgD values and because of the familial aggregation of these values, the study was extended to include first-degree relatives of subjects with low plasma IgD. Blood samples from 92% of living first-degree relatives, 134 individuals, were analyzed for their level of IgD, and the results of segregation and pedigree analyses of these data were compatible with autosomal recessive inheritance of an allele for low plasma IgD levels. IgD values in plasma from siblings of probands for low IgD were also non-unimodal in distribution with a nadir at congruent with2.15 IU/ml. The results suggest that there is autosomal recessive inheritance of an allele for low plasma IgD.


Minimal oxygen consumption in infants cared for under overhead radiant warmers compared with conventional incubators. Infants under radiant warmers have large increases in insensible water loss compared with infants in single wall incubators. To answer the question of whether or not a minimal rate of oxygen consumption could be achieved under overhead radiant warmers, we measured oxygen consumption, carbon dioxide production, and abdominal skin, cheek, rectal, thigh, and environmental temperature in ten healthy newborn infants in incubators and radiant warmers, using each infant as his/her own control. The minimal VO2 ranged from 4.41 to 8.87 and from 4.35 to 9.06 cc/kg/minute in the incubator and radiant warmer, respectively. The differences were clearly not significant (paired Student t-test, P greater than 0.60). There were no significant differences between the respiratory quotients, VCO2, or abdominal skin, check, rectal or environmental temperatures. These data support the hypothesis that a thermoneutral environment can be provided with a radiant warmer and imply that large increases in insensible water loss can occur without affecting minimal oxygen consumption.


Fever and survival: the role of serum iron. 1. The effects of bacterial infection and temperature on serum iron levels were investigated in the lizard Dipsosaurus dorsalis. 2. Changes in body temperature from normal (38 degrees C) to febrile (41 degrees C) did not alter serum iron levels. Injection with Aeromonas hydrophila led to a significant reduction in serum iron levels, comparable to that found in mammals. This reduction in serum iron level was independent of the lizard's body temperature. 3. When grown in vitro, A. hydrophila grew equally well at afebrile (38 degrees C) and febrile (41 degrees C) temperatures. When the iron levels of the growth medium were reduced, the bacterial growth was diminished at the febrile temperature but was not significantly affected at the afebrile temperature. 4. The addition of iron supplements to bacterially infected lizards led to an increase in the percent mortality. 5. These results indicate that one of the mechanisms behind the beneficial, or adaptive value of fever in D. dorsalis is the decrease in iron available to the pathogenic micro-organisms.


Chronic inflammatory gingival and periodontal disease. Gingivitis and periodontitis account for more than 95% of all inflammatory diseases of the tissues surrounding the teeth, comprising the principal cause of tooth loss in adults. Gingivitis is a relatively innocuous inflammation of the gums, with associated bleeding and exudation. Gingivitis may convert to periodontitis, a destructive aggressive disease with resorption of alveolar bone, destruction of collagen with fibrosis, and formation of deep pockets around the necks of the teeth. Gingivitis and periodontitis are caused by microorganisms populating the gingival sulcus and periodontal pocket. Treatment is directed toward arresting the progress of the disease through debridement and stabilization of the teeth. Toothbrushing and other measures by which the teeth are mechanically cleaned remain the most effective way to control plaque accumulation and periodontal disease.


Myofibroblasts and free silicon around breast implants. Fibrous tissue capsules, from around silicone breast implants, were examined by light microscopy, and by transmission and scanning electron microscopy, the latter combined with energy dispersive X-ray analysis. Contractile fibroblasts (myofibroblasts) were found in most of these fibrous capsules, and especially in those recently formed or manipulated. The element silicon was positively identified by X-ray analysis in half the tissue specimens. This material was found only around gel-filled implants. In the specimens studied, the clinical hardness of the breast was unrelated to the presence of silicon in the capsule.


Saccadic velocity studies in Möbius syndrome. Eight patients with Möbius syndrome were examined and their eye movements studied with horizontal saccadic velocity measurements. A marked decrease in velocity of horizontal saccades was noted, indicating both medial and lateral rectus weakness. Significant esotropia, when present, may be improved with conventional recession-resection surgery.


[Squamous cell papilloma of the 3rd cerebral ventricle]. An extremely rare tumor of the III brain ventricle, a squamous cell papilloma, in a man of 49 is described. The localization of the neoplasia without any topical association with the vascular plexus confirms the opinion that squamous cell papilloma of the III ventricle belongs to the group of craniopharyngiomas.


Perception of blur in optometric test.

Perception of blur in optometric test. Sensitivity to blur detection was measured for 30 optometric patients by having them match the clarity [or blur] of the target words at the test endpoint with 1 of an identical set of photographically defocused words. The group showed considerable variance in their blur scores which approached a normal distribution. Some clinical implications are discussed.


Absorption of inhaled antigen into the circulation of isolated lungs from normal and immunized rabbits. The purpose of this study was to determine whether the absorption of inhaled antigen (Ag) across the pulmonary air-blood barrier of the isolated perfused lung can be modulated by immunologic mechanisms. Lungs from immunized or nonimmunized rabbits were removed, ventilated, and perfused with autochthonous blood. Radioiodinated Ag (human serum albumin or ovalbumin) was introduced as an aerosol into the isolated lung for 15 min and blood samples were taken over a 4-h period. The results showed that radioactivity fom inhaled Ag entered the perfusing blood as two fractions. One fraction was precipitable by 5% trichloroacetic acid or antiserum. The TCA-soluble fraction chromatographed differently from iodide and may have represented metabolites of the Ag. Immunization specifically reduced the amount of antigenically intact protein entering the blood. On the other hand, the metabolite reached higher concentrations in the blood of immunized lungs. We conclude that the alveolar capillary barrier of the normal rabbit lung could provide a significant route of entry for inhaled antigen into the systemic circulation and that immunization reduces absorption via this route and enhances pulmonary metabolism of the Ag.


The role of non-biting flies in the transmission of enteric pathogens (Salmonella species and Shigella species) in Beirut, Lebanon. In the summer and early autumn of 1974, flies were trapped in the Beirut districts of Ashraffiyah, Burj, Burj-Hammoud, Quarantine, the New Slaughter House, Ras Beirut, American University Campus, and the suburbs of Chiyah and Mreyjieh. Musca domestica, Muscina stabulans, Calliphora vicina, Phormia regina, Phaenicia sericata, Sarcophagidae spp. and Fannia canicularis were identified. The rural areas of Mreyjieh and Chiyah had higher densities of Musca domestica while higher densities of Calliphoridae spp. were found in the Slaughter House, Quarantine and Burj-Hammoud districts. Twenty-nine isolates, ten of Shigella spp. and 19 of Salmonella spp. were obtained from the bacteriological studies of 72 batches of Muscidae spp. and 84 Calliphoridae spp. These results indicate the hyperendemicity of salmonellosis and shigellosis in the areas under study, due to the prevalent poor sanity conditions and high fly infestation. It is suggested that in countries where valid health statistics are not available, bacteriological studies of flies may provide essential epidemiological information.


Behavioral marriage therapy: I. A psychodynamic-systems analysis and critique. After briefly summarizing the major theoretical premises and treatment strategies of Behavioral Marriage Therapy (BMT), five major clusters of implicit assumptions in BMT are identified and critically examined: I. "The Rational Observing Ego Shall Conquer All"; II. "Behavior Should Not Mean, But Be"; III. "What's Sauce for the Goose is Sauce for the Gander"; IV. "Repression Is Good for Your Marital Mental Health"; V. "The Folly of the Therapist as Technician." Throughout this analysis, the conceptual and clinical limitations of a strictly or predominantly behavioral approach to couples therapy are described, and BMT is reconsidered in the light of object relations theory and communication theory perspectives on marital dysfunction and its treatment.


Renin-sodium profile and its therapeutical implications in arterial hypertension. In 35 patients with moderate or severe essential hypertension (EH) four groups could be identified by plasma angiotensin II (AII) (formula: see text) and by exchangeable sodium (ENa) (formula: see text) determination. In 6 patients with high AII (135.9 pg/ml +/- 26.29) and normal ENa (98.83% +/- 1.40) propranolol significantly lowered both blood pressure (BP) and AII, suggesting that these forms of EH are renin dependent. In 15 patients with normal AII (36.43 pg/ml +/- 2.27) and high ENa (124.23 +/- 2.78) and in 6 patients with low AII (8.36 pg/ml +/- 3.39) and high ENa (125.16% +/- 5.71) the maximal hypotensive effect was achieved after ENa reduction with thiabutazid. These forms of EH appear to be volume-sodium dependent. In 8 patients with increase of both AII (76.53 pg/ml +/- 5.72) and ENa (112% +/- 1.72), propranolol associated with thiabutazid lowered the BP, AII and ENa suggesting that these cases are mixed forms. ENa determination appears to be a reliable index for renin profiling; such a renin-sodium profile allows to identify some pathophysiologic forms of arterial hypertension.


Behavioral marriage therapy. II. Empirical perspective. Two recent published reviews of research on behavioral marriage therapy stimulated us to supplement these accounts with additional relevant data. First, we place research on behavioral couples therapy in the broader context of outcome research on nonbehavioral marital therapy. We then summarized the results of 23 studies of behavioral couples therapy not included in these previous reviews and conclude that these additional data on controlled and comparative studies do little to enhance the current empirical status of efficacy of behavioral marriage therapy and in no case do they establish the superiority of social learning approaches. It is concluded that an open mind to all sources of data on the efficacy of marital therapy is needed if the field is to make meaningful advances.


Behavioral marriage therapy. III. The contents of Gurman et al. may be hazardous to our health. This paper was written as a reply to a critique of behavioral marital therapy (BMT) by Gurman, Kniskern, and Knudson (6, 7). The reply is divided into four sections. First, the paper addresses the critics' comments on the conceptual model put forth by BMT, correcting and clarifying various misconceptions, and restating some of the basic ideological principles in the behavioral model. Second, the paper discusses behavioral change techniques and technology, along with extratechnological treatment considerations. Again, misrepresentations of BMT are corrected. Third, an analysis of the literature investigating the therapeutic efficacy of BMT is reviewed, and the conclusion is reached that BMT is demonstrably effective, at least for a substantial number of mildly to moderately distressed couples. Criticisms are made of the analysis of the same literature conducted by Gurman et al. We conclude that, contrary to the spirit of the paper by Gurman et al., BMT is a viable framework for conceptualizing and treating relationship problems and that the commitment of its adherents to experimental investigation promises continued evolution, refinement, and improvement.


Behavioral marriage therapy. IV. Take two aspirin and call us in the morning. The Jacobson-Weiss critique of the Gurman-Knudson and Gurman-Kniskern discussions of behavioral marriage therapy (BMT), while scholarly, derives from such a narrow conceptual set that, with only minor exceptions, Jacobson and Weiss have failed basically to comprehend the essence of our theoretical and logical criticisms of BMT. Moreover, a careful reanalysis of the research cited by our critics as evidence for the efficacy of BMT reveals the strength of the empirical foundation of this approach to have been greatly exaggerated. While few of our concerns about a preominantly behavioral approach to marriage therapy have been ameliorated by Jacobson and Weiss' commentary, some success seems to have been achieved in terms of our original purpose: to stimulate critical thinking about the premises and process of marital therapy.


A feminist approach to family therapy.

A feminist approach to family therapy. Although family therapy recognizes the importance of the social context as a determiner of behavior, family therapists have not examined the consequences of traditional socialization practices that primarily disadvantage women. The unquestioned reinforcement of stereotyped sex roles takes place in much of family therapy. A feminist therapy orientation that considers the consequences of stereotyped sex roles and the statuses prescribed by society for females and males should be part of family therapy practice. This paper describes the ways in which family therapists who are aware of their own biases and those of the family can change sexist patterns through applying feminist principles to such areas as the contract, shifting tasks in the family, communication, generational boundaries, relabeling deviance, modeling, and therapeutic alliances.


Fluorouracil therapy in patients with carcinoma of the large bowel: a pharmacokinetic comparison of various rates and routes of administration. The pharmacokinetics of fluorouracil after oral, intravenous and rectal administration were compared in 12 patients with colorectal cancers. Oral administration of 10 to 15 mg/kg gave variable plasma levels (0 to 10.5 microgram/ml) and bioavailability (0 to 74%; mean 28%). Bioavailability increased markedly with increases in dose, suggesting saturation of the 'first pass' hepatic metabolism of the drug. Differences in bioavailability could not be related to standard liver function tests or the presence of metastatic deposits in the liver. Plasma levels were not detectable after rectal administration in the 4 patients studied and were very low (0 to 8 microgram/ml) during high dose (20 to 30 mg/kg/24h) slow intravenous infusion in 6 patients. These findings indicate that different dose schedules and routes of administration produce markedly different plasma levels. They suggest that the rate of degradation of fluorouracil by the liver is quite variable and may become saturated with increasing dose. For these reasons monitoring of plasma levels of the drug in individual patients may be useful.


Individual and family growth: a Gestalt approach. Gestalt therapy is described as a comprehensive framework of theory and techniques for experiential family threapy. Like other experientially oriented therapies, it is systems-oriented, immediate-experience-oriented, and affect-oriented. Unlike others, this method regards the client system's emergent processes as the central focus, and it emphasizes that growth occurs as the family and its members are helped to greater self-awareness and responsibility for their own functioning.


An interactional approach to dysfunctional silencing in family therapy. This paper presents an interactional approach to the problem of dysfunctional silencing in family therapy. Silencing is classified as dysfunctional if it satisfies two conditions: (a) it occurs repeatedly and independently of content, and (b) it functions as negative feedback that limits change in the family system. Dysfunctional silencing is defined as those efforts of one or more family members to limit change by repeatedly blocking the communication of another family member, who in turn colludes by tacitly agreeing to remain silent. The interactional approach presented utilizes conflict-resolution techniques and videotape feedback; it is illustrated by a case example.


Through the looking glass: the experiences of two family therapy trainees with live supervision. A thorough investigation of the literature pertaining to therapy supervision reveals that supervision has never been examined from the viewpoint of the trainee. This paper examines live supervision of family therapy from that viewpoint. It suggests that live supervision is a powerful and effective tool--a tool that engenders strong emotional responses.


The influence of bronchial smooth muscle tone on critical narrowing of dependent airways. Critical narrowing of the dependent airways was examined in anaesthetized dogs with closed chests. Two techniques were used, (a) "closing" volume (CV), measured from the expired nitrogen plateau and (b) tantalum bronchography, to measure the calibre of airways of 3-8 mm diameter in the upper (UZ), middle (MZ) and lower (LZ) zones. The point of airway "closure" at the junction of phases III and IV of the alveolar plateau coincided with an inflection in the diameter-lung volume curve of the airways in the most basal zone of the lung. This was accompanied by a sudden large increase in the calculated resistance of the airways in LZ compared with UZ. Following stimulation of the vagi CV increased and there was increased narrowing of airways, particularly in LZ. The addition of 0.5% halothane to the anaesthetic abolished the effect of vagal stimulation on CV and on airway resistance.


Changes in airway calibre following pulmonary venous congestion. "Closing volume" (CV) was measured in 18 anaesthetized dogs before, during and after pulmonary vascular congestion produced by inflation of a balloon placed in the left atrium. In group A 10 dogs were anaesthetized with pentobarbitone. CV increased from 30.0 +/- 1.2 to 42 +/- 5.6% of vital capacity (P less than 0.05) when pulmonary wedge pressure was increased from 0.21 +/- 0.27 to 1.54 +/- 0.44 kPa (1.6 +/- 2.0 to 11.6 +/- 3.3 mm Hg) (P less than 0.05). In seven of these 10 dogs gas exchange was impaired after an increase of left atrial pressure. These changes in lung function during pulmonary vascular congestion were not associated with an increase in lung water. In group B, eight dogs were studied after anaesthesia with chloralose and urethane. Vagotomy or vagal cooling to 0 degrees C returned CV to baseline values in six dogs with pulmonary vascular congestion. In two dogs in which bilateral vagotomy had been performed before pulmonary vascular congestion there was no change in CV after balloon inflation. Isoprenaline abolished the effect of pulmonary vascular congestion on closing volume. This suggests that the vagus mediates the changes in lung mechanics associated with pulmonary vascular congestion.


Ventilatory effects and plasma concentration of morphine in man. The relationship between the plasma concentration of morphine and morphine-induced changes in ventilation and the ventilatory response to carbon dioxide was studied in 17 healthy adults undergoing elective surgery under general anaesthesia. Each subject was given morphine sulphate 0.15 mg kg-1 i.m.; ventilation (Ve), end-tidal PCO2(PE'CO2), mixed venous PCO2(PVCO2) and ventilatory response to carbon dioxide (delta Ve/deltaPCO2) were measured before and within 90 min after injection. Mixed venous PCO2 and deltaVe/deltaPCO2 were measured by standard rebreathing methods; plasma morphine concentration was measured by radioimmunoassay. Maximum plasma morphine ranged from 30 to 120 ng ml-1, between 4 and 60 min after injection. There was a significant increase in mixed venous PCO2 (P less than 0.001), and PE'CO2 (P less than 0.01) after morphine while Ve decreased insignificantly. Morphine displaced the carbon dioxide response curve to the right (P less than 0.01) and delta Ve/delta PCO2 decreased from 12.3 to 10.0 litre min-1 kPa-1 (P less than 0.05). The magnitude of changes in Ve and deltaVe/deltaPCO2 were not related to the peak plasma concentration of morphine or to the mean concentration immediately before and after the carbon dioxide response measurement. Plasma concentrations of morphine, under the conditions of the present study, are not an objective indicator of pharmacological activity between one patient and another.


Low ventilatory response to carbon dioxide not associated with increased depression by morphine. Ventilation (Ve), end-tidal (Pe' CO2), mixed venous PCO2 (PVCO2) and the ventilatory response to carbon dioxide (deltaVE/deltaPCO2) were measured before and within 90 min after morphine 0.15 mg kg-1 i.m. given to 17 adult patients undergoing elective surgery under general anaesthesia. The hypothesis that patients with a low ventilatory response to carbon dioxide are more susceptible to the ventilatory depressant effects of morphine was tested. Morphine induced increases in PE'CO2 and PVCO2 were not correlated with either the slope or the position of hte preinjection response to carbon dioxide. Mean delta Ve/deltaPCO2 was depressed after morphine (P less than 0.05), but individual responses varied widely. Seven patients whose control delta Ve/PCO2 was 9.9 litre min-1 kPa-1 or less decreased delta Ve/deltaPCO2 after morphine. In four patients, delta Ve/deltaPCO2 increased after morphine; however, in each case, PE'CO2 and PVCO2 increased also. Morphine displaced the carbon dioxide response to the right (P less than 0.001) but no correlation was found betwen either the magnitude of the displacement or change in slope and control delta Ve/deltaPCO2. The results suggest that patients with a low value for delta Ve/deltaPCO2 are not more susceptible to the ventilatory depressant action of morphine.


Effects of fentanyl on intracranial pressure and cerebral perfusion pressure during hypocapnia. Ten patients presenting for carniotomy were studied. Each was anaesthetized with thiopentone or Althesin followed by tubocurarine and the lungs were hyperventilated with nitrous oxide in oxygen. Fentanyl 0.2 mg was administered i.v. and the intracranial pressure (i.c.p.) and mean arterial pressure were recorded continuously for 10 min. At the time of administration of fentanyl nine of the 10 patients were hypocapnic (PaCO2 less than 4 kPa). The changes in i.c.p. were small. Cerebral perfusion pressures less than 50 mm Hg were observed in two patients who had moderate hypotension before the drug was given. We conclude that fentanyl is a valuable agent in the hyperventilation technique in patients with intracranial space-occupying lesions, provided that hypotension is absent.


Biodegradation of halothane, enflurane and methoxyflurane. The biodegradation of halothane, enflurane and methoxyflurane was studied in 22 patients undergoing abdominal surgery, by measuring the uptake and elimination of each agent and the fluoride excretion in urine. Six control patients were anaesthetized with nitrous oxide in oxygen together with neuromuscular blocking drugs, five patients with nitrous oxide in oxygen and 0.93% halothane, five with nitrous oxide in oxygen and 1.30% enflurane, and six with nitrous oxide in oxygen and 0.31% methoxyflurane. The ratio of the fluoride excretion in urine to the total amount of fluoride contained in the amount of each anaesthetic agent absorbed during anaesthesia was estimated to be 17.7% for halothane, 2.3% for enflurane and 46.3% for methoxyflurane. The serum fluoride concentration increased to a maximum of 15.8 +/- 3.8 mumol litre-1 (mean +/- SD) at 6 h after anaesthesia with methoxyflurane, while it did not exceed 8 mumol litre-1 with the other anaesthetic agents.


Frequency of atopy and allergy in an anaesthetic patient population. Ten thousand patients presenting for anaesthesia in the British Isles were questioned about a possible history of atopic or allergic disorders. The overall percentage frequency of atopy was 8.5, comprising eczema 2.4, hay fever 3.8 and asthma 3.5. The frequency of allergies was 13.5, of which penicillin was the most common (6.2). Females had a significantly greater frequency of atopy or allergy than males. Patients with a history of atopic disorders had a higher frequency of allergies than the non-atopic group (36.2% compared with 11.4%) and vice versa.


Effect of halothane on the rate of acid production, lactate production and pyruvate dehydrogenase activity of malignant hyperpyrexia human muscle. The rates of acid production were compared in thin strips of muscle biopsy samples isolated from malignant hyperpyrexia and control vastus internus human muscle. Halothane doubled the rate of acid production by malignant hyperpyrexia susceptible muscle but had no effect on control samples. This increased rate of release of acid from muscle was not from lactate. In addition, the pyruvate dehydrogenase activity of both control and malignant hyperpyrexia muscle samples was not stimulated by halothane.


Extradural analgesia revisited. A statistical study. The results of 334 lumbar extradural analgesics, administered in a standard manner, allowed reassessment of some factors influencing the spread of local anaesthetic solution in the extradural space. There was no evidence of increased spread in patients with degenerative vascular disease when compared with a control group free from such disease. The patient's height and age had a small effect on spread. The results contradict the earlier assumption of a direct relationship between the volume of anaesthetic solution injected and the number of segments blocked.


Bacterial contamination of anaesthetic gases. The bacterial content of oxygen and nitrous oxide immediately before and after passing through clean and used breathing systems (circuits) was measured using a specially constructed agar chamber (Bourdillon's slit sampler). The content per litre of oxygen from the outlet of the anaesthetic machine was 4.0 X 10-2, and 2.9 X 10-2 for nitrous oxide, corresponding to 3.5 X 10-2 for a 50% mixture of the gases. After passing through cleaned circuits, the bacterial pollution of the gas mixture had increased by 30%, but more than elevenfold after passing through used circuits. The content from cleaned circuits was less than that measured previously in the air of hospital wards and operating theatres, whereas gases from used circuits were polluted to approximately the same extent. It is concluded that used circuits may increase the risk of cross-infection. The cleaning method employed by us (dish-washer--hot airy drying) appeared to be acceptable.


Effect of heating on the osmotic fragility of stored blood. The effect of incubation at 37 degrees C, 46 degrees C, 47 degrees C and 48 degrees C for 1 h on the osmotic fragility of blood was determined. Blood taken from volunteers into ACD and CPD was examined after 1, 7, 14 and 21 days of storage. In addition, 22-day-old blood stored in CPD was examined. The osmotic fragility was unchanged after incubation at 37 degrees C and 46 degrees C, slightly increased at 47 degrees C and markedly increased at 48 degrees C. The duration of storage did not have any marked effect. The results suggest that incubation of stored blood at 46 degrees C for 1 h does not cause red cell damage.


Assessment of recovery from short anaesthesia using the cerebral function monitor. In 18 females undergoing minor gynaecological surgery, recovery from anaesthesia, which included methohexitone, has been assessed using: clinical examination, six different psychomotor tasks and, in six patients, e.e.g. The cerebral function monitor (CFM) was used also to determine its value in such patients. Clinical signs and the results of performance tests returned to the pre-anaesthetic values 2 h following anaesthesia, but CFM tracings were still significantly different at 8 h (P less than 0.05). Similar changes in e.e.g. were significant only in the first 2 h; this may be a result of the visual analysis of the traces. The results suggest that CFM is a sensitive indicator of persistent effects of anaesthesia.


Cardiac arrhythmia induced by pneumoencephalography. Cardiovascular collapse associated with pneumoencephalography (PNE) has been reported but there has been no prospective study of its nature and cause. We have recorded prospectively the e.c.g. of 82 unselected patients, with no cardiovascular or metabolic disease, undergoing PNE under general anaesthesia. The frequency of arrhythmia following air injection was 60%; bradycardia 22%; ventricular ectopic beats 26%; nodal rhythm or sinus tachycardia 11%. Cardiovascular collapse occurred in three patients; two with "torsades de pointes" and one with bigeminy and q.r.s. block. Arrhythmia was more frequent in patients with a pituitary tumour and intracranial hypertension (91%). Eight postoperative control PNE examinations were uneventful. Three of four patients with frontal lobe tumours and four of seven with posterior fossa tumours exhibited arrhythmia.


Use of propanidid and lignocaine to modify the increase in serum potassium concentration following injection of suxamethonium. A technique of general anaesthesia involving the use of propanidid, nitrous oxide, oxygen and halothane followed by a slow injection of suxamethonium and lignocaine is described. The technique decreased the increase in serum potassium concentration that follows the injection of suxamethonium and, it is suggested, possesses advantages over the existing practice of the injection of non-depolarizing neuromuscular blocking drugs before suxamethonium in an attempt to reduce the frequency of serious cardiac arrhythmia.


Unusual response to extradural analgesia in the presence of an intradural spinal tumour. A patient is presented in whom indications of the presence of an intradural, extramedullary tumour became apparent during the induction of an extradural block. It is suggested that a combination of signs should arouse suspicions of such a tumour close to the puncture site. Pain within an area covered by an extradural block does not indicate necessarily a supraspinal cause for the pain.


Sodium nitroprusside for aneurysm surgery in pregnancy. Report of a case. A 25-year-old woman in the 7th month of pregnancy was operated upon for a ruptured cerebral aneurysm. Sodium nitroprusside was used to achieve effective controlled hypotension. Signs of foetal distress were transient. Subsequent delivery was spontaneous and uneventful. Development of the child at 2 yr was satisfactory. The various physiological aspects and the action of nitroprusside on both mother and foetus are discussed.


The clinical pharmacology of mexiletine. 1. Mexiletine was given to 156 patients by intravenous or oral routes of administration. 2. There was great interpatient variation in kinetics and plasma concentrations with both routes of administration. 3. The mean volume of distribution was 6.63 l/kg. The mean plasma elimination haf-life after chronic oral therapy was 11.31 h. 4. Plasma concentrations between 0.75 and 2.00 microgram/ml were usually effective. Within this therapeutic range severe side effects were uncommon. 5. Plasma concentrations within this range were achieved in 72% of patients when doses of 10--14 mg-1 kg-1 day were given orally.


Comparison of intra-arterial and indirect blood pressures at rest and during isometric exercise in hypertensive patients before and after metoprolol. 1. Blood pressure was measured both directly and indirectly in seven hypertensive patients before and after a single oral dose of 100 mg metoprolol, at rest and during sustained handgrip. 2. Intra-arterially measured systolic and diastolic blood pressure increased linearly with time during sustained handgrip at 50% of maximal voluntary contraction. This linearity persisted for 60 s or more in most cases. Heart rate increased linearly for the first 30 s. 3. Indirectly measured blood pressure using an observer bias minimizing Auto-Manometer, under-read systolic and over-read diastolic pressure both at rest and during handgrip. 4. By exact timing of recorded values during handgrip and linear extrapolation (or interpolation) from base-line readings, mean values at 30 and 60 s of handgrip were calculated. The relationship between direct and indirect values remained the same at base-line and 30 s of handgrip. At 60 s of handgrip, this was true only for diastolic pressure. For systolic pressure, indirect and direct values almost coincided. 5. After metoprolol, directly recorded pressure fell slightly (7--12 mm Hg, 0.02 less than P less than 0.10), both at rest and during handgrip, and heart rate fell by 15--18 beats/min (P less than 0.01). The systolic blood pressure and heart rate effect of metoprolol at 1 min handgrip correlated with peak plasma drug levels. Indirectly measured blood pressure did not  change significantly. 6. The rate of rise in heart rate and blood pressure from base-line to 60 s handgrip was not significantly influenced by metoprolol.


Plasma protein binding of propranolol and isoprenaline in hyperthyroidism and hypothyroidism. 1. The possibility that thyroid disease might result in alterations in the plasma proteins binding of drugs has been investigated by studying the binding of propranolol and isoprenaline in patients with hyperthyroidism and hypothyroidism. 2. Plasma protein binding of propranolol and isoprenaline has been measured in seven hyperthyroid patients and ten hypothyroid patients. Plasma binding was estimated by equilibrium dialysis at 37 degree C using triatiated propranolol and isoprenaline, both when the patients had thyroid dysfunction and again when they were euthyroid. 3. In the hyperthyroid group, mean propranolol binding varied from 86 +/- 1.7% when hyperthyroid to 88.4 +/- 0.8% when euthyroid. The comparable isoprenaline figures were 65.1 +/- 3.2% and 68.1 +/- 1.4% respectively. Neither difference was significant. 4. Isoprenaline binding was significantly lower (64.3 +/- 1.6%) when patients were hypothyroid than when they became euthyroid (68.8 +/- 1.2%). Propranolol binding was not altered by hypothyroidism. 5. It is concluded that clinically important alterations in free drug concentrations of propranolol or isoprenaline do not occur in hyperthyroidism or hypothyroidism.


Effects of piretanide, bumetanide and frusemide on electrolyte and urate excretion in normal subjects. 1. The pharmacological actions of a new short acting loop diuretic were investigated in nine healthy male subjects and compared with those of frusemide and bumetanide. Subjects received 6 mg piretanide/day, 40 mg frusemide/day or 1 mg bumetanide/day for a period of 1 week. 2. Comparison of effects following the first dose administered showed that 6 mg piretanide is of similar potency to 40 mg frusemide in terms of diuresis, natriuresis and kaliuresis but is less potent than 1 mg bumetanide. 3. All three diuretics caused a decrease in urate excretion and a rise in serum uric acid. 4. Piretanide was well tolerated. Further investigation is required to ascertain what clinical advantage it offers over frusemide and bumetanide.


Plasma, bone, hip capsule and drain fluid concentrations of ampicillin and flucloxacillin during total hip replacement after intravenous bolus injection of magnapen. 1. A rapid intravenous bolus injection of 4.0 g Magnapen (which contains 2.0 g of ampicillin and 2.0 g of flucloxacillin) was to seven patients undergoing total hip replacement immediatly before induction of general anesthesia. Postoperatively the patients patients received 2.0 g Magnapen by intramuscular injection every 6 h for up to 72 h until removal of the wound drains. 2. The plasma, bone, hip capsule and drain fluid concentrations of ampicillin and flucloxacillin were measured by a differential small plate microbiological assay method using Sarcina lutea and a penicillinase producing Staph. aureus Russell as the test organisms. 3. The mean +/- s.e. mean concentrations of ampicillin after this regimen were 4222.2 +/- 285.0 microgram/ml (plasma), 65.6 +/- 1.3 microgram (g (hip capsule), 19.1 +/- 3.8 microgram/g (cancellous bone), and 211.1 +/- 65.6 microgram/g (ground up bone) respectively. 4. The mean +/- s.e. mean flucloxacillin concentrations after this regime were 137.2 +/- 28.4 microgram/ml (plasma), 61.8 +/- 15.0 microgram/g (hip capsule), 47.1 +/- 9.5 microgram/g (cancellous bone) and 139.4 +/- 21.8 microgram/g (ground up bone) respectively. 5. An intravenous bolus injection of Magnepen (4.0 g), given immediately before induction of general anaesthesia, provides concentrations of ampicillin and flucloxacillin in plasma, hip capsule, cancellous and ground up bone, and drain fluid that exceed the MICs of these antibiotics against Staph. aureus and E. coli. 6. The plasma, hip capsule, cancellous and ground up bone concentrations of ampicillin after this dose of Magnapen do not, however, exceed the MICs of the Gram negative anaerobes that sometimes cause postoperative wound infections in these patients.


Irradiation of human skin by short wavelength ultraviolet radiation (100--290 nm) (u.v.C): increased concentrations of arachidonic acid and prostaglandines E2 and F2alpha. 1. Human abdominal skin was irradiated with six times the minimal erythema dose of ultraviolet C (100--290 nm) radiation. Erythema appeared at 3 h, was of moderate degree by 6 h and was maximal at 12--24 h. It was reduced at 48 h and by 72 h had disappeared. 2. A suction bulla technique was used for the recovery of exudate from normal and inflamed skin at 6, 18, 24 and 48 h after irradiation. 3. Prostaglandin-like activity, estimated by bioassay, showed maximum increase at 18 h, when erythema was also maximum. PGF 2alpha, measured by both radioimmunoassay and by combined gas-liquid chromatography--gas spectrometry, followed a similar time course then fell to normal, or near normal, levels at 48 h. 4. Prostaglandin E2 and arachidonic acid concentrations, measured by gas chromatography--mass spectrometry, were maximally raised at 18--24 h. At 48 h, when some erythema was still present, though reduced, prostaglandin E2 concentrations were still raised above control values. 5. The results provide direct evidence in support of the view that the erythma following irradiation of human skin by u.v.C involves activation of arachidonic acid metabolism. However, the relationship between the erythema and increased prostaglandin activity is not fully understood.


Factors determining the potency of cholinomimetic miotic drugs and their effect upon the light reflex in man. 1. Television pupillometry was used to measure the effect of six topically applied cholinomimetic drugs on the resting diameter and light reflex amplitude of the human pupil. Drug potency was obtained from dose response curves. 2. The tertiary amines arecoline, aceclidine and pilocarpine were considerably more effective miotics than the choline esters carbachol, methacholine and acetylcholine. 3. All the drugs which caused miosis also reduced light reflex amplitude proportionally. 4. The in vitro potency of these drugs was also measured on preparations of rabbit iris sphincter and guinea pig ileum. 5. Dose response relationships for pilocarpine in man and in vitro showed evidence of partial agonist activity on the rabbit iris only. 6. A comparison of the in vivo and in vitro results showed that three factors influenced the potency of topically applied miotics: accessibility to the iris; sensitivity to cholinesterase; and cholinoceptor agonist potency.


Drowsiness, impaired performance and tricyclic antidepressants drugs. 1. The effects of amitriptyline, protriptyline, protriptyline, and a chemically related potential antidepressant, BW247, on performance tests and subjective ratings were studied. 2. Two groups of twelve healthy subjects received drugs and lactose dummy in identical capsules at weekly intervals according to a balanced design, under double-blind conditions, and with standarized tests and environment. 3. Amitriptyline produced the most marked effects, with significant (P less than 0.05) impairment in auditory vigilance after 6.25 mg. Auditory reaction time, tapping rate, arithmetic, and digit symbol substitutions were impaired by amitriptyline 12.5 and 25 mg and all doses produced increased ratings of mental sedation. The effects began 1.5 h after drug and lasted approximately 5 h. 4. Nortriptyline produced fewer effects which were later in onset. Tapping at 1.8 h and auditory vigilance at 3.5 to 4.5 h were impaired by nortriptyline 25 mg whereas reaction time was prolonged by both doses at 5 h. No change in rating of mental sedation occurred. 5. No significant change in performance or subjective ratings followed protriptyline 10 mg or BW247, 12.5 and 25 mg. 6. The findings are discussed in relation to the presence of secondary and tertiary amines on the side chain of the compounds, and their relative abilities to block neuronal uptake of noradrenaline and 5-hydroxytryptamine.


Three-centre study on urinary hydroxyproline excretion in cancer of the breast. A study instigated by the British Breast Group and involving 3 centres (Edinburgh, Glasgow and Liverpool) was carried out to compare 3 methods for the estimation of urinary hydroxyproline. No significant difference between the first and the second 24 h urine collection was found for each measure of urinary hydroxyproline, within laboratories and within patient groups. Reliable hydroxyproline studies can, therefore, be performed on one 24 h urine collection. The Grant and Ellis/Goldberg methods gave comparable results and the excretion of hydroxyproline in the urine measured by either of these 2 methods could be used to distinguish cases of breast cancer with osseous involvement (as demonstrated by X-rays) from those without. The Hypronosticon Kit method was found to be unreliable as it has 29.4% false negatives in breast-cancer patients with X-ray demonstrable metastases. The incidence of elevated urinary hydroxyproline excretion in breast-cancer patients with negative X-rays was 11/14 (25%), 5/34 (15%) and 8/43 (19%) for the Ellis/Goldberg, Hypronosticon and Grant methods respectively. No conclusion can be drawn regarding the outcome of this group of patients because of the short period of follow-up.


A soft-agar procedure measuring growth of human colonic carcinomas. Cell suspensions from 5 human colonic carcinomas were fractionated by velocity sedimentation and plated in soft agar. Cluster formation was restricted to the purest fraction of epithelial cells, as had been determined by immuno- and histochemical criteria. Plating efficiencies for the 5 specimens were 1.0-4.5%. The effects of varying the incubation period and inoculum size upon growth were studied using unseparated cell suspensions from 6 specimens. Clusters were apparent after 3 weeks in culture, and maximum cluster formation was typically seen by 5 weeks. Cluster formation appeared concentration-dependent, and individual specimens varied with respect to the inoculum most conducive to growth. The maximum plating efficiencies for unseparated cells were unseparated cells were 0.4-1.7%.


Effect of dose fractionation on the enhancement by radiation or cyclophosphamide of artificial pulmonary metastases. Thoracic irradiation or cyclophosphamide (CP) treatment of mice before an i.v. injection of tumour cells enhances the number of lung colonies produced by a factor of up to 100+. The effect of fractionation of the X-ray or CP dose on this phenomenon was investigated in several ways.The dose-response curve for the number of lung colonies as a function of the dose of thoracic irradiation was linear, and the degree of enhancement was independent of the number of tumour cells injected. Splitting a dose of 1,000 rad into 2 equal fractions separated by times varying from 1 to 24 h gave the same enhancement as that produced by a single dose of 1000 rad. Similarly, fractionation of 1000 rad into 5 × 200 rad, or 2000 rad into 5 × 400 rad (each interval between fractions being 3 h) had no effect on the radiation enhancement of colony formation.A single dose of 200 mg/kg of CP was compared with 3 doses of 66·7 mg/kg (each dose separated by 12 h) and with a continuous infusion of 200 mg/kg given over 24 h. In this case, fractionation and infusion produced a small reduction in the CP-induced increase, but the factor of colony enhancement compared to control mice remained >100.These data emphasize the potential hazard of prophylactic treatment of pulmonary metastases by X-rays or CP in clinical situations in which control of the primary tumour is not achieved.


Effect of x-irradiation of tumour bed on tumour blood flow and vascular response to drugs. The blood flow of tumours growing in rat mammary glands previously exposed to 1500 R X-rays was 52% that of same-sized tumours in unirradiated host tissue. About 2 months after irradiation, the blood flow of the mammary gland was raised and that of the skin was unchanged, compared with the corresponding unirradiated tissue. Tumours growing in preirradiated and unirradiated mammary glands responded similarly to bolus injections of noradrenaline, angiotensin II, and isoprenaline. The responses of the irradiated tissues to these drugs were, however, not always the same as those of the corresponding unirradiated tissues. Exposure of the lungs to approximately 1500 R X-rays made the animals uniquely sensitive to bolus injections of noradrenaline and angiotensin II.


Enhancement of tumour growth in two syngeneic C3H murine systems by immunization via the intracaecal route. Over the past 70 years many experiments have been designed to promote tumour growth. These studies were all carried out in allogeneic tumour systems or by artificially influencing the immunization process. In the present study, the growth of syngeneic mammary tumour cells was enhanced by prior immunization via the intracaecal route. Such induced enhancement could be transferred to untreated animals by serum or by spleen cells. Tumour growth was also enhanced in another syngeneic system by immunization via the intestinal route with frozen-thawed ascites tumour cells. The result is in direct contrast to that obtained by similar immunization with live cells, which affords protection against a later challenge.


A tumour-associated antigen from the pleural effusion of patients with squamous-cell carcinoma of lung. A fraction showing tumour-associated antigenic properties has been isolated from pleural effusions of patients with squamous-cell carcinoma of the lung. Purification of the material was accomplished by ion-exchange and affinity chromatography, and by immunoabsorbents. The antigenic activity was monitored by its inhibitory capacity in a specific complement-dependent cytotoxic system. The final fraction has a mol. wt. of approximately 1.7 X 10(5), as judged by gel filtration on Sephadex G200, and the main component appears to be a glycoprotein with N-acetyl-D-glucosamine groups. The most purified antigen preparation exhibited a highly selective capacity to inhibit in the cytotoxic assay and to bind, when labelled with 125I, to 2 specific antisera. The active fractions isolated from pleural effusions fully crossreacted with fractions prepared from squamous-cell carcinoma extracts. CEA and bacterial antigens were not detected in the material, and the presence of alpha-fetoprotein, HLA and blood-group antigens may be ruled out on account of their respective molecular weights.


Immunopathology of angioimmunoblastic lymphadenopathy. Eight patients with angioimmunoblastic lymphadenopathy have been studied by a variety of immunological and pathological techniques. They exhibited a spectrum of immunological reactivities that, in this small series, could be roughly correlated with survival. Those patients with relative B-cell predominance as shown by cell marker studies, histologically showed large numbers of plasma cells, and this pattern was associated in 3 of our patients with a survival of 3 years or more. T-cell predominance or both B- and T-cell depletion was associated histologically with large numbers of blast cells and eosinophils, but with few plasma cells. These patients responded poorly to therapy and had short survival times. One patient with B-cell predominance subsequently died of a histiocytic lymphoma.


Formylhydrazine carcinogenesis in mice.

Formylhydrazine carcinogenesis in mice. Administration of 0.125% formylhydrazine in drinking water to 6-week-old randomly bred Swiss albino mice for life, induced lung tumours. Compared to untreated controls, the lung-tumour incidence rose from 15 to 94% in the females and from 22 to 100% in the males. The treatment had no detectable tumorigenic effect in other organs.


Squamous lesions in lungs of rats exposed to tobacco-smoke-condensate fractions by repeated intratracheal instillation. Twice-weekly intratracheal instillations in rats of up to 24 mg of Fraction (R + P)G suspended in either infusine (I) or buffered saline/gelatine (BS/G) gave rise to foci of squamous metaplasia of alveolar epithelium (SqM) and squamous neoplasms (SqN). Fraction (R + P)G, which is a fraction of cigarette-smoke condensate almost as tumorigenic for mouse skin as the nearly 30 × larger mass of condensate from which it is derived, could be given in this way for up to 40 weeks without excessive mortality or any marked effect on the rate of body-weight gain. By contrast, similar treatment with Fraction N(QG), a fraction having very low tumorigenic activity for mouse skin, induced no SqN and barely any excess of SqM over that induced by either vehicle alone.The effects of Fraction (R + P)G on the incidence of SqM and SqN were both time and dose related, the effect on SqM incidence being already evident after 10 weeks of treatment. No SqN seen were unequivocally malignant, though, due to the design of the experiment, only 5 rats exposed to Fraction (R + P)G were observed more than 60 weeks after the start of the experiment.Other changes in the lung, including aggregates of alveolar macrophages laden with golden-brown pigment (GBM) and foci of cuboidal/columnar metaplasia of alveolar epithelium (CCM), were frequently seen in response to both fractions. Fraction (R + P)G administered in I was more effective in causing SqM and SqN than the same fraction administered in BS/G. The implications of the findings are discussed, particularly the possibility that the intratracheal/instillation technique might be useful as a rapid bioassay for comparing the tumorigenicity of different cigarette-smoke condensates.


The contributions of diet and childbearing to breast-cancer rates. Mean, age-standardized breast-cancer mortality rates for women of 41 countries, during 1970-71, were closely correlated with diet for 1964-66. Partial correlation analysis indicated that breast-cancer rates were positively correlated with total fat, animal protein and animal calories, independently of other components of diet. These 3 components were correlated with one another so closely that it was not possible, with available data, to say whether any one was associated with breast cancer independently of the other 2. In addition to, and independently of, these correlations, breast cancer was associated with consumption of refined sugar.Breast-cancer mortality rates at 50-54 years during 1964-67 for 26 countries were closely correlated with childbearing, expressed as mean family size for women aged 45-49 years in 1960-61. However, this correlation was not independent of the correlations with diet, and it was concluded that variation of breast-cancer rates between countries arose predominantly from differences in diet. The variation of breast-cancer risk with childbearing, observed in clinial studies, seemed best regarded as a second gradient of risk, seen more readily as variation of breast-cancer rates within a population, where differences in diet would be relatively small.The physiological basis for the association between breast cancer and diet was not clear. The dietary associations did not correlate in an obvious way with height, obesity and oestrogen levels, factors observed in clinical studies to influence risk of breast cancer. That the observed statistical associations were real was supported by published findings on effects of diet on mammary cancer in experimental animals, as well as the lower rates of breast cancer amongst vegetarians.


Epidemiological evaluation of sunlight as a risk factor of lip cancer. A total of 3,169 cases of lip cancer in males and 303 cases in females were diagnosed in Finland and reported to the Finnish Cancer Registry in 1953-73. The diagnosis was verified histologically in 95% of the cases in males and in 92% in females. The mean annual age-adjusted incidence rate was 7·3/10(5) in males and 0·5/10(5) in females. The annual incidence for males has decreased since the early 1960s. The decrease involved all age groups and was not due to a cohort effect. Only a very slight decrease in the risk was observable in females. The incidence was clearly higher in rural than in urban areas, the urban/rural ratio of the age-adjusted incidence rates being 0·6 for males. A decrease in the risk with time was observable for both urban and rural populations. The risk was highest in the northern and eastern parts of the country, for both urban and rural areas. It was concluded that the decrease in the incidence of lip cancer in Finland cannot be accounted for solely by the process of urbanization. An inverse relationship was found between the mean annual amount of solar radiation and the risk of lip cancer. The results are not in accordance with the theory of the association between exposure to actinic radiation and the risk of lip cancer. The synergistic action of some other factors related to outdoor occupation, and probably smoking, would provide a better explanation for the observations in this study.


Enzymes of glucose metabolism in carcinoma of the cervix and endometrium of the human uterus. Twelve enzymes related to the direct oxidative and glycolytic pathways of glucose metabolism were assayed in 88 cancers of the cervix and 48 cancers of the endometrium of the human uterus, and the activities compared with those obtained from a group of control tissues. Significant increases for all but one of the enzymes studied (alpha-glycerolphosphate dehydrogenase) were found in cancer of the cervix, when compared with normal cervix epithelium. Hexokinase, phoshofructokinase, and aldolase appear to be rate-limiting in normal cervix epithelium; however, since the increase in activity of the first two in cancers was least of all the glycolytic enzymes, redundant enzyme synthesis probably occurs in the malignant cell for the enzymes catalysing reversible reactions. There was virtually no correlation between the activity of any enzyme measured in the cancer sample and histological assessments of the degree of malignancy of the tumour, or the clinical stage of the disease. All enzymes except pyruvate kinase had significantly higher activity in normal endometrium than in normal cervix epithelium, presumably reflecting the greater metabolic requirements of the former tissue. Only phosphoglucose isomerase and pyruvate kinase were significantly higher in endometrial cancer than in normal endometrium, and there were few significant differences between cancers of the cervix and of the endometrium, despite the marked differences in their tissues of origin. These results suggest the changes occur during malignant transformation to the activities of both regulatory enzymes and those catalysing reversible reactions, in a manner justifying the conclusion that the general metabolism of tumours is convergent.


Epithelial repair in chronic gastric ulcers. Features of epithelial repair, namely mitotic activity, cell migration, and cell differentiation have been investigated in 17 mucosal biopsy samples from the edges of chronic gastric ulcers in 16 patients, using light and electron microscopy. Results have shown that mitosis persists at the margins of these lesions and that mitotic figures are significantly more numerous in the region of chronic ulcers than in normal mucosa. Cells with the ultrastructural features of migratory cells are present but adjacent epithelium shows abnormalities of differentiation. Lack of cell production does not appear to be the limiting factor in epithelialization and some other cause such as an abnormality of cell or re-establishment must be sought.


Changes induced by vascular antigens in the aorta of guinea-pigs: immunological and morphological studies. The effects have been studied of human vessel wall on the cell-mediated and humoral immune response, as well as the morphological changes produced in the aorta in guinea-pigs. In animals immunized with calcium chloride-tris-citrate extracts of the aortic and vessel wall a definite cell-mediated and humoral immune response was observed. A cross-reaction was found between the 2 vessel wall extracts in the skin test and in the migration inhibition test. The induction of desoxyribonucleic acid synthesis was found to be specific. Antibody production as well as the concentration of IgG in the serum was increased. Simultaneously with increased production of the antibodies the cellular immune response did not diminish util the 9th week. A definite alteration was found in the aortic intima by histological, histochemical, immunofluorescence and electron microscopic methods. In addition some slight changes could be observed in the media and in the aventitia of the aorta.


Survival of human 51Cr erythrocytes in guinea-pigs. A guinea-pig model for study of the survival of human erythrocytes has been developed. The T1/2 survival of human erythrocytes in guinea pigs treated with ethyl palmitate and cobra venom factor is about 3 days. This model is particularly suited to the study of the pathogenesis and therapy of certain intrinsic red cell disorders, such as sickle-cell disease.


Nitroblue tetrazolium test: early gross detection of human myocardial infarcts. The hearts from 81 cases of suspected myocardial infarction were stained with the nitroblue tetrazolium (NBT) test to show damaged heart muscle in the gross at necropsy. Thirty-seven cases were of stated clinical age less than 12 h and 27 of these were less than 5 h. Seven out of 17 cases under 1 h were negative with NBT, but all other cases showed either focal diminution of staining with the dark blue diformazan or patchy red staining with the monogormazan of NBT. Thus the method may be of diagnostic value at necropsy from 1 h onwards after the time of apparent infarction (stated clinical onset). Satisfactory results were obtained up to 3 days at ambient temperature after death and for longer when the corpse was stored at 4 degrees C.


Perineural angiogenesis in mice bearing subcutaneous tumours. Cells of myeloma or fibrosarcoma were inoculated s.c. into BALB/c mice. Intact skins and tissue sections from animals killed at periodic intervals after inoculation of tumor cells were examined macroscopically and microscopically. The development of new blood vessels, probably involved in vascularization of the tumor, was observed around the nerves adjacent to the deposit of tumour cells. This occurred 5 days after inoculation of cells and before the tumour had a mean diameter of less than 1 mm. Lesser degrees of "perineural angiogenesis" were noted after s.c. inoculation of mineral oil, Freund's complete adjuvant or implantation of intact spleen, but none was observed with killed tumour cells.


Inhibitory effect of prostaglandin A1 on neutrophil motility. Using Boyden chambers, Prostaglandin A1 (PGA1) was shown to inhibit directed movement of polymorphonuclear (PMN) leucocytes to the chemoattractants endotoxin-activated serum and casein, and in random migration systems. Depressed chemotaxis could not be entirely attributed to defective random migration, as the drug was shown to inhibit both chemokinesis (stimulated random migration) and "true chemotaxis". In addition, PGA1 inhibited the movement of neutrophils out of capillary tubes and substantially reduced hexose monophosphate shunt (HMPS) activity. Mice injected with PGA1 demonstrated significantly less PMN movement into trypticase-soy-broth-induced peritoneal exudates, and it is postulated that during inflammatory processes release of PGA1 increases cell accumulation at the site, thereby amplifying the inflammatory response.


Induction of the acute-phase serum protein SAA requires both RNA and protein synthesis. SAA is a normal acute-phase serum protein which has been identified by its cross-reaction with antibodies to the amyloid A fibril protein, AA, that is associated with secondary amyloidosis. The induction of SAA by bacterial lipopolysaccharide (LPS) has been studied with 3 inhibitors of protein synthesis: cycloheximide, actinomycin D, and galactosamine. Each of the 3 agents when administered simultaneously with LPS completely abolishes induction of SAA for at least 6 h. They are all significantly effective when given 1.5 h after LPS but 3 h after LPS the inhibitory effect of actinomycin D on SAA induction is markedly reduced. Cycloheximide alone can also induce significant concentration of SAA, but a longer time is required than for LPS. Thus it appears that the acute-phase SAA response is characterized by both RNA and protein synthesis which is initiated by the acute-phase inducing agent and which precedes the appearance of elevated SAA concentrations in the serum.


The effect of isoprenaline and pilocarpine on mitotic index and goblet cell number in rat respiratory epithelium. The effect of both isoprenaline (IPN) and pilocarpine (PCP) on mitotic activity and goblet cell number has been studied at 5 levels of the bronchial tree in male and female animals. While both drugs increased mitotic index and goblet cell number at most of the airway levels studied, differences in their effect were detected. After both drugs, nuclei in division were more often superficial within the epithelium than basal but IPN caused a greater increase in mitotic index than PCP. IPN increased goblet cell number at all levels, PCP only in the trachea and larger intrapulmonary airways. The types of goblet cell increased by IPN were particularly those containing acid glycoprotein, whereas PCP increased all types of goblet cell, that is, both those containing neutral and acid glycoprotein. After the drugs, the concentration of cells per unit length of airway epithelium was higher than normal. This is the first study demonstrating the effect of these two drugs on both goblet cell number and cell division. While the two drugs differ in their pharmacological action, the result of their stimulation of airway epithelium is similar. The way in which each effect is produced is discussed.


Lymphoedema of the rabbit ear following partial and complete lymphatic blockade; its effects on fibrotic development, enzyme types and their activity levels. The dorsal surface of the rabbit ear was found to be a suitable place for the production of long-lasting lymphoedema. Its major tissues (skin and sub cutaneous) are those to which secondary lymphoedema is confined in clinical situations. After 32 weeks of partial lymphatic blockade total tissue activity levels of neutral proteinase and beta-glucuronidase were depressed while alkaline phosphatase was elevated. Subsequent complete lymphatic blockade for a further 5 weeks resulted in severe fibrosis of the s.c. tissues. The total tissue activity levels of 3 characteristic lysosomal macrophage hydrolases--acid protease, beta-glucuronidase and acid phosphatase--were significantly increased. There were strong correlations between the activity levels of these enzymes and the extent of fibrosis, increased fibrosis being characterized by higher activity levels. This, together with other evidence, suggested--as fibrosis became more severe--the total number of macrophages increased, but a high proportion of these were non-stimulated. Since these cells (when stimulated) are normally responsible for the lysis of collagen and removal of fibrotic tissue the impairment of their function as occurs in chronic lymphoedema results in further fibrosis and the continuation of the vicious circle.


Histopathological effects of methotrexate on mouse liver. Mice were injected with up to 9 doses of methotrexate and killed at intervals after treatment. Liver changes were assessed histopathologically and by image analysis, and included vacuolation and ballooning degeneration of centrilobular liver cells. There was considerable irregularity in nuclear size in methotrexate-treated mice, in which hepatic nuclei were significantly larger than those of control animals. Fatty change was not induced in the liver by these doses of methotrexate, and there was no cellular infiltration or fibrosis.


Profile of epidermal metabolic activity in autosomal dominant ichthyosis and small bowel disorders. The in vitro incorporation of 14C acetate by the epidermis has been studied in patients with autosomal dominant ichthyosis and in patients with a dry, itchy, slightly scaly skin associated with a disorder of the small bowel. Analysis of 14C acetate containing lipid moieties by thin layer chromatography has indicated that there are both quantitative and qualitative differences in the uptake of 14C acetate between autosomal dominant ichthyosis and normal. In particular an increased incorporation into the triglyceride and phosphatidyl choline fractions was noted. No such differences were apparent in those patients with disorders of the small bowel. In addition the in vitro incorporation of radioactively labelled thymidine, proline and histidine has been studied in these patients. In both groups of patients the rate of incorporation of tritiated thymidine and histidine into epidermal macromolecules was found not to differ significantly from normal. On the other hand the rate of incorporation of tritiated proline was increased in both groups of patients.


Corticosteroid effect on epidermal cell size. Changes in the epidermis following application of three corticosteroids, betamethasone 17-valerate, hydrocortisone 17-butyrate, and hydrocortisone have been studied histometrically in human volunteers. The reduction in epidermal thickness observed correlated significantly with a reduction in size of the viable epidermal cells. There was no significant reduction in the number of cells constituting the viable epidermis. These findings indicate that thinning of the epidermis is a function of cell size rather than cell number. The epidermal changes developed quickly and were rapidly reversible. It is suggested that measurement of cell size may be an early and sensitive index of atrophogenicity induced by topical corticosteroids. 0.1% Hydrocortisone 17-butyrate and 0.1% betamethasone 17-valerate showed equivalent potency in causing epidermal thinning and reduction in cell size. Reduction in cell size paralleled increasing concentrations of betamethasone 17-valerate, indicating a positive dose-effect relationship.


Melanoma specific protein: occurrence in the urine of patients with halo naevus and vitiligo. Melanoma specific protein is immunologically related to altered naevus cell cytoplasm. It is excreted by patients with malignant melanoma but in no other malignancy. The protein has been detected in patients with actively developing halo naevi but not when repigmentation is taking place. It also occurs in patients with very active vitiligo but in no other pigment condition we have studied. It is suggested that the protein is a marker of active destruction of naevus cells by immune mechanisms and that the release of toxic materials during this immune reaction may be responsible for the production of the halo phenomenon and for the areas of vitiligo that may be seen elsewhere on the skin.


Cyclophosphamide induced nail pigmentation. Cyclophosphamide therapy may occasionally cuase black pigmentation of the nails. We report five cases with this side effect and review the data on eleven cases in the literature. These changes start in the proximal nail beds and progress distally; on withdrawal of cyclophosphamide, clearing of the nail pigmentation proceeds in a similar fashion. The development of the nail pigmentation does not bear any relation to the primary condition for which cyclophosphamide was prescribed. The dose of the drug before the onset of pigmentation ranged from 1.2 to 12.3 g; the duration of treatment ranged from 10 days to 26 weeks. The mechanism of the nail pigmentation is unknown.


Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)--therapeutic problems. A patient with subcorneal pustular dermatosis with a fatal outcome is presented. Treatment with corticosteroids, vitamin E, dapsone, sulphapyridine and levamisole was ineffective. Only systemic treatment with retinoic acid and a new aromatic retinoic acid derivative (Ro 10-9359) produced a satisfactory clinical response, but a complete remission was not obtained.


Multiple naevocellular naevi in brothers with albinism. Multiple naevocellular naevi occurring in two albino brothers are described. The light and electron microscopic findings of the naevi are described and the nature of the pigment discussed.


Zosteriform lentiginous naevus with ipsilateral rigid cavus foot. A patient is presented with a rigid cavus deformity associated with a painful linear keratotic lesion on the lateral plantar border. A unilateral zosteriform lentiginous naevus is found on the same side as the foot deformity. Electrodiagnostic evaluation suggests the presence of a non-specific neuromuscular process on the affected side. This association has not previously been reported.


Immunologic aspects of psoriasis. III. Fc-gamma-receptor bearing mononuclear cells in peripheral blood. An anti-IgG activity has previously been reported at the cellular level in patients with psoriasis. This activity was demonstrated by the so-called 'rheumatoid' rosette test. In the present work the nature of 'rheumatoid' rosette-forming cells was studied in comparison with other EA rosette techniques. The use of purified cell populations showed that the lymphocytes participating in the 'rheumatoid' rosette phenomenon were lacking conventional T and B cell membrane markers, and were thus referred to as null cells. Such mononuclear cells bearing a receptor for the Fc part of IgG were able to act as killer cells to IgG-coated target cells. The cytotoxic activity was mainly restricted to a small proportion of lymphocytes forming 'rheumatoid' rosettes which had a high avidity for EA complexes. Such cytotoxicity could contribute to the aetiology of lesions in psoriasis.


IgA and C3 complement in the uninvolved skin in dermatitis herpetiformis after gluten withdrawal. IgA deposits in the skin in 53 patients with dermatitis herpetiformis (DH) have been studied in relation to treatment. In 19 patients the disorder was controlled by a gluten-freen diet (GFD) alone, in 13 patients by dapsone and GFD and in 18 by dapsone alone. In 3 patients the skin disorder became insignificant and required no treatment. Of the patients taking a GFD alone, six had been clear of skin lesions for 7 years, 5 for 3--5 years, and 8 for periods of 6 months--3 years. IgA deposits were found in all patients in an initial biopsy in a second biopsy after treatment for periods varying from 1 to 7 years. There was no difference in the quantity of IgA, as assessed by the amount of fluorescence, whether patients were controlled with a GFD alone, GFD and dapsone, dapsone alone, or in those in clinical remission. The C3 component of complement was present in the skin in 3 of the 19 patients (16%) controlled by a GFD alone, 6 of the 13 patients (46%) of those controlled by a GFD and dapsone, and in 12 of 18 (66%) of the patients taking dapsone alone, and in one of the patients in clinical remission.


Acid hydrolases in blister fluid. 3. Characterization and quantification of peptide hydrolases. Cathepsin B1 and Cathepsin C have been characterized and quantified in suction blister fluid. These enzymes revealed practically no activity in interstitial fluid and serum. Arylamidase was also investigated and found to have similar concentrations in serum, blister fluid and interstitial fluid. The properties of arylamidase from these sources were identical.


Acid hydrolases in blister fluid. 4. Influence of ultraviolet radiation. Large, dose-related increases have been demonstrated in the activity of lysosomal hydrolases in the fluid of experimental suction blisters raised on skin previously irradiated with UVR-B. These increases appear after a latent period of 11--18 h, and the pattern of changes shows an extremely good correlation with the hydrolase profile of epidermis. These observations offer strong support for the concept that lysosomes participated in the sequence of events following UV irradiation, but seem to rule out the lysosome as the initial target for UVR.


Mycosis fungoides, nitrogen mustard and skin cancer. The prevalence of epithelial cancer was determined in 202 patients with mycosis fungoides and the Sézary syndrome and was found to be 10.5%. In an attempt to establish a possible association with topically applied nitrogen mustard, it was noted that 4.0% of these patients had lesions prior to nitrogen mustard therapy (although over half subsequently developed further lesions) and 6.5% of the patients developed them de novo after therapy. In two patients in this latter group, malignancies developed in are as not usually associated with solar-induced cancer. These findings indicate that epidermal neoplasia is not uncommon in these patients and that nitrogen mustard may function as a carcinogen or a co-carcinogen.