Joint Committee on Aviation Pathology: XVI. Studies on the relation between carboxyhemoglobin concentration and toxicity. A study was made on the effect of I.P. injection of 100% CO in dogs. Although elevated concentrations of COHb were obtained, no Co toxicity occurred. Inasmuch as the combination of CO and erythrocytes after I.P. injection of CO should be similar to that after inhaling CO, The lack of toxicity cannot be explained by Drabkin's "Haldane effect." It is suggested that the lack of CO toxicity after I.P. injection was due to removal of dissolved CO from the blood by passage through the lungs. On the contrary, when Co is inhaled there is significant dissolved CO in the blood leaving the lungs and when it reaches the organs, especially the heart and brain. To cause toxicity, dissolved CO must be present in the blood to cross into the tissues and interfere with the combination of O2 and cytochrome a3. It is concluded that random COHb values may not be related to those obtained in studies of the relationship of human responses to COHb concentrations.


Joint Committee on Aviation Pathology: XVIII. Correlation of occurrence of aircraft accidents with biorhythmic criticality and cycle phase in U.S. Air Force, U.S. Army, and civil aviation pilots. The correlation of occurrence of aircraft accidents to critical and negative phases of the biorhythm cycles was investigated. Data from 880 U.S. Air Force pilot-involved accident cases were studied and added to 4,279 previously reported cases. The data were tested by chi-square analysis under the null hypothesis that there is no effect of biorhythm on aviation accidents. Under this hypothesis, the expected number of accidents occurring on critical days should be 179.13 for the U.S. Air Force; there were 179. In analyzing the effect of biorhythmic criticality for pilot-involved cases from all sources, there were were 300 individual chi-square values computed. The frequency of these values by their percentile distribution so closely matched the theoretical distribution that there was no evidence whatsoever to indicate an effect of biorhythmic criticality. There no correlation between multiply negative or individually negative phases of the biorhythm cycles and aircraft accidents in the U.S. Air Force or in the combined pilot-involved accident group.


Physiological analysis of repetitive lifting. It was hypothesized that physical factors associated with the act of lifting, and also known to adversely affect cardiovascular functions (e.g., increased intrathoracic and intraabdominal pressures), would disturb the linear relationships normally noted among measures of cardiopulmonary variation during exercise. Data collected during repetitive lifting, performed on a unique ergometer (described in the paper), did not support the hypothesis. It was concluded that relationships among energy expenditure rate, pulmonary ventilation, heart rate, and workload were essentially linear through the range of lifting workloads from 1 to 50 W for 18 male Caucasians ranging in age from 21 to 55 years.


Metabolic responses to exercise in three thermal environments. Male and female "physically active" but untrained subjects walked on a treadmill grade approximating 58% vo2 max as determined in 25 degrees C under three environmental conditions. The environments represented thermal neutrality (Ta = 25 degrees C), a "warm" environment (Ta = 32 degrees C), and a "hot" environment (Ta = 40 degrees C). Relative humidity was 50 to 55%. Exercise vo2 values were significantly influenced by increased environmental temperature. In 40 degrees C, male and female vo2 increased 12% above values in 25 C. VE increase 25% for the female and 32% for the male subjects during exercise in 40 degrees C. In both male and female subjects, true O2 increased slightly in 32 degrees C. but decreased in 40 degrees C from values obtained in 25 degrees C. It was postulated that as Ta increased, blood flow was diverted from metabolically active muscle to nonmetabolically active tissue to enhance heat dissipation via conduction and convection. As a result, oxygen extraction declined, and an increased respiratory drive was incurred.


Shallow habitat air dives I and II: human hematologic responses to compressed air saturation diving. Two subjects each were exposed to pressure equivalents of 50 (SHAD I) and 60 (SHAD II) feet of sea water gauge (FSWG) for 30 and 28 d, respectively. Red blood cell (RBC) count, hemoglobin (Hb) content, and reticulocyte count of venous blood from divers were measured before, during, and after these exposures. RBC count of the divers decreased a maximum of 7.1% in the 50-ft dive and 10.7% in the 60-ft dive compared to surface control values. Hb content fell 7.7% and 11.1% in the 50- and 60-ft dives, respectively, when compared to nondiving subjects. Reticulocyte counts tended to increase late in the pressurization phase and during the recovery. The total month-long responses of Hgb in SHAD I, and RBC, Hgb, and reticulocyte count in SHAD II were significantly altered when compared to those of the surface control subjects. The changes in these factors were directly attributable to the month-long exposure to the total hyperbaric environment. The threshold for hematological effects of chronic exposure to compressed air would seem to lie between 50 and 60 FSWG.


Prediction of airbone target detection.

Prediction of airbone target detection. The visibility of a uniformly luminous object depends on the apparent contrast between the object and its background, the angular subtense of the object, the contrast threshold of the observer at the level of luminance to which the eyes are adapted, the conditions and technique of observing, and the shape of the object. Techniques for combining the influence of the various factors have been applied to the problem of predicting airborne target detectability. Recommendations for achieving the desired detectability are made.


Femur-bending properties as influenced by gravity: III. Sex-related weakness after 4-G mouse growth. Optimum gravitational intensity for growth stimulation depends upon the type of growth measurement. Although the 4-G field resulted in relatively weaker male bones, relative bone size increased. The more moderate 3-G field is known to stimulate relative bone-strength as well. Femurs from 36 male white mice demonstrated no growth of load-supporting ability Fu after 1 to 8 weeks of chronic centrifugation at 4-G from the fifth week of age. Although measurable with 35 female mice, this growth intended to fall below the control rate. When compared to 82 younger control femurs of the same cross-sectional geometry, experimental female femurs could sustain comparable moments Mu while experimental male femurs could not.


Transfer functions for eye-level blood pressure during +Gz stress. A description of the eye-level blood-pressure response to +Gz stress in relaxed humans was obtained as an empirical, ensemble-average, G-to-blood-pressure transfer function based on three subjects' responses to a total of 23 simulated aerial combat maneuvering runs on the USAFSAM human centrifuge. Three different analytic transfer functions were fitted to the empirical function for frequencies from 5 to 200 mHz, and predictive performance of the empirical and three analytic functions was examined. The double-zero, double-pole mathematical model most closely fit the empirical transfer function and displayed reasonable predictive ability.


Effect of increased oxygen on kidney function in the rat during and after 21 ATA He-O2 exposure. Two groups of four adult male rats each were exposed continuously for 12 d to 1.2 or 21 ATA He-O2 at 400 mm Hg 02. A third group was maintained under room-air conditions. Urine samples were collected every 12 h for the first 60 h of exposure and for the first 48 h post-decompression. Parameters measured included urine volume, urea, creatinine, calcium, and phosphate. In the 21-ATA group at pressure, urine volume and urea/creatinine increased, and total creatinine decreased; during recovery, total calcium, calcium/creatinine, and urea/creatinine increased and total phosphate decreased. In the 1.2-ATA group, during exposure, urea/creatinine and phosphate/creatinine increased. Diuresis in the 21-ATA group required 48 h to fully develop; however, recovery to normal occurred within 12 h post-decompression. The results reveal a moderate water diuresis and no serious alterations in kidney function during or after 21-ATA exposure at 400 mm Hg O2. There was a mild stress response at pressure and an undefined effect on calcium homeostasis post-decompression.


Effect of sojourn at 3200-m altitude on spinal reflexes in young adult males. Studies of the H reflex and the Achilles tendon reflex (ATR) were performed in 12 healthy males under six conditions: 1) sea level control, 2) during the first 1-3 h at altitude while normoxic conditions were maintained, 3-5) at 6, 24 and 72 h of hypoxia, and 6) after Ve acclimatization at altitude in 5-14 d. After altitude acclimatization, the peak-to-peak amplitude of the H reflex and the ATR response was significantly elevated over control. A trend toward decreased amplitudes of both the ATR and the H reflex was observed at 6 h after the onset of hypoxia. There was no significant alteration in latency of the H reflex under any test condition. These findings suggest that sojourn at altitude by sea level residents induces changes in spinal motor reflexes. These changes are most probably mediated by altered high central modulation of the cord.


Influence of systemic factors on hyperbaric oxygen toxicity in the rat visual system. The electroretinogram (ERG) was measured in lightly anaesthetised rats exposed to 4-7 atm O2 until death. An initial increase and later decrease in amplitude with increase in latency was seen which, although not consistently related to the appearance of seizures characteristically seen above 4.5 atm 02, appeared closely linked to systemic factors. A fall in respiration rate always preceded the fall of the ERG, and apnoea preceded ERG extinction. When blood pressure and ERG were measured in two comparable groups of rats exposed to 5.76 atm O2, both records showed similar time courses. The cerebral visual evoked response (VER) was measured at 5.76 atm O2 simultaneously with the ERG. The later VER waves showed a degree of enhancement at the time of seizures, but otherwise amplitude and waveform were maintained until late in toxicity. EEG spiking gave the earliest indication of toxicity, and it is concluded that the primary projection to the rat visual cortex is comparatively resistant to high-pressure oxygen.


Motion sickness and otolith sensitivity: a pilot study of habituation to linear acceleration. Astronauts, particularly in Skylab flights, experienced varying degrees of motion sickness lasting 3-5 d. One possible mechanism for this motion sickness adaptation is believed to be a reduction in otolith sensitivity with an attendant reduction in sensory conflict. In an attempt to determine if this hypothesis is valid, a ground-based pilot study was conducted on a vertical linear accelerator. The extent of habituation to accelerations which initially produced motion sickness was evaluated, along with the possible value of habituation training to minimize the space motion sickness problem. Results showed that habituation occurred for 6 of the 8 subjects tested. However, in tests designed to measure dynamic and static otolith function, no significant differences between pre- and post-habituation tests were observed. Cross habituation effects to a standard Coriolis acceleration test were not significant. It is unlikely that ground-based pre-habituation to linear accelerations of the type examined would alter susceptibility to space motion sickness.


Prediction of carboxyhemoglobin concentration from transient carbon monoxide exposure. The mathematical model of Coburn, Forster, and Kane (2) was investigated for use in estimating carboxyhemoglobin concentrations resulting from transient carbon monoxide exposures. The model proved useful in estimating the probable pattern of carbon monoxide exposures in two fatal cases. In each circumstance, using the predictive capabilities of the model in the reconstruction of events, the obvious source of exposure could be absolved.


Comment on Munsinger's adoption study.

Comment on Munsinger's adoption study. The recent adoption study reported in this journal by Munsinger appears to provide clear and powerful evidence for a large genetic determination of IQ. The study has been cited as methodologically superior to all other adoption studies. With the repudiation of Burt's data, the Munsinger study has taken on particular importance. Perusal of the raw data published by Munsinger clearly establishes that serious errors have been made in the determination of socioeconomic status. The entire study depends on these erroneous data and must therefore be dismissed.


Effect of endotoxin-induced shock on the reticuloendothelial system. Phagocytic activity and DNA-synthesis of reticuloendothelial cells following endotoxin treatment. There was a marked decrease in the RES phagocytic activity during the first 12 hours after injection of high concentrations of endotoxin in rats. Phagocytic activity then increased considerably, reaching maximum values on days 3 to 5 and it was still higher than in control animals 20 days later. Parallel studies on 3H thymidine incorporation showed a significant increase in the rate of DNA-synthesis of reticulum cells of the liver during the 5 days period following endotoxin injection. Peak values were obtained on day 2 when the number of labelled cell were 50 times higher than in the controls. A likely reason for the increased DNA-synthesis is a repair of RES following endotoxin induced damage but it may also represent an endotoxin induced proliferation of reticulum cells that may at least partly account for the enhanced phagocytic activity.


The exfoliating epithelial surface of the uterine cervix. IV: Scanning electron microscopical study in invasive squamous carcinoma of human subjects. The exfoliating epithelial surface of 15 invasive squamous carcinomas of the uterine cervix was investigated with the aid of the scanning electron microscope (SEM). At low magnification (less than or equal to 5,000 X) thirteen tumors presented irregular cobblestone-like structures and the remaining two, irregular intermediate formations (i.e. between cobblestones and mosaics). Cellular overlapping was found in three tumors. At higher magnifications (up to 25,000 X) all 15 tumors showed irregular disorganized structures such as bizarre microvilli with or without fragmented microrugae. Seven tumors had in addition tall finger-shaped protrusions and two rumors crater-like formations covered by irregular microvilli. The SEM structure found in invasive squamous carcinoma differed from the SEM structures earlier reported for the normal squamous or glandular epithelium, squamous metaplasia, dysplasia or carcinoma in situ of the uterine cervix.


[Pathogenesis of endocarditis verrucosa simplex in the newborn (author's transl)]. Verrucous endocarditis in the newborn is not only a rare but also a problematic disease as concerns its etiology and pathogenesis. In the older literature septic infections of mother and child were said to be the causative factors. Recent experiences with the pathophysiology and pathomorphology of shock have also shown new aspects of the origin of this kind of endocarditis. Two cases from our own experience are compared with 7 cases from the literature. In the maternal history of gestation there was no infectious disease which could explain the endocarditis of the newborn. A short time after delivery the children showed a respiratory distress syndrome and died between 1.5 hours and 3 days after birth. At autopsy verrucous vegetations up to 8 X 5 X 4 mm in diameter were found on the tricuspid valve in 8 cases, once on the mitral valve and twice on both mitral and tricuspid valve. Malformations of the hearts were not noted. Histologically the fresh vegetations consist of clotted platelets and a fibrin network. At the base of the verruca the valvular leaflets show an edema, occasional fibroblastic changes and tiny lympho-histiocytic infiltrates in the subendothelial layer. Extracardial findings are hyaline membranes of the lungs and microthrombi in small vessels of lung, heart, liver and kidney due to shock and consumption-coagulopathy. According to Mittermayer et al. (1971a, b) who studied endocarditis verrucosa simplex in adults and animal-experiments endocarditis verrucosa simplex of the newborn is probably caused by intrauterine or perinatal shock.


[Anti-Bg(HL-A) antibodies].

[Anti-Bg(HL-A) antibodies]. The presence of specific anti-Bg hemaggluttinine in the sera of four patients, is shown. All our patients with anti-Bg antibodies had the antigen B27 on the HLA complex present. Anti-Bg antibodies were prooved by the Coombs technique.


[Epidemiology and etiology of acute leukoses in children]. In their work authors have analyzed some epidemiologic and etiologic data that can be taken as the elements of risk in leukemogenesis. The investigations have been done retrospectively in 212 children suffering from acute leukemia and treated in Pediatric Clinic in Beograd. Certain factors of risk are particularly studied as: repeated viral infections, repeated use of antibiotics, diagnostic and therapeutic irradiation of children, familiar data on congenital anomalies and cancer and same harmful prezygotic and prenatal influences of possible significance. The authors also presented the results of their cytogenetic investigations obtained from 32 children. It is especially pointed out the significance of detailed data taken from patients suffering from these diseases.


[Correlation between the frequency of HL-A antigens and antigens of the P system in the population of Serbia]. We studied the correlation between the antigens of the P system and the antigens and haplotypes of the HLA system in 334 nonrelated persons and 46 chosen families consisting of 166 members. On our material we found a distinct linear correlation between the antigens of the segregant serie A and especially of the segregant serie B and the P antigen of the blood groups. The correlation between the association of the antigens of series A and B and the antigens of the P system same as between the most frequent HLA haplotypes and the antigens of the P system, is also distinct. We described two cases of crossing over between the P and HLA system; the frequency of crossing over of 0,0435. We have confirmed the linkage between HLA and P and the likelihood that the genes are located on the same chromosome.


[Antibodies against HBs antigens as identified using the radioimmunologic method]. Antibodies to hepatitis Bs antigen identified only by radioimmunoassay, which is 8000 times more sensitive than counterelectrophoresis, were found in blood donors in 17%, in the Haemodialysis centre in 44%, in the patients of this centre in 47%. HBsAg and the antibodies have been tested in different series of albumin and gammaglobulin. Immunoglobulin anti HBs was prepared by the Blood transfusion centre in Ljubljana, and the Imunoloski zavod in Zagreb, and the problem of prevention, and production is discussed. Antigen-antibody complexes were prepared in vitro, and the results of the respective tests described.


[Prednisone therapy in patients with pernicious anemia (report of 2 cases)]. The effects of Prednisone therapy at two patients with pernicious anemia were studied on haematologic response, gastric secretion and gastric mucosal hystology. The treatment resulted in each case in correctin of the megaloblastic to normoblastic erythropoesis, and increse in reticulocytes, hemoglobin level and red cell count. Schilling-s test was normalised in one case that means that Prednison enchanced B12 absorption. Gastric secretion of acid and gastric hystology were not respond during the Prednisone therapy. It was discused about immunological problems in pernicious anemia which are very important and required continued investigations.


Tissue-specific esterases in the Xiphophorine fish Platypoecilus maculatus, Xiphophorus helleri, and their hybrid. Tissue-specific esterases of the xiphophorine fishes Platypoecilus maculatus (platyfish), Xiphophorus helleri (swordtail), and their F1 hybrid have been analyzed using disc electrophoresis. Seven esterase zones (resolved into a maximum of nine bands) exist in these fishes, and these have been classified by employing specific inhibitors. Five of the seven zones, EST-1, EST-2, EST-5, EST-6, and EST-7, appeared to be carboxylesterases; while the two remaining zones, EST-3 and EST-4, were classified as cholinesterases. In the liver of the platfish, all seven esterase zones were detected, while the liver of the swordtail exhibited only five esterase zones. EST-1 and EST-3 were lacking in the liver tissue of the swordtail. All seven esterase loci were expressed in the liver tissue of the F1 hybrid. The reciprocal crosses gave the same results. In the fin, skin, skeletal muscle, and eye tissues from all three genotypes, three major esterase zones, EST-2, EST-5, and EST-7, were detected. In addition, EST-1 was frequently detected in all these tissues of the platfish and the F1, but was lacking in the swordtail. Serum from three genotypes showed one prominent esterase zone, EST-5; however, trace activity of EST-2 and EST-7 zones could also be detected. It seems that in all tissues of the F1 hybrid there is expression of all the esterase genes from the platfish. The results of the present study are discussed in the comparison to those from other studies on teleost esterases.


Biochemical characterization of six trisomics of grain sorghum, Sorghum bicolor (L.) Moench. To determine protein differences of grain sorghum disomics and trisomics, we analyzed leaf extracts from six trisomics and a disomic control by disc gel, gel isoelectric focusing, and SDS gel electrophoresis. Based on the number and position of protein bands revealed by Coomassie blue staining, the disomic control could be differentiated from the trisomics, and trisomics could be shown to differ among themselves in most cases. SDS gel revealed the most protein bands, followed by isoelectric focusing and disc gel. However, disc gel electrophoresis was the simplest technique of the three and was just as effective in identifying trisomics and differentiating trisomics from the disomic control.


Bovine serum transferrin phenotypes AA, D1D1, D2D2, EE: their carbohydrate compositions and electrophoretic multiplicity. Samples of homozygous bovine serum transferrins have been prepared and their purity has been ascertained by immunological techniques and electrophoretic analysis in SDS. Measurements of carbohydrate composition show that no significant differences exist among the phenotype variants AA, D1D1, D2D2, and EE. Chromatography of transferrin AA on DEAE-cellulose separated four subfractions, each of which corresponded well with one band obtained by polyacrylamide gel electrophoresis. Carbohydrate analyses of the individual subfractions did not show significant differences in sialic acid, hexose, or hexosamine contents. After desialylation with neuraminidase, each subfraction was converted to a major band and a minor band on gel electrophoresis. From the relative band positions of the desialylated transferrins, it was concluded that possession of sialyl residued by bovine transferrin is not the primary cause of electrophoretic multiplicity. Rather, sialic acid masks an underlying heterogeneity which most likely resides within the polypeptide chain. Further characterization of this heterogeneity will best be undertaken with the isolated asialotransferrin subfractions.


Genic homozygosity in an ancient reptile (Alligator mississippiensis). Proteins assayed electrophoretically showed variation at only three of 49 presumed genetic loci in alligators from southwestern Louisiana. Average heterozygosity per individual was 0.021+/-0.012; proportion of polymorphic loci was 0.06. Data on the history, structure, and ecology of this alligator population are consistent with natural selection as the primary factor accounting for this low genetic variability. However, neither a historic population bottleneck nor some genetic mechanism limiting variability can be dismissed as a possible factor.


Characterization of electrophoretically cryptic variation in the alpine butterfly Colias meadii. Enzyme polymorphism was characterized among the proteins of 14 loci of Coliae meadii by replicate electrophoresis in polyacrylamide gels of differing pore size. The results reveal a large number of variants, with a very skewed frequency distribution. A large fraction of the variants cannot be differentiated by electrophoresis in 5--7% acrylamide gels. This gel sieving approach permits an estimate of the relative contributions of charge and of conformation to electrophoretic mobility. Many of the variant proteins do not differ in charge. Most variants exhibit different degrees of interaction with the gel and presumably differ in conformation.


Membrane function in cystic fibrosis. I. Putrescine transport in normal and cystic fibrosis fibroblasts. Putrescine transport was examined in normal and cystic fibrosis fibroblasts. No differences were observed in accumulation pattern, kinetics of uptake, or efflux between CF and normal cells. In both growing and growth-arrested CF and normal fibroblasts, exogenously supplied putrescine remained unchanged for at least 60 min. Some differences were observed in the response of CF and normal cells to environmental (media) changes.


Gene duplication in salmonid fishes: evidence for duplicated but catalytically equivalent A4 lactate dehydrogenases. Skeletal muscle tissues from many species of salmonid fish are known to exhibit a set of three of five isozymes for A4-type lactate dehydrogenase (L-lactate: NAD oxidoreductase, E.C. 1.1.1.27), but the genetic basis for this isozyme system has not previously been assessed. This isozyme system was purified to homogeneity from salmon (Oncorhynchus tshawytscha) and shown to be composed of two polypeptides. Aalpha and Abeta, in binomial tetrameric combinations. Amino acid analysis revealed that Aalpha and Abeta are closely related but genetically distinct proteins, and thus are coded for the recently duplicated structural loci. Catalytic studies on the purified intact salmon isozyme system and on the isozymically pure Aalpha4 and Abeta4 homotetramers from brown trout (Salmo trutta) revealed no significant differences in catalytic properties among these enzymes, suggesting equivalent catalytic function of Aalpha and Abeta. These results, in combination with studies on polypeptide and isozyme ratios, suggest that one of the duplicated loci in salmon may be drifting toward a nonfunctional state by accumulation of mutations in regulatory DNA rather than in the structural gene itself.


Isoenzyme status and genetic variability of serum esterases in the lesser snow goose, Anser caerulescens caerulescens. A maximum of 22 bands comprising four esterase subgroups--acetylesterase, carboxylesterase, cholinesterase, and acetylcholinesterase--were detected following electrophoresis of lesser snow goose sera on polyacrylamide gels. A minimum of seven structural genes was surmised to be involved in the biosynthesis of these enzymes following physiochemical characterizations. The genetic variability of these loci was calculated to be 1.25% average heterozygosity, while 14.3% of the loci were polymorphic. These estimates of genetic variability were substantially lower than those reported for other vertebrate species. The low degree of genetic variability found in snow goose serum esterases coupled with the extensive protein multiplicity observed may possibly reflect an adaptive strategy based on "biochemical plasticity" rather than genic heterozygosity for this species. The nature of evolutionary forces acting upon multiple enzyme systems such as esterases is discussed. The concept of "conditional neutrality" is introduced and defined within this context.


Glucose-6-phosphate dehydrogenase Porbandar: a new slow variant with slightly reduced activity in a South African family of Indian descent. A new variant of the red cell enzyme glucose-6-phosphate dehydrogenase has been detected in a South African male of Indian descent and in several of his relatives. The enzyme variant is characterized by slow electrophoretic mobility, low Michaelis constants for the substrates glucose-6-phosphate and NADP, and increased utilization of the substrate analogues 2-deoxyglucose-6-phosphate and deamino-NADP relative to the normal (B+) enzyme. There is no evidence that the enzyme variant, for which the name "G6PD Porbandar" is suggested, is associated with any hematological abnormality.


The combining site of the dinitrophenyl-binding immunoglobulin A myeloma protein MOPC 315. Magnetic-resonance techniques are used to refine the model of the combining site of the Fv fragment of the dinitrophenyl-binding mouse myeloma protein MOPC 315 constructed by Padlan, Davies, Pecht, Givol & Wright (1976) (Cold Spring Harbor Symp. Quant. Biol.41, in the press). Light-absorption studies indicate a dinitrophenyl-tryptophan interaction in the Fv fragment of the type occurring in free solution. The Dnp-aspartate-tryptophan complex is therefore used as a starting point for the n.m.r. (nuclear-magnetic-resonance) analysis of the dinitrophenyl-Fv fragment interaction. Ring-current calculations are used to determine the geometry of the complex. The specificity of complex-formation between dinitrophenyl and tryptophan is confirmed by the lack of ring-current shifts of the dinitrophenyl resonances when tryptophan is replaced by any other aromatic amino acid. Proton n.m.r. difference spectra (at 270MHz), resulting from the addition of a variety of haptens to the Fv fragment, show that the combining site is highly aromatic in nature. Calculations on the basis of ring-current shifts define the geometry of the combining site, which involves a dinitrophenyl ring in van der Waals contact with four aromatic amino acid residues on the protein. The observation of a nuclear Overhauser effect on the H((3)) resonance of the dinitrophenyl ring provides additional constraints on the relative geometry of the H((3)) proton and an aromatic amino acid residue on the Fv fragment. The specificity of the Fv fragment for dinitrophenyl ligands arises from a stacking interaction of the dinitrophenyl ring with tryptophan-93(L), in an ;aromatic box' of essentially tryptophan-93(L), phenylalanine-34(H) and tyrosine-34(L); asparagine-36(L) and tyrosine-34(L) also contribute by forming hydrogen bonds with the nitro groups on the dinitrophenyl ring. The n.m.r. results also confirm that the antibody-hapten reaction may be visualized as a single encounter step. An Appendix shows the method of calculation of ring currents for the four aromatic amino acids and their use in calculating structures.


Specificity of interactions of hapten side chains with the combining site of the myeloma protein MOPC 315. The pKa values of the three histidine residues in the Fv fragment (variable region of the heavy and light chains) of the mouse myeloma protein MOPC 315, measured by high resolution n.m.r. (nuclear magnetic resonance), are 5.9, 6.9 and 8.2. The perturbation of the pKa of one of the histidines (pKa 6.9) on the addition of hapten and the narrow linewidth of its proton resonances suggests that it is at the edge of the combining site. References to the model of the Fv fragment [Padlan, Davies, Pecht, Givol & Wright (1976) Cold Spring Harbor Symp. Quant. Biol. 41, in the press] allows assignment of the three histidine residues, histidine-102H, histidine-97L and histidine-44L. The determination of the pKa of the phosphorus group, by 31P n.m.r., of a homologous series of Dnp- and Tnp- (di- and tri-nitrophenyl) haptens has located a positively charged residue. Molecular-model studies on the conformations of these haptens show that the residue is at the edge of the site. The model suggests that the positively charged residue is either arginine-95L or lysine-52H.


Characterization of double-stranded ribonucleic acid sequences present in the initial transcription products of rat liver chromatin. At low ionic strength and with a low exogenous RNA polymerase/DNA ratio, rat liver chromatin directs the synthesis in vitro of RNA sequences rich in double-stranded segments. All the transcripts contain at least one double-stranded sequence. Most of the double-stranded segments are formed by intramolecular base-pairing of inverted complementary sequences separated by a single-stranded loop. They are heterogeneous in size, 35-45% of them being more than 80 nucleotides long. They contain 61-64% G+C, whether synthesized by rat liver RNA polymerase (form B) or Escherichia coli RNA polymerase. The largest double-stranded sequences are found in the largest transcripts, and are the most thermostable. The fidelity of base-matching is better in double-stranded transcripts synthesized on rat liver chromatin by homologous polymerase than in those synthesized on it by a bacterial polymerase, or in those synthesized by either of the two polymerases on pure DNA.


Purification and properties of histidinol dehydrogenases from psychrophilic, mesophilic and thermophilic bacilli. As a first step in elucidating one molecular mechanism of adaptation to life at extreme temperatures, we purified and characterized the enzyme histidinol dehydrogenase (EC 1.1.1.23) from a number of bacilli whose growth temperatures range from 5 degrees t to 90 degrees C. The enzymes were purified by (NH4)2SO4 precipitation, ion-exchange chromatography on Sephadex, affinity chromatography on histamine- or histidine-Sepharose and preparative gradient gel electrophoresis. All had similar mol.wts. (29200), sedimentation coefficients (S20,w 2.56S), affinities for histidinol and NAD+ (Km = 48 micron and 0.2 mM respectively) and all had pH optima at 9.6. Marked differences were observed in stability with respect to temperature and the temperature at which the initial velocity for histidinol dehydrogenation was optimal. These optima range from 25 degrees C for the enzyme from the psychrophilic species through to 41 degrees C for the mesophiles to 85-92 degrees C for the extreme thermophiles. It is concluded that the ability of the enzymes to operate at their various optimum temperatures is an intrinsic property of their amino acid sequences.


N-phenylglycolhydroxamate production by the action of transketolase on nitrosobenzene. The incubation of nitrosobenzene with yeast transketolase and D-xylulose 5-phosphate resulted in the production of N-phenylglycolhydroxamic acid. The addition of D-ribose 5-phosphate decreased the amount of hydroxamic acid that was produced. This conversion of nitrosobenzene into the glycollic acid-derived hydroxamic acid was shown to be an enzymic process, and a chemical mechanism for the conversion was proposed.


Substrate-induced deactivation of penicillinases. Studies of beta-lactamase I by hydrogen exchange. The conformational motility of beta-lactamase I from Bacillus cereus was studied by hydrogen exhange. The time course of the isotopic replacement of peptide hydrogen atoms was followed by 'exchange-in' or 'exchange-out' experiments. Many of the substrates for this enzyme that have o-substituted aromatic or heterocyclic side chains (e.g. methicillin or cloxacillin) are known to effect a decrease in enzymic activity ('substrate-induced deactivation'). There was a marked discontinuity in the exchange-out curve when methicillin or cloxacillin was diffused into the enzyme solution. About one-half of the hydrogen atoms that were probed were affected by the presence of these substrates, and the change in the reactivity of the hydrogen atoms was also large. Substrates that do not bring about deactivation (benzylpenicillin and cephalosporin C) do not affect the hydrogen exchange, nor do reversible competitive inhibitors such as the penicilloic acid or penilloic acid. On the other hand, Zn2+ ions do affect the hydrogen exchange; their effect is similar to that of methicillin or cloxacillin.


Specificity of flavobacterial glycuronidases acting on disaccharides derived from glycosaminoglycans. The specificity of the unusual flavobacterial glycuronidases that act on disaccharides containing delta4,5-unsaturated uronic acids was reinvestigated. The results show that the enzyme that hydrolyses the uronidic bond in disaccharides from hyaluronic acid and the chondroitin sulphates appears to be mainly specific for beta-D-(1 leads to 3)-derived linkages. The enzyme that hydrolyses the uronidic bond in a variety of disaccharides obtained from heparan sulphate and heparin appears to be specific for beta-D-(1 leads to 4)- and alpha-L-(1 leads to 4)- derived linkages. Thus the glycuronidases seem to be specific for linkage position rather than anomeric configuration, as had been thought previously. In addition, the data confirm other evidence that the major glucuronidic linkages in heparan sulphate and heparin have the beta-D-configuration, and the iduronidic linkages the alpha-L-configuration.


Acetyl-coenzyme A and coenzyme A analogues. Their effects on rat brain choline acetyltransferase. Choline acetyltransferase has the same affinity for acetyl-CoA, propionyl-CoA and butyryl-CoA (Km=1.4 micron). Choline acetyltransferase may use the two latter compounds as substrate, but the longer the acyl chain the lower will be Vmax. CoA is an inhibitor (Ki=1.8 micron). The position of the 3'-phosphate is of primary importance. Desphospho-CoA is a weak inhibitor (Ki=500 micron). 5'-AMP is already an inhibitor (Ki=2500 micron). Phosphopantetheine is not an inhibitor. Dextran Blue is a potent inhibitor (Ki=0.05 micron). Choline acetyltransferase binds to hydrophobic affinity columns. Because of its affinity for nucleotides, affinity for Dextran Blue and hydrophobicity, it is proposed that it contains the 'nucleotide fold', which is a common structural domain present in several enzymes binding nucleotides.


Subtilisin modification of monodeamidated ribonuclease-A. Limited proteolysis of RNAase-Aa(1) (monodeamidated ribonuclease-A) by subtilisin results in the formation of an active RNAase-S type of derivative, namely RNAase-Aa(1)S. RNAase-Aa(1)S was chromatographically distinct from RNAase-S, but exhibited very nearly the same enzymic activity, antigenic conformation and susceptibility to trypsin as did RNAase-S. Fractionation of RNAase-Aa(1)S by trichloroacetic acid yielded RNAase-Aa(1)S-protein and RNAase-Aa(1)S-peptide, both of which are inactive by themselves, but regenerate active RNAase-Aa(1)S' when mixed together. RNAase-Aa(1)S-peptide was identical with RNAase-S-peptide, whereas the protein part was distinct from that of RNAase-S-protein. Titration of RNAase-Aa(1)S-protein with S-peptide exhibited slight but noticeably weaker binding of the peptide to the deamidated S-protein as compared with that of native protein. Unlike the subtilisin digestion of RNAase-A, which gives nearly 100% conversion into RNAase-S, the digestion of RNAase-Aa(1) gives only a 50% conversion. The resistance of RNAase-Aa(1) to further subtilisin modification after 50% conversion is apparently due to the interaction of RNAase-Aa(1) with its subtilisin-modified product. RNAase-S was also found to undergo activity and structural changes in acidic solutions, similar to those of RNAase-A. The initial reaction product (RNAase-Sa(1)) isolated by chromatography was not homogeneous. Unlike the acid treatment of RNAase-A, which affected only the S-protein part, the acid treatment of RNAase-S affected both the S-protein and the S-peptide region of the molecule.


The structure of L-lactate oxidase from Mycobacterium smegmatis. 1. An improved purification was developed for L-lactate oxidase from Mycobacterium smegmatis. 2. The mol.wt. of the native enzyme by a sedimentation-equilibrium analysis was 345 000, and other ultracentrifuge methods gave values in the range 345 000-350 000. 3. An amino acid analysis, determinations of protein and flavin, a sedimentation-velocity analysis and an approach to equilibrium analysis gave values for the subunit mol.wt. in the range 43 500-47 000. 4. It was concluded that L-lactate oxidase contains eight subunits of mol.wt. 43 500. 5. Cross-linking of the subunits with dimethyl suberimidate and electron-microscopy studies were consistent with an octameric structure.


Modification of lactate oxidase with diethyl pyrocarbonate. Evidence for an active-site histidine residue. 1. Diethyl pyrocarbonate inactivated l-lactate oxidase from Mycobacterium smegmatis. 2. Two histidine residues underwent ethoxycarbonylation when the enzyme was treated with sufficient reagent to abolish more than 90% of the enzyme activity, but analyses of the inactivation showed that the modification of one histidine residue was sufficient to cause the loss of enzyme activity. The rates of enzyme inactivation and histidine modification were the same. 3. Substrate and competitive inhibitors decreased the maximum extent of inactivation to a 50% loss of enzyme activity and modification was decreased from 1.9 to 0.75-1.2 histidine residues modified/molecule of FMN. 4. Treatment of the enzyme with diethyl [(14)C]pyrocarbonate (labelled in the carbonyl groups) confirmed that only histidine residues were modified under the conditions used and that deacylation of the ethoxycarbonylhistidine residues by hydroxylamine was concomitant with the removal of the (14)C label and the re-activation of the enzyme. 5. No evidence was found for modification of tryptophan, tyrosine or cysteine residues, and no difference was detected between the conformation and subunit structure of the modified and native enzyme. 6. Modification of the enzyme with diethyl pyrocarbonate did not alter the following properties: the binding of competitive inhibitors, bisulphite and substrate or the chemical reduction of the flavin group to the semiquinone or fully reduced states. The normal reduction of the flavin by lactate was, however, abolished.


The high-performance liquid-chromatographic analysis of ficaprenol and dolichol. A high-performance liquid-chromatographic method was devised which is capable of resolving the p-nitrobenzoyl derivatives of polyprenols containing 35-110 or more carbon atoms. This procedure was used for the determination of ficaprenol and pig liver dolichol composition and can be applied to mixtures of polyprenols as an analytical or preparative technique.


Partial purification of two lithocholic acid-binding proteins from rat liver 100 000g supernatants. 1. The partial purification of two lithocholic acid-binding proteins from liver 100 000g supernatants is described. 2. Gel-filtration, (NH4)2SO4 fractionation, Ca3(PO4)2 fractionation and ion-exchange chromatography were used. 3. Both proteins exhibited glutathione S-transferase activity; one may be the non-specific anion-binding protein ligandin. 4. Glutathione S-transferase activity of one of the binding proteins was inhibited by lithocholic acid.


The isolation and structure of C4, the fourth component of human complement. The fourth component of complement, C4, was isolated from human serum in good yield, and in confirmation of previous reports was shown to be formed from three peptide chains, alpha, beta and gamma, with apparent mol.wts. 90 000, 80 000 and 30 000 respectively. Preparative methods are described for the isolation of the three peptide chains and their amino acid analyses reported. Component C4 contains 7.0% carbohydrate, alpha-chain 8.6% and the beta-chain 5.6%. The N-terminal amino acid sequences are given for 12 residues of the alpha-chain, eight of the beta-chain and 19 of the gamma-chain.


Accumulation of O6-methylguanine in non-target-tissue deoxyribonucleic acid during chronic administration of dimethylnitrosamine. 1. BD-IV rats were given labelled dimethylnitrosamine (2 mg/kg) by stomach tube on weekdays (Monday to Friday) for up to 24 weeks. The rats killed after 2, 4, 8, 16 and 24 weeks of treatment (72 h after the final dimethylnitrosamine gavage) and DNA was isolated from the pooled livers, kidneys and lungs. Purine bases were released from the DNA by mild acid hydrolysis and separated by Sephadex G-10 chromatography. 2. Throughout the experiment, the content of 7-methylguanine in liver DNA was approx. 16 times that in kidney and lung. The amount of this product increased in the DNA of all three tissues up to 16 weeks, but by 24 weeks had decreased by 20% in the liver and 46% in the other tissues. 3. O6-Methylguanine was not detected in liver DNA, but was easily measured in kidney and lung DNA after 4 weeks of dimethylnitrosamine administration. The amount of O6-methylguanine in kidney and lung DNA increased relative to that of 7-methylguanine, and by 24 weeks was 60% of the 7-methylguanine content in both tissues. 4. Incorporation of radioactive C1 breakdown products of dimethylnitrosamine into normal purines in DNA increased continuously in all three tissues. 5. The results are discussed with respect to the specific hepatocarcinogenic effect of chronic administration of dimethylnitrosamine and the possible contribution of increased DNA repair and DNA synthesis.


Purification and properties of a nuclear protein kinase from rat mammary gland. A nuclear protein kinase that shows a high degree of substrate specificity for the phosphorylation of the acidic proteins casein, phosvitin and non-histone chromatin proteins, rather than the basic proteins histones and protamine, was partially purified from lactatingrat mammary gland. The enzyme is associated with the acidic protein fraction of chromatin. Nuclear kinase requires Co(2+) for activity, and other bivalent cations such as Mg(2+) and Mn(2+) can substitute partially for Co(2+). The kinase is further activates (2-3-fold) by various salts, their concentration for maximum stimulation being: NaCl, 150mm; KCl, 200mm; sodium acetate, 300mm. The sedimentation coefficient of the nuclear kinase is 8.9S and its mol.wt. is approx. 300000 by gel-exclusion chromatography. The enzyme is not activated by cyclic AMP or cyclic GMP and is inhibited neither by the regulatory subunit of mammary cyclic AMP-dependent protein kinase nor by the heat-stable protein kinase inhibitor from ox heart. Analysis of (32)P-labelled protein products reveals that the kinase transfers the terminal phosphate of ATP to serine and threonine residues of proteins. The enzyme, however, has specificity for the phosphorylation of threonine in casein and serine in phosvitin. Molecular size and enzymic characteristics of the nuclear protein kinase are clearly different from those of the cytosol enzyme previously characterized.


Semisynthetic analogues of insulin. The use of N-substituted derivatives of methionine as acid-stable protecting groups. 1. We describe the use of benzyloxycarbonylmethionine and ethoxycarbonylmethionine for the selective protection of the amino groups of glycine-A1 and lysine-B29 of pig insulin. We have used the Edman method to remove residues from the N-terminal and of the B-chain of the N(A1)N(B29)-di-protected derivatives. The benzyloxycarbonyl group shows slight but noticeable lability in the acid-cleavage step, but the ethoxycarbonyl group remained intact even after five cycles of degradation. 2. We have prepared the following truncated forms of insulin via the di(ethoxycarbonylmethionyl) derivative: des-Phe(B1)-insulin;des-(Phe(B1)-Val(B2))-insulin; des-(Phe(B1)-Val(B2)-Asn(B3))-insulin;des- (Phe(B1)-Val(B2)-Asn(B3)-Gln(B4))-insulin; des-(Phe(B1)-Val(B2)-Asn(B3) -Gln(B4)-His(B5))-insulin. 3. Insulin was re-synthesized from the di-protected des-Phe(B1)-insulin by reaction with an active ester of t-butoxycarbonyl-l-phenylalanine. The product after deprotection crystallized, and the immunoreactivity of the crystalline material was identical with that of the native protein. 4. We have prepared the following analogues of insulin in a similar manner: [l-Ala(B1)]insulin; [l-Val(B1)]insulin; [l-Tyr(B1)]insulin; [m-F-l-Phe(B1)]insulin; [o-F-l-Phe(B1)]-insulin; [o-F-l-Phe(B2)]des-Phe(B1)-insulin. All had between 34 and 62% of the activity of insulin in the fat-cell test. 5. We have also investigated the use of the benzyol, toluene-p-sulphonyl, p-nitrobenzyloxycarbonyl and 2,4-dinitrophenyl groups for the N-protection of the methionine active esters. Each should have had some particular advantage over the benzyloxycarbonyl and ethoxycarbonyl groups, but all proved in practice to have disadvantages that more than outweighed anything in their favour.


A simplified electrophoretic system for determining molecular weights of proteins. Electrophoresis of 31 different proteins in commercially prepared polyacrylamide gradient gels, Gradipore, yields a linear relationship between a hypothetical limiting pore size (the reciprocal of a limiting gel concentration, GL) and the cube root of the mol.wt., over the range 13 500-9000 000. A regression analysis of these data reveals that 98.6% of all variability in 1/GL is explained by the molecular weight, and this degree of accuracy compares favourably with existing methods for the determination of molecular weight by retardation of mobility in polyacrylamide. This new procedure has the additional advantages that molecular-weight standards can be obtained from readily available body fluids or tissue extracts by localizing enzymes and other proteins by standard histochemical methods, and that the same electrophoretic system can be used in determining molecular weights as is used in routine surveys of populations for individual and species variation in protein heterogeneity.


Characterization of glyoxalase I purified from pig erythrocytes by affinity chromatography. Glyoxalase I (EC 4.4.1.5) was purified about 10000-fold from pig erythrocytes in a yield of approx. 20%. The purification included affinity chromatography on S-hexylglutathione coupled to Sepharose 4B. The purified enzyme normally contained two catalytically active components which were resolved by polyacrylamide-gel electrophoresis. After treatment with reduced glutathione only one component was found. The two components were also demonstrable after isoelectric focusing or DEAE-cellulose chromatography and could also in these cases be fused into one species by preincubation with reduced glutathione. It is proposed that the most acidic form of glyoxalase I is a mixed disulphide with glutathione. Except for these interconvertible forms, the purified enzyme was homogeneous, as judged by disc electrophoresis and sodium dodecyl sulphate/polyacrylamidegel electrophoresis. The molecule is a dimer (48000 daltons), composed of apparently identical subunits (24000 daltons). The isoelectric point was 4.8 at 4 degrees C. The amino acid composition was consistent with the low isoelectric point. The enzyme contained about two thiol groups per enzyme molecule. EDTA inactivated the enzyme and bivalent metal ions could restore fully or partially the catalytic activity; Mg(2+) and Mn(2+) gave highest activity. It is proposed that a major biological function of glyoxalase I is the detoxification of methylglyoxal formed by enterobacteria in the alimentary canal.


Purification and properties of a ribosomal casein kinase from rabbit reticulocytes. A casein kinase was isolated and purifed from rabbit reticulocytes. About 90% of the enzyme activity co-sedimented with the ribosomal fraction, whereas about 10% of the enzyme activity was found in the ribosome-free supernatant. Both casein kinases (the ribosome-bound enzyme as well as the free enzyme) showed identical activity and the same molecular weight. On sodium dodecyl sulphate/polyacrylamide-gel electrophoresis a single band of about 70 000 mol.wt. was observed. Sucrose-gradient analysis, however, showed that the enzyme activity sedimented with a s20,w of approx. 7.5S. This observation suggested that the casein kinase is a dimer composed of subunits of identical molecular weight. The enzyme utilizes GTP as well as ATP as a phosphoryl donor. It preferentially phosphorylates acidic proteins, in particular the model substrates casein and phosvitin. Casein kinase is cyclic AMP-indepenoent. The Km values for ATP and GTP with phosvitin as a substrate were determined as 1.2 and 8.8 micrometer respectively.


Effect of lipophilic character on the biological activity of synthetic angiotensin peptides. [Ile5]angiotensin II (angiotensin) derivatives bearing acetyl, propionyl, butyryl, pentanoyl or hexanoyl moieties at the N-terminal amino group were synthesized. The myotropic effects in vitro (on guinea-pig ileum and rat uterus) of desamino-angiotensin and of the above compounds did not correlate with their partition coefficients in butan-1-ol/acetic acid/water. The pressor effects in vivo in rats showed a negative correlation with the partition coefficients, discouraging further attempts to raise the pressor potency of angiotensin analogues by increasing their hydrophobicity. The half-times for onset and reversal of the biological responses also did not correlate with partition coefficients, but reversal was retarded by the presence of a free amino group. It is concluded that partition between aqueous medium and the lipophilic receptor environment is not a limiting factor for angiotensin activity.


A novel mechanism of enzymic ester hydrolysis. Inversion of configuration and carbon-oxygen bond cleavage by secondary alkylsulphohydrolases from detergent-degrading micro-organisms. The hydrolysis was studied of potassium (+)-octan-2-yl sulphate by two analogous, optically stereospecific, secondary alkylsulphohydrolases purified from two detergent-degrading micro-organisms, Comamonas terrigena and Pseudomonas C12B. Polarimetry studies have shown that (+)-octan-2-yl sulphate prepared from (+)-octan-2-ol is hydrolysed by both enzymes to yield (-)-octan-2-ol. This inversion of configuration implies that the enzymes are catalysing the scission of the C-O bond of the C-O-S linkage, a type of bond scission apparently not hitherto encountered among hydrolytic enzymes acting on ester bonds. Enzymic hydrolysis of potassium (+)-octan-2-yl sulphate in the presence of H218O and analysis of hydrolysis products for the presence of 18O has confirmed that C-O bond scission (and not O-S bond scission) occurs with both enzymes.


Carbon-2 proton exchange at histidine-41 in bovine erythrocyte superoxide dismutase. The C-2 proton of one histidine residue in bovine erythrocyte superoxide dismutase is shown to be particularly labile. This residue is identified by tritiation, protein digestion and subsequent peptide 'mapping' as histidine-41. A half-life for the exchange of histidine C-2 1H for 2H in 2H2O as solvent, at pD 8.1 and 40 degrees C, is estimated as approx. 9.2h, by 1H nuclear-magnetic-resonance spectroscopy.


Lymphocyte activation in rheumatoid synovial effusion. A rapid method based upon increase in intranuclear birefringence occurring in early stages of lymphocyte activation was used to examine whether there is any difference in lymphocyte activation between lymphocytes from synovial fluid and those from peripheral blood in patients with rheumatoid arthritis and other joint diseases. Increased activation of synovial fluid lymphocytes compared with peripheral blood lymphocytes was seen only in synovial effusions obtained from patients with rheumatoid arthritis.


Radioimmunoassay of serum myoglobin in polymyositis and other conditions. Radioimmunoassay of serum myoglobin was done in 53 patients with polymyositis syndromes and other conditions. Serum myoglobin values in 33 healthy subjects ranged from 4 to 77 [mean 33.3 +/- 19.8 (SD)] ng/ml. Fifty percent of polymyositis patients had elevated serum myoglobin levels (greater than 80 ng/ml). Serum myoglobin values in polymyositis patients fluctuated more sensitively than CPK and GOT. Combined estimation of myoglobin and CPK offers advantages for the detection of muscle injury and the prediction of disease exacerbation.


Severe systemic lupus erythematosus with nephritis in a boy with deficiency of the fourth component of complement. A young boy with severe systemic lupus erythematosus was found to be totally deficient in the fourth component of complement. Family studies were consistent with an autosomal recessive mode of transmission and with linkage of the gene(s) determining C4 deficiency to the major histocompatibility complex; no disease states were associated with heterozygosity. This patient has had severe multisystem disease and immune complex glomerulonephritis presumably the alternative pathway of complement was utilized in the pathogenesis of his nephritis.


Localizing of C-reactive protein in synovium of patients with rheumatoid arthritis. Synovial biopsies from 8 patients with rheumatoid arthritis, 2 patients with degenerative osteoarthritis, and 4 patients with nonarthritic disease were studied for localization of C-reactive protein (CRP) using immunofluorescence microscopy. The nuclei of many synoviocytes and histiocytes in rheumatoid synovial membrane were found to bind CRP. Cultures of rheumatoid synovium in 14C-labeled amino acids produced radioactive IgG, IgM, IgA, and C3; but not CRP, indicating the synovial-bound CRP was not of local origin. A few CRP-binding nuclei were present in one osteoarthritis synovium, but none was found in the other and none in synovium from the 4 nonarthritis patients. The nature of the nuclear CRP ligand in rheumatoid synovium was not determined.


Adsorption of polymorphonuclear leukocyte lysosomal enzymes to monosodium urate crystals. Monosodium urate (MSU) crystals induced prompt release of lysozyme, and slower release of beta-glucuronidase, alpha-mannosidase, and lactic dehydrogenase (LDH) from polymorphonuclear leukocytes. At increasing crystal concentrations, an increasing delay in the apparent onset of beta-glucuronidase release was detected which appears to be due to selective absorption of enzyme activities to the MSU crystals: beta-glucuronidase greater than LDH greater than alpha-mannosidase greater than lysozyme. Lysosomal enzyme adsorption by MSU crystals may then contribute to experimental error or may modulate gouty inflammation.


Destruction of joint homografts. An experimental study. The host synovium undergoes a striking transformation at about 26 weeks after joint homografting. Histologically the synovium invaded and destroyed the graft with which it came in contact, becoming markedly hypercellular; the infiltrate consisted mainly of plasma cells and lymphocytes. The synovium at this stage closely resembled a rheumatoid pannus. The cartilage in contact with this invasive synovium lost its staining qualities, failed to take up S-35, and was gradually destroyed. The mechanism causing this transformation remains unclear. It is postulated that these changes could be due to an inflammatory or immune response.


Acute bilateral symmetrical pathologic fractures of the lateral tibial plateaus in a patient with Gaucher's disease. A 41-year-old woman with Gaucher's disease developed bone crises of both proximal tibiae and of her spine concurrent with a syndrome of severe gastroenteritis. Three to six months later the bilateral symmetrical pathologic collapse of both lateral tibial plateaus occurred. The unusual occurrence of multiple bone crises with the gastroenteritis suggests a common causative agent, possibly a severe viremia.


Synovectomy and total joint arthroplasty for recurrent hemarthroses in the arthropathic joint in hemophilia. Severe hemophiliacs with intractable bleeding into one or more joints despite adequate clotting factor replacement therapy are difficult management problems. Synovectomy has controlled bleeding only in joints without significant arthritis destruction. Total joint replacements have been performed in arthropathic joints, but not when uncontrolled bleeding was a concurrent problem. This report describes a hemophiliac with uncontrolled bleeding into an arthritic knee who was successfully managed by combining synvectomy with total knee replacement.


Allopurinol hepatotoxicity. Case report and literature review. Significant hepatotoxicity due to allopurinol seems to be rare. Only 6 such cases have been recorded in the literature. The clinical and histopathologic findings of allopurinol-induced liver injury are variable in the previously reported cases. Described herein is another patient with allopurinol hepatotoxicity. Of interest is the similar histopathology between the present case and the two previously reported cases of allopurinol-induced granulomatous hepatitis; thus this is the third such recorded case. Allopurinol should be suspected when liver abnormalities occur following use of this drug.


[Treatment of carotid-cavernous fistula with the Serbinenko balloon catheter]. After a critical survey of the methods of treating carotid-cavernosus fistulae employed until now and some special techniques, the endovasal method using the flow-in catheter with droppable microinflator after Serbinenko is described. In this technique, a latex inflator is filled intracavitarily with cold-vulcanized silicon rubber by the transcutaneous-transcarotidal route and left in situ for a selective closure of the fistula. 3 cases treated by the author with late results show the advantages of the method by which the carotid can be reconstructed.


[Problem of the special pathology of brain tumors]. The post-mortem material of the Erfurt Pathological Institute covering the period from 1953 to 1975 included 1376 primary tumours of the central nervous system, which corresponds to 2.6 per cent of all autopsies and 9.6 per cent of the autospies for malignant tumours. Thus, tumours of the central nervous system show the same frequency as leukoses and lymphomas and tumours of the female genitals and range before the tumours of the colon. The age distribution confirms well known conditions, but shows as apecu liarity that in infancy cerebral tumours occur just as frequently as in childhood and that the frequency of the occurrence of meningiomas before and after the 60th year of life is practically the same; but after that time they are clinically diagnosed in a distinctly less frequent number. Wrong clinical diagnoses were made in 23.5 per cent of the observations. Finally, it is pointed out that the intraoperative picture of the tumours may be misleading and only histological examinations will be helpful.


[Problems in the general pathology of brain tumors]. The various classifications of tumours of the central nervous system employed at present are analysed. A generally accepted classification is still missing. In any case, one should avoid to place cerebral tumours outside the systems, or even to exclude them from the considerations of general oncology. A solution to the problem requires as far as possible a complete detection of all cerebral tumours by autopsy. In particular, patients who were not opperated can on furnish essential indications. Even histologically and clinically so important indications with regard to dignity and malignity cannot be obtained with absolute certainty. For the greater part of cerebral tumours, degrees of malignity ("grading") cannot be established with sufficient reliability. In the GDR tumour statistics, cerebral tumours are almost as frequent as leukoses or the so-called lymphomas.


[Experiences from the conception of a complex-diagnostic neuroradiologic department integrated into a neurosurgical clinic (model of a novel functional and structural solution)]. For planning and designing the reconstruction of an superannuated radiological department of a neurosurgical supra-regional hospital the following requirements had to be taken into account: 1. Complex-diagnostic working style of a neuroradiological department integrated in the hospital complex. 2. Ensuring of a comprehensive operative-technical examination programme by appropriately equipped work places. 3. The aim to improve the working conditions of the personnel and the medical care of the population. The ideal solution was achieved by an extension of the neurosurgical clinic in the form of a diagnostic tract comprising neurosurgical O.P.D. and an after-care department, electro-diagnostic and neuroradiological departments. In the centre of the novel solution there is the function tract of the neuraradiological department in which the complex building method enables a clear division into main zones (patients zone, function zone, personnel zone). It ensures economical working for the benefit of both patients and personnel. Charts showing the sequence of operations and graphic representations of the constructional solution as well as recommendations for equipment standards for the work places illustrate the project, which is certainly suitable for serving as an internation model of similar special establishments of public health services.


[Possibilities for error in the diagnosis of craniopharyngiomas]. Age of affection, preferential seat, clinical picture and instrumental diagnosis of craniopharyngiomas are discussed on the basis of 30 observations. Although childhood and adolescence are the leading age groups, there also was a 64-year-old patient. Three courses of the disease were selected: a 6-year-old girl presented both clinically and by instrumental examination indications of a cerebellar tumour; a mandarin-sized arachnoid cyst near the midline was removed. One year later, a suprasellar craniopharyngioma of the size of a chestnut was removed  subtotally. Retrospectively, the arachnoid cyst was only seen as a side-finding. A 13-year-old girl showed angiographically and in the pneumoencephalogram signs of a cerebellar tumour located in the middle; the operation showed regular conditions. Only frontal trepanation showed a plum-sized cystic retrochiasmal craniopharyngioma. Similar conditions were found in another 6-year-old girl.


[Rare traction injury to the radial nerve]. Presenting 3 examples, the author deals with the traction damage of the N. radialis in which the lesion was located in the region of the elbow. In each case, the injury of the nerve was caused by a violent hyperflexion of the wrist when the back of the hand was struck by a heavy blow. The symptoms were produced immediately after the trauma. Complete recovery was achieved in all patients after a few weeks.


[1st experience with laser beams in the treatment of neurosurgical diseases]. The Sharplan 791 type CO2-laser, specially adapted to neurosurgical requirements, was used in the surgery of 9 gliomas, 10 meningeomas, 6 patients presenting metastasis, 1 case of vascular malformation, intracranial interventions, 1 case of hippocampectomy, 2 cases of neurinomas, 2 intramedullar tumours of the spinal cord, 1 case of thoracic commissurotomy, 1 case of thoracic prolaps of intravertebral disc, 1 case of vertebral metastasis and in 3 cases of stump neurinoma. Detrimental effects on the patients as well as any hazards to the surgical staff have not been observed. The cutting effect was mainly used for the incision of soft part, in some cases also for the formation of bony cover. Moreover the CO2-laser beam was used for coagulation and vaporisation. Particular advantages are offered by the equipment when working under the surgical microscope. Topografic precision and energetic dosing make the equipment a valuable supplement of the surgical instruments, available until now.


[Serum immunoglobulin (IgG, IgM, IgA) levels in patients with primary brain tumors (author's transl)]. The concentration of serum immunoglobulins (IgG, IgM, IgA) in 63 patients of primary brain tumors were determined by the method of single radial immunodiffusion. 1) The mean values and standard deviations of three major serum immunoglobulins in 18 cases of meningioma were as follows; IgG, 1297.0 +/- 387.9 mg/dl, IgM, 165.1 +/- 153.4 mg/dl, IgA, 219.5 +/- 76.7 mg/dl. These values were not significantly different with those in normals. 2) 45 cases of gliomas showed; IgG, 1190.5 +/- 378.3 mg/dl, IgM, 160.0 +/- 75.9 mg/dl, IgA, 189.8 +/- 91.5 mg/dl. These values were in normal levels as compared with normal serum immunoglobulins. 3) Values of serum immunoglobulins in 19 cases of glioblastoma multiforme were compared with those in 18 cases of astrocytoma to know the relationship between histological malignancy and levels of serum immunoglubulins. But no significant difference was observed between these values. The levels of three major serum immunoglobulins either in meningiomas or in gliomas were not significantly different with those in normals. Therefore, the levels of serum immunoglobulins could not be used as a diagnotic procedure in cases of primary brain tumors.


[Follow-up results of microsurgery of intracranial aneurysms (author's transl)]. In the past 7 years, 403 cases of intracranial aneurysms were submitted to microsurgical operations. The operative mortality was 5.4%, and in the follow-up, 82.4% are working, 6.2% are caring for self and 5.9% are either bed-ridden or dead from other causes after discharge. If 6 cases of Grade V are excluded from the statistics and the day of subarachnoid hemorrhage (SAH) is counted as the 1st day, cases submitted to microsurgery on the 1st, the 2nd and the 3rd days showed no mortality and 72.7% of them are working in the follow-up. Cases undergone micro-surgery on the 4th through the 8th day showed a high mortality of 15.2% due to postoperative vasospasm, whereas in cases submitted to micro-surgery in the 2nd week after SAH the operative mortality was 6% and in cases submitted to micro-surgery later than the 2nd week it was 3%. In the follow-up 84% and 85.6% are working in the latter two respectively. These results seem to encourage ultra-early surgery for ruptured aneurysm cases. However, one should always bear in mind that the acute stage of SAH should be regarded as a "systemic disease", not as a "local disease", and only those who have ability and facility to manage this systemic disease may be qualified to perform early surgery for ruptured aneurysms.


Laryngeal incompetence during experimental "relative analgesia" using 50% nitrous oxide in oxygen. A preliminary report. Ten healthy adult volunteers inhaled 50% nitrous oxide in oxygen while dental treatment was simulated for a period of 30 min. During this time 15 ml of radio-opaque dye was placed at the back of the tongue. A similar control study was performed 1 week later, the subjects inhaling pure oxygen without nitrous oxide. X-ray examination revealed that two of the 10 volunteers had aspirated dye while breathing nitrous oxide and oxygen, but no aspiration was apparent in the control study.


Right versus left lateral tilt for Caesarean section. In 60 mothers with normal placental function, the relative merits of right and left lateral tilt during Caesarean section were assessed. Maternal-foetal biochemical values and relationships were generally more satisfactory with the left lateral position. The incidence of hypotension (revealed aorto-caval occlusion) before and after induction of anaesthesia, was significantly greater (P less than 0.001) with the "right side down" posture.


Placental transmission of atropine at full-term pregnancy. Measurements of placental transmission of atropine were performed during Caesarean section. Twenty-five patients received 3H-atropine 0.5 microgram . kg-1 i.v. 1-30 min before delivery. Maternal venous blood was sampled before the induction of anaesthesia and at the moment of delivery, together with umbilical arterial and venous blood. Total hydrogen-3 activity was determined by liquid scintillation counting. The stability of 3H-atropine was confirmed by paper chromatography. The concentrations in the umbilical vein 1 and 5 min after injection were respectively 12% and 93% of the corresponding maternal value. Those in the umbilical artery were approximately 50% of those in the umbilical vein during the same period.


Blood volume replacement in acute anaphylactic cardiovascular collapse related to anaesthesia. In seven patients who suffered anaphylactic cardiovascular collapse during anaesthesia the degree of haemoconcentration was used to assess changes in blood volume. The patients who were resuscitated with electrolyte solutions, or electrolyte solutions with a small volume of colloid, showed haemoconcentration suggesting plasma loss of 20.2-37%. Patients who were resuscitated initially with colloid solutions showed minimal haemoconcentration. In anaphylactic cardiovascular collapse, the reduction of blood volume is a result of loss of plasma and colloid solutions should be used to replace the volume deficit.


Spread of extradural analgesia following caudal injection in children. A statistical study. Data on the segmental spread of analgesia from three independent studies of caudal extradural blocks in children with three different local anaesthetic agents were examined with multiple regression techniques to find the effects of age on dose requirements. All three studies confirmed the existence of a linear relationship between the spread of analgesia and age. As there were no significant differences between the three regression lines a common regression line was calculated. This may be used as a guideline for predicting dose requirements in the daily routine of anaesthesia. By injecting a mixture of a radio-opaque substance and 4% lignocaine it was shown by comparison of the radiological spread of the solution and the distribution of clinical analgesia that the latter always exceeded the former by four to six segments. This may indicate the occurrence of diffusion.


A prospective study of hepatocellular function after repeated exposures to halothane or enflurane in women undergoing radium therapy for cervical cancer. Ninety-nine Black females receiving radium therapy for carcinoma of the cervix uteri under either halothane (50 patients) or enflurane (49 patients) anaesthesia were studied. Thirty-six received a second and 13 a third exposure to halothane or enflurane. There were no significant changes from the control values in the serum concentrations of aspartate aminotransferase (s.g.o.t.), gamma glutamyl transpeptidase (gammaGT), lactic dehydrogenase (SLD), alkaline phosphatase (SAP) and proteins. Total serum bilirubin (TSB) decreased significantly during the first exposure to enflurane (P less than 0.01). This trend was reversed with subsequent anaesthetics in both the halothane and enflurane groups.


Suxamethonium pains and electromyograph recordings in children. Surface electromyography was used to investigate muscle activity in children following the administration of suxamethonium. The duration, amplitude and frequency of muscle action potentials recorded in children were similar to those in adults. Twenty-three children had muscle action potential frequencies in excess of 50 Hz, but only two suffered pain after operation. The relationship between high frequency discharge rates of motor units noted in adults in earlier studies does not apply to children.


Use of neostigmine after snake bite.

Use of neostigmine after snake bite. Cobra venom consists of a neurotoxin which is responsible for respiratory paralysis simulating that associated with a non-depolarizing muscle relaxant. A combination of artificial respiration and neostigmine has been useful in resuscitating a child bitten by a snake.


Depression of hypoxic ventilatory response by halothane, enflurane and isoflurane in dogs. The ventilatory responses to isocapnic hypoxia and hypercapnia were studied in six dogs each with a tracheostomy, awake and during anaesthesia with halothane, enflurane and isoflurane (1-2.5 MAC). Isocapnic hypoxic ventilatory response (HVR) was expressed as the parameter A, such that the greater the value of A, the greater the hypoxic response. In the anaesthetized dogs HVR (A) was reduced significantly from the awake value of 2010 +/- 172 (mean + SEM) to 630 +/- 173 by 1 MAC halothane, 495 +/- 105 by 1 MAC enflurane and 952 +/- 157 by 1 MAC isoflurane (PL0.05). All three anaesthetic agents produced significant depression of HUR at 1 MAC, but enflurane was more depressant than isoflurane. At 1.5 MAC all three anaesthetics produced equal and significant depression of HVR at equianalgesic concentrations. Further increases in anaesthetic concentration caused no increase in depression. Hypercapnic drive, as measured by the slope of the VE/PACO2 response curve, was reduced significantly from 9.75 litre min-1 kPa-1 +/- 2.4 in awake dogs to 0.83 +/- 0.56 after 1 MAC halothane, 0.68 +/- 0.53 after 1 MAC enflurane and 1.58 +/- 0.75 after 1 MAC isoflurane. In addition, hypercapnia-induced augmentation of the hypoxic drive was abolished by 1 MAC halothane or enflurane and diminished markedly by 1 MAC isoflurane. It may be clinically significant that hypoxia and hypercapnia during anaesthesia with these agents did not produce optimal stimulation of ventilation.


Calcium and magnesium contents of malignant hyperpyrexia-susceptible human muscle. The calcium and magnesium contents of muscle obtained by muscle biopsy of patients referred for malignant hyperpyrexia screening were determined. The susceptibility to malignant hyperpyrexia was made on the basis of the halothane contracture test. No difference in cation concentrations was found between the normal and malignant hyperpyrexia-susceptible groups.


Effects of morphine and ketamine anaesthesia and surgery on plasma concentrations of luteinizing hormone, testosterone and cortisol in man. Thirty patients received morphine and 27 received ketamine. Morphine anaesthesia did not influence plasma concentrations of luteinizing hormone (LH) significantly, but there was a significant increase during ketamine anaesthesia. Plasma LH increased in the early stage of surgery under both anaesthetics. A significant decrease in the plasma concentration of testosterone was found during and following both techniques of anaesthesia, the lowest concentration being detected on the first day after surgery. Ketamine anaesthesia, but not morphine, stimulated adrenocortical function significantly. Furhter stimulation was detected in the periods during and after operation with both anaesthetic techniques.


Anaesthetic management of patients with phaeochromocytoma. A review of 102 cases. A total of 102 patients with phaeochromocytoma who underwent surgery by the same team between 1964 and 1976 were allocated to three groups according to the anaesthetic protocol used: (1) balanced anaesthesia and control of hypotension with noradrenaline; (2) anaesthesia with halothane and replacement of blood volume; (3) neuroleptanalgesia (droperidol and phenoperidine) and replacement of blood volume. None of the patients in any of the three groups received adrenergic inhibitors before anaesthesia. Comparison of the results in the three groups revealed that the major factor responsible for reduction of operative mortality to almost zero was control of hypotension by replacement of blood volume rather than by the use of noradrenaline following resection of the tumour, whereas the type of anaesthetic agent used was of secondary importance.


Respiratory effects of extradural analgesia after lower abdominal surgery. Blood-gas tensions, FRC and volume of trapped gas (VTG) in the lung were measured in patients on the day before lower abdominal gynaecological surgery, and twice on the day following surgery, before and after establishing lumbar extradural block (EDB) using 0.5% bupivacaine to provide analgesia after operation. FRC and VTG were measured with the closed-circuit helium-dilution technique. Mean VTG was 175 ml before operation and 275 ml after operation. PaO2 decreased significantly after operation, and the changes in FRC and VTG that occurred were related qualitatively. EDB did not significantly alter FRC, VTG or PaO2. Individual changes in FRC could not be related to changes in VTG or PaO2. Although EDB provided effective analgesia, the variables measured did not indicate that EDB conferred an immediate respiratory advantage.


Early and late radiation reactions in mouse feet. The relationship between early and late radiation damage has been analysed by comparing the early skin reaction (desquamation in the first month) with the late foot deformity seen at 6 months, for mice from a wide variety of different fractionation experiments. A close correlation was observed between the early and late reactions in each experiment and the relationship was the same for all the experiments except for 17-64 fractions given over a short time. The fractionation schemes included single doses and 2-64 fractions, and the overall times ranged from 1 day to 6 months. This close correlation for such a wide variety of treatments suggests that the two end points are not necessarily independent responses of different tissues and that late damage in the mouse foot can result secondarily from depletion of the basal layer of the epidermis. Late foot deformity is therefore not a reliable model for the response of a slowly proliferating tissue.


Tumour volume response, initial cell kill and cellular repopulation in B16 melanoma treated with cyclophosphamide and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The relationship between tumour volume response and cell kill in B16 melanoma following treatment in vivo with cyclophosphamide (CY) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) was investigated. Tumour volume response, expressed as growth delay, was estimated from measurements of tumour dimensions. Depression of in vitro colony-forming ability of cells from treated tumours was used as the measure of tumour cell kill. The relationship between these parameters was clearly different for the two agents studied. CY produced more growth delay (7.5 days) per decade of tumour cell kill than CCNU (2 to 3.5 days). The possibility that this was due to a technical artefact was rejected in favour of an alternative explanation that different rates of cellular repopulation in tumours treated with CY and CCNU might be responsible. Cellular repopulation was measured directly, by performing cell-survival assays at various times after treatment with doses of CY and CCNU which produced about 3 decades of cell kill. The rate of repopulation by clonogenic cells was much slower after treatment with CY than with CCNU, and this appears to account for the longer duration of the growth delay obtained with CY.


Alterations of mononuclear phagocyte function induced by Lewis lung carcinoma in C57BL mice. The function of the reticulo-endothelial system in mice bearing Lewis lung carcinomas has been measured by(1) the rate of clearance of carbon particles from the circulation in vivo and calculation of the phagocytic index K; (2) chemotactic locomotion of macrophages in vitro in the presence or absence of serum or tumour supernate. The ability of the bone marrow to develop macrophage colonies in vitro in the presence or absence of sera from tumour-bearing mice has also been tested. A clear depression of macrophage locomotion and macrophage colony formation in vitro was found in the presence of sera or tumour supernates from tumour-bearing mice as early as 24 to 72 h after tumour inoculation. Similarly, tumour-bearing mice showed marked depression of carbon clearance in tests repeated throughout the first 72 h after tumour inoculation. This early depression of macrophage function may be an important step in allowing escape of tumour cells from host resistance.


Follow-up studies on the immune status of patients with Hodgkin's disease after splenectomy and treatment, in relapse and remission. Sixty-two patients with Hodgkin's disease have been followed for one year from the start of treatment. Immunological assessments were repeated after intensive treatment, in patients relapsing and in those in remission at one year. In patients achieving remission, overall cellular immunity, after deteriorating with therapy, particularly cytotoxic chemotherapy, returned to pre-treatment levels in remission when there was little evidence of cellular immune disturbance. Serum IgG and IgM levels fell with intensive chemotherapy in splenectomized patients. IgA and IgM levels were lower (irrespective of splenectomy or therapy status) in remission than at presentation or after treatment. Relapse or non-response was usually associated with deteriorating cellular immunity. Herpes zoster/varicella and candida infections (seen in 6 patients) were preceded by, or associated with, deterioration of cellular immunity.


Second primary cancers in patients with tumours of the salivary glands. In a series of patients drawn from the Birmingham Regional Cancer Registry (England) with tumours of the salivary glands, a significant excess of second primary tumours was observed. For females, the excess was found mainly in breast and bronchus and, for males, in prostate and skin. In a parallel series of female breast-cancer patients, the observed number of second primary tumours in salivary glands significantly exceeded expectation. These results support the reported association between salivary gland and breast cancer, and suggest that other hormone-dependent sites are also at risk.


Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Androgenetic alopecia in the female occurs much more frequently than is generally believed. The condition is still considered infrequent, for it differs, in its clinical picture and in the sequence of events leading to it, from common baldness in men. To facilitate an early diagnosis (desirable in view of the therapeutic possibilities by means of antiandrogens) a classification of the stages of the common form (female type) of androgenetic alopecia in women is presented. The exceptionally observed male type of androgenetic alopecia can be classified according to Hamilton or to the modification of this classification proposed by Ebling & Rook.


Vitiligo: a new classification and therapy. Local injection of physostigmine revealed that dermatomally distributed vitiligo was associated with a dysfunction of the sympathetic nerves in the affected skin and that non-dermatomally distributed vitiligo was not. These observations led to the hypothesis that the primary disturbance of dermatomally distributed vitiligo lies in the sympathetic nerves of the affected area and that non-dermatomally distributed vitiligo has its primary disturbance in the melanocyte itself, where an autoimmune mechanism is suspect. Results of therapy supported this hypothesis by showing that topical cortisteroid is effective only in the latter, while the former reacts to oral nialamide. It is proposed that non-dermatomally distributed vitiligo be referred to as Type A and dermatomally distributed vitiligo as Type B.


Depigmented haloes associated with the involution of flag warts. Depigmented haloes developed around involuting flat warts in two patients whose warts were treated with a 6% salicylic acid-propylene glycol gel formulation. The clinical picture was indistinguishable from that seen in halo naevus.


Eruptive naevi: report of two cases, with enzyme histochemical, light and electron microscopical findings. The cases of two young adults with widespread multiple eruptive naevi are described. In the first patient, more than 100 lesions appeared during a period of 6 months. Young lesions were small flesh-coloured telangiectatic papules; older lesions were larger and verrucose with histological features of cellular naevi. In the second patient, a great number of lentigines developed in the course of 2 years. Light and electron microscopy showed that giant melanosomes were present within the lesions. The plasma level of beta-MSH-like immuno-reactivity was normal.


Light sensitivity in mycosis fungoides.

Light sensitivity in mycosis fungoides. Because of suspected photosensitivity, twelve patients suffering from mycosis fungoides have been phototested with various wavebands. Four patients experienced a burning sensation and erythema following sun-exposure, after the disease had progressed to stage II. On phototesting, abnormal reactions were observed in 7 patients. The offending wavebands were situated mostly in the UVA range, but also in the UVB range and in visible light.


Influence of wind on chronic ultraviolet light-induced carcinogenesis. Wind enhances the carcinogenic effect of chronic Iltraviolet radiation (UVL). This was demonstrated in hairless mice that were irradiated for 42 weeks with mercury are lamps. One group of animals was exposed to continuous wind flow of 2.7 m/s except for the daily I-2 min time interval when they were removed from the wind tunnel and irradiated. Another group of animals received identical irradiation but were protected from wind. The first tumour appeared in the UVL and wind group after 105 days of irradiation, and at 164 days of irradiation all surviving mice in the group had developed tumours. The group of mice receiving identical irradiation but protected from wind had their first tumour appear at 154 days of irradiation, and by 164 days of irradiation only 40% of the mice had developed tumours.


Psoriasis and stress.

Psoriasis and stress. 132 psoriasis patients who had been completely cleared with dithranol were assessed and then followed up over a 3-year period. The incubation time from specific incidents of stress to the development of psoriasis was between 2 days and 1 month. Specific stress within a month before the first attack was recalled by 51 patients (39%); chance association was excluded by studying a control group where there was significantly less specific stress. The prognosis for the psoriasis patients who recollected specific stress a month prior to the onset was significantly better than for the rest of the patients where none had been recalled.


Cutaneous beta-glucuronidase: cleavage of mycophenolic acid by preparations of mouse skin. Mycophenolic acid, a new chemotherapeutic agent for the treatment of psoriasis, is known to be rapidly conjugated on absorption and to circulate largely in the form of its glucuronide conjugate. Since this metabolite does not readily penetrate intact cells and is cleaved by the enzyme beta-glucuronidase to yield free mycophenolic acid, the ability of preparations of mouse skin to cleave mycophenolic glucuronide was studied. The time course of mycophenolic acid liberation by such preparations and the dependence upon the amount of enzyme preparation were demonstrated. Preparations of mouse skin and mouse liver, kidney, spleen, lung, heart and small intestine were assayed for beta-glucuronidase activity using p-nitrophenyl-beta-D-glucuronide as substrate. Skin yielded preparations with higher beta-glucuronidase activity per/mg protein than any of the other organs tested. When expressed on the basis of beta-glucuronidase activity recovered per milligram of tissue DNA, skin, liver and kidney showed higher levels than the other organs tested.


Post-kala-azar dermal leishmaniasis.

Post-kala-azar dermal leishmaniasis. Ten patients with post-kala-azar dermal leishmaniasis (2 females, 8 males-aged 17-47 years) are described. Two of them had macular lesions in which very few Leishman-Donovan bodies were seen and who responded well to treatment with stibophen. Five patients had both macular and nodular lesions, Leishman-Donovan bodies being present in nodules but not in macules. Treatment with stibophen caused partial regression of nodules. Nodular lesions were found in three patients, who did not have macules. They contained numerous Leishman-Donovan bodies and treatment produced only temporary improvement. The variable response to treatment with stibophen may have been due to differences in parasitic load. The difficulty in distinguishing this disease from leprosy is discussed.


Generalized eczéma craquelé as a presenting feature of lymphoma. Two cases of lymphoma are reported--in both, extensive eczéma craquelé resistant to treatment was a presenting feature.


Acquired ichthyosis: multiple causes for an acquired generalized distrubance in desquamation. Four patients with acquired ichthyosis are described and the results of histological, histometric, autoradiographic and enzyme histochemical studies reported. Three of the patients were found to have in addition the following underlying diseases--malnutrition, reticulum cell sarcoma and panhypopituitarism. The fourth patient did not have any systemic disorder and the provoking cause of his ichthyotic condition remains obscure. Clinically these patients demonstrated the skin changes of autosomal dominant ichthyosis although their condition tended to fluctuate in severity. The various studies performed indicated that the histological and metabolic changes tended to reflect the clinical state of the patients and that these parameters did not differ significantly from those observed in atuosomal dominant ichthyosis.


Darier's disease: a kindred with a large number of cases. Over 70 cases of keratosis follicularis (Darier's disease) were noted in a study of a single kindred consisting of more than 200 individuals. Data were obtained through questionnaires, interviews and physical examinations. Results strongly support an autosomal dominant mode of inheritance since the ratio of affected to unaffected members was I:I and there were nearly equal numbers of males and females with this condition. Large sibships were common in this kindred, which extended over seven generations, and most of the affected individuals were located in the southwestern New York-northwestern Pennsylvania region of the United States.


Obstetric practice and infant morbidity. A method is described of using matched pairs of index infants and controls to examine the hypothesis that induction or some other obstetric practice is associated with increased morbidity in the mature infant. All infants over 2250 g and 37 weeks gestation, without severe congenital defect or history of severe maternal disorder, born in the John Radcliffe and admitted to the Special Care Baby Unit in 1975 were identified. For each of these index infants a matched control was chosen using strict criteria. Contrast between the 109 matched pairs showed no significant differences between maternal characteristics, induction of labour, use of forceps or duration of labour. There was an excess of index infants born to mothers who had had epidural anaesthesia (P less than 0.05).


Pregnancy and the acute porphyrias.

Pregnancy and the acute porphyrias. An analysis is presented of the obstetric histories of 50 women with acute porphyria, comprising 39 with acute intermittent porphyria, 3 with variegate porphyria and 8 with hereditary coporporphyria. Fifty-four per cent of the women with acute intermittent porphyria had an acute attack of porphyria in pregnancy and/or the puerperium. Only one maternal death was recorded. One patient with variegate prophyria and two with hereditary coproporphyria had an attack related to pregnancy. The total fetal wastage was 13 per cent. The babies born to mothers with acute intermittent porphyria, who experienced an acute attack during pregnancy, were smaller than those in which no such attack occurred (P less than 0.001). In 13 non-porphyric primigravidae there was a rise in urinary excretion of delta-aminolaevulinic acid, porphobilinogen and coproporphyrin up to the 28th week of gestation. It is probable that pregnancy has some deleterious effects in acute prophyria but the prognosis of the porphyric pregnancy is much better than the literature suggests.


Nonspecific decelerations in fetal heart rate during high-risk pregnancy. Solitary nonspecific decelerations in fetal heart rate occurring in three patients during antepartum cardiotocography are described. The decelerations were nonspecific in that they were neither variable nor late nor associated with maternal hypotension. All occurred in pregnancies complicated by hypertension and placental insufficiency. In the three patients described, the fetus lived for at least three days after the first nonspecific deceleration was observed. Although solitary nonspecific decelerations may indicate may indicate danger to the fetus from placental insufficiency, these decelerations should not be considered as an indication for immediate delivery.


The uterine and cardiovascular effects of oral fenoterol hydrobromide. Fenoterol hydrobromide was administered as a 5 mg tablet to 10 patients in oxytocin-induced labour and the effects on uterine activity and on the cardiovascular system of mother and baby were evaluated. The drug took effect within 30 minutes in 8 of the 10 patients and it reduced uterine activity to less than 30 per cent of the original. Fenoterol caused a moderate maternal tachycardia, raised systolic and decreased the diastolic blood pressure.


Circulating levels of pregnancy-specific beta1-glycoprotein in early pregnancy. Circulating levels of pregnancy-specific beta1-glycoprotein (SP1 or PSbetaG), luteinizing hormone (LH) and human chorionic gonadotrophin (HCG) were measured serially in 9 subjects immediately after conception. Ovulation occurred spontaneously in 3 subjects, or followed administration of clomiphene citrate (2 subjects) or bromocriptine (4 subjects). The timing of ovulation was determined by the appearance of the LH surge. Levels of HCG were detected 10 to 16 days, and SP1, 18 to 23 days after ovulation. These findings suggest that the measurement of plasma levels of SP1 may provide valuable additional biochemical evidence of pregnancy.


Changes in prostaglandin F and 13,14-dihydro-15-keto-prostaglandin F concentrations in amniotic fluid at the onset of and during labour. Concentrations of prostaglandin F (PGF) and its major circulating metabolite 13,14-dihydro-15-keto-PGF (PGFM) have been measured in amniotic fluid during spontaneous labour at term. Levels of both PGF and PGFM were significantly higher during early spontaneous labour, at a cervical dilatation of less than 4 cm, than before the onset of labour. Patients who started labour spontaneously but later required oxytocin therapy for failure to progress in first stage had lower levels of PGF and PGFM than patients who progressed adequately without oxytocin therapy. During spontaneous labour, concentrations of both PGF and PGFM increased significantly with advancing cervical dilatation. These indicate that the accumulation of prostaglandins in amniotic fluid during labour is not due to decreased metabolism. They furthermore provide the strongest evidence available so far for an increase in intrauterine prostaglandin synthesis during human parturition.