"Swimmers' itch" (cercarial dermatitis). Cercarial dermatitis is a parasitic disease affecting the skin. It may be encountered in fresh or salt water and is global in its distribution. It is a potential economic hazard to persons who work in aquatic environments and to the tourist industry. Cercarial dermatitis should be considered a potential risk whenever warm-blooded and molluscan hosts share a water resource with man. It is characteristically a self-limited, severely itching rash that lasts about one week and may be easily mistaken for insect bites. Prevention of the disease is difficult. Treatment is primarily directed toward relief of symptoms and prevention of infection.


Safety of hot and cold liquids in patients with acute myocardial infarction. Patients with acute myocardial infarction are frequently not fed hot and cold liquids because of possible deleterious effects on heart rate, blood pressure, and cardiac rhythm. In an attempt to identify and quantify such changes, hot liquid with a temperature in excess of 70 degrees C and cold liquid at an average temperature of 7 degree C were ingested by 20 patients within 36 hours of documented myocardial infarction and by 11 control patients with severe anginal episodes or chest wall syndromes. Heart rate and rhythm were continuously monitored during ingestion of the hot and cold liquids, and blood pressure was recorded intermittently. No patient in either group had a change in cardiac rhythm or an increase in ectopy during ingestion of the hot and cold liquids. Changes in blood pressure and heart rate were also not significant during liquid ingestion by patients with infarction and control patients. The practice of avoiding ingestion of hot and cold liquids by patients with acute myocardial infarction is not supported by these observations.


Fatal air embolism to the right side of the heart during pneumonectomy for carcinoma. Result of broncho-azygous vein communication and positive-pressure ventilation. A 59-year-old white man had an extensive bronchogenic carcinoma of the right upper lobe. During the course of pneumonectomy, the patient died unexpectedly. At autopsy, massive right-sided air embolism was evident, associated with broncho-azygous vein communication. The cause of the air embolism and subsequent death was almost certainly related to positive-pressure ventilation, allowing entry of air into the systemic venous system through the broncho-azygous vein communication. Because of the clinical implications of this problem, the case is reported, and suggestions for management are offered.


Amyotrophic lateral sclerosis presenting with respiratory failure. Diaphragmatic paralysis and dependence on mechanical ventilation in two patients. Described are two patients whose initial symptom was acute respiratory failure requiring mechanical ventilation. Initially, the cause of the respiratory failure in each patient was obscure, but diaphragmatic paralysis was subsequently demonstrated fluoroscopically in each case. Further neurologic evaluation then supported the diagnosis of amyotrophic lateral sclerosis. Postmortem examination corroborated this diagnosis.


Cytochemical and ultrastructural studies on the synaptonemal complex of rat spermatocytes. The effects of several dehydration treatments on the synaptonemal complex (SC), histone solubility in 2.0 M NaCl, and histone-DNA interaction in unfixed rat spermatocytes were evaluated. Freeze substitution with ethanol or dehydration with polyethylene glygol resulted in loss of the SC, preservation of histone solubility and DNA-histone salt linkages. Dehydration with ethylene gylcol or hexylene glycol resulted in preservation of SC with a clear delineation of attachment of the chromatin fibrils to the lateral elements, but a loss of histone solubility and histone-DNA linkages. Dehydration to a fifty percent concentration with glycerol with completion of dehydration with ethylene glycol had the same effect but also resulted in an even distribution of chromatin fibrils. Dehydration with glycerol alone resulted in clumping of chromatin and loss of SC structure, histone solubility and histone-DNA linkages. Partial dehydration to a fifty percent concentration with these three solvents followed by freeze substitution with ethanol resulted in the loss of SC structure and histone solubility but the preservation of histone-DNA linkages. It is likely that these nonaqueous solvents affected the histone hydrophobic groups and thereby altered histone conformation and interactions. These alterations, depending on the treatment used, resulted in the loss or preservation of SC, histone solubility and histone-DNA interactions thereby indicating that the hydrophobic interactions of the histones are crucial for the preservation of these feature of meiotic chromosomes. These results also demonstrate that neither does the preservation of the histone-DNA salt linkages suffice for the preservation of the SC nor does their disruption necessarily result in its loss. The lysine-rich histones, particularly that one unique to meiotic cells, may through their interactions play a crucial role in SC structure.


Localization of tubulin in the mitotic apparatus of mammalian cells by immunofluorescence and immunoelectron microscopy. Antitubulin antibody was used as an immunofluorescent and immunoelectron microscopic probe to localize tubulin in components of the mitotic apparatus of rat kangaroo (strain PtK1) cells in vitro. In addition to the detection of tubulin in the spindle microtubules and centrioles, other structures were found to display specific staining including kinetochores, amorphous pericentriolar material and small virus-like particles associated with the centrioles. The kinetochores consisted of a densely stained outer layer about 400 A thick which is separated from an inner layer of the same dimension by a lightly staining middle layer. Microtubules were primarily associated with the outermost plate of the kinetochore but tubulin was uniformly distributed in both outer and inner plates. Colcemid treatment prevented the assembly of spindle microtubules and resulted in specific alterations of the kinetochore but failed to diminish the staining of the kinetochores. These observations suggest that tubulin molecules may comprise an important structural component of the kinetochore.


[Raynaud's phenomenon in dialysed patients (author's transl)]. In 158 uraemic patients on haemodialysis complaints resembling Raynaud's disease were observed more frequently (85 patients = 54%) than in an equal number of age and sex matched control persons (10 probands = 6%). The complaints were also registered in the arm without the fistula. Triggering causes were exposure to cold or isometric muscular exercise. The complaints were slightly more frequent in women and occurred in 28% prior to dialysis in the terminal stage of renal insufficiency. They were improved only in a minority of those treated with haemodialysis, however they disappeared after successful renal transplantation. Veno-occlusive plethysmographic investigations showed that in asympatomatic patients the resting perfusion at room temperature, the perfusion in reactive hyperaemia, and perfusion at 0 degrees C were not different from control persons. Patients with Raynaud's phenomenon had on average a diminished resting perfusion and a normal perfusion after reactive hyperaemia. The perfusion at 0 degrees C was lower than in asymptomatic patients but still higher than in patients with Raynaud's disease. Increased cooling of the skin and delayed rewarming were objectively measured by using skin temperatures. There was not correlation between the complaints or perfusion values and the vibration threshold.


Incorporation of 14C-amino acids into rat hypothalamus in vitro. Biosynthesis of peptides in vitro in male rat hypothalamic fragments wasinvestigated by incubating the tissue with 14C-labelled leucine, proline and glycine. Depending on the amino acid used, 4 or 6 labelled peptides were extracted from the tissue fragments with organic solvent mixture. The incorporation of the label into peptides was time dependent. LH-RH and oxytocin thus synthesized were identified by thin layer chromatography and high voltage electrophoresis using cold LH-RH and oxytocin as standards.


Changes of LH and FSH levels in plasma after intaventricular administration of LH-RH. The possibility of influencing the pituitary through the cerebral ventricle was examined. Synthetic LH-RH was introduced into the third ventricle of male and female rats and after 4 and 8 minutes, the plasma LH and FSH levels were determined by radioimmunoassay. Both in the male female rats, the LH levels were elevated, but FSH levels remained unchanged. The results show that, after intraventricular LH-RH administration, the LH level can be elevated within a few minutes. It is presumed that the non responsiveness of FSH level after LH-RH may support the view on a separate control of release of each of both hormones.


A daily neural signal for luteinizing hormone release in the untreated ovariectomized rat: changes in gonadotropin-releasing hormone content of the preoptic area and hypothalamus throughout the day. Gonadotropin-releasing hormone (GnRH) content of preoptic areas (POA) and hypothalami, and serum gonadotropins of rats ovariectomized six weeks earlier were measured throughout the day in two experiments. In the first, rats were decapitated at 2 h intervals between 0800 and 1800 h. The entire preoptic-hypothalamic region was removed and extracted for radioimmunoassay (RIA) of GnRH. Serum gonadotropins measured by RIA were highly variable but mean concentrations were not significantly different throughout the day. However, preoptic hypothalamic content of GnRH declined markedly between 1000 and 1200 h. In the second experiment, 75 rats were divided into three groups and were untreated or were implanted sc with empty Silastic capsules or capsules containing estradiol-17beta (E2). Two days later, groups of five rats from each of the three treatment groups were decapitated at 0800, 1100, 1400, 1700 and 2000 h. The preoptic area was separated from the hypothalamus by a transverse cut at the caudal aspect of the optic chiasm. POA and hypothalamic content of GnRH correlated well (r=0.74, P less than 0.001, n=75). Two-way analysis of variance failed to reveal any effect of treatment on the GnRH content in either the POA or hypothalamus. GnRH content of both regions decreased significantly between 1100 and 1700h regardless of whether E2 was administered. In striking contrast, gonadotropin surges occurred in the late afternoon only in the E2-treated rats. Serum GnRH was undetectable (less than 5 pg/ml) in all groups of animals. These experiments demonstrate that in the untreated ovariectomized rat GnRH content of the POA and hypothalamus decreases during the early afternoon. This study supports the concent of a daily neural signal for LH release and that E2 is necessary for expression of the daily LH surge in the ovariectomized rat.


Blockade of LH release and ovulation in the rabbit with inhibitory analogues of luteinizing hormone releasing hormone. Plasma LH levels and ovulation were studied in female rabbits following administration of several inhibitory analogues of luteinizing hormone-releasing hormone (LHRH) before and after mating with experienced males. Administration of (D-Phe2, D-Leu6)-LHRH (1.5 mg/kg sc) to does 30 min before mating did not prevent either LH release or ovulation. However, a single sc injection of (D-Phe2, L-Phe3, D-Phe6y-LHRH (6 mg/kg) given 30 min before mating in 4 rabbits resulted in a 30-60 min delay in the coitus-induced release of LH when compared with post-coital changes in the same animals injected with vehicle; however, all of the does ovulated. When multiple dosages of 4 mg/kg (D-Phe2, L-Phe3, D-Phe6)-LHRH were administered 3-5 times at half-hourly intervals beginning 30 min prior to mating there was a considerable reduction in plasma LH elevations at 0.5, 1.0, 2.0 and 4.0 h after mating and 3/5 treated rabbits showed partial or complete blockade of ovulation. Quite similar results were obtained with the same dosage of (D-Phe2, D-Trp3, D-Phe6)-LHRH. An early sharp peak in LH release and full ovulation were stimulated in 6 out of 6 does by a single iv injection of synthetic LHRH (500 ng/kg). However, in another experiment, three half-hourly sc injections (4 mg/kg) of (D-Phe2, L-Phe3, D-Phe6)-LHRH beginning 30 min before administering LHRH markedly reduced the rise in plasma LH (P less than 0.01) and completely blocked ovulation in all of the same 6 animals. An unsuccessful attempt was made to provide a test animal for LHRH analogue investigations by implanting 4 cm of silastic tubing filled with crystalline estradiol (E2) sc in ovariectomized (OVX) AND INTACT DOES. In OVX does the silastic E2 implants resulted in a progressive decline in the ability to release LH in response to mating at 6 and at 20 days after implantation. With ovaries present, the E2 implant permitted post-coital LH release and ovulation at 4 d but not at 30 d post-implantation. At 30 d after removal of the E2 implant three out of four does had fully recovered the ability to release LH and ovulate post-coitally. Collectively, these results indicate that inhibitory analogues of LHRH can effectively block the ovulatory response to exogenous LHRH in rabbits, but that coitally-induced LH release and ovulation are less susceptible to blockade by the analogues. Silastic E2 implants, however, progressively and reversibly reduce the capacity of does to release LH after mating.


Release of gonadotrophin-releasing hormone (Gn-RH) from isolated, perifused medial-basal hypothalamus by melatonin. Basal release of Gn-RH from perifused medial-basal hypothalami of rats was at or below levels detectable by radioimmunoassay. Infusion of norepinephrine, dopamine, acetylcholine or serotonin (0.1-10 mM) as 10-20 min pulses was not associated with a detectable increase of Gn-RH in the effluent. However, 10-20 min pulses of melatonin (0.1-1.0 mM) consistently caused release of Gn-RH.


Successful cultivation of isolated islets of Langerhans without attachment: relationship between Glucose- and theophylline-induced insulin release and insulin content in rats islets after cultivation. The effect of various inhibitors of insulin secretion such as mannoheptulose (20 mM), atropine (1 mM), diphenylhydantoin (20 microng/ml), high concentration of Mg++ (5.3 mM) in the presence of 20 mM glucose (control) on insulin content and secretion from collagenase-isolated rat pancreatic islets was studied in vitro by cultivation of islets up to 5 or 9 days in glass Petri dishes without attachment. In a following short-term incubation for 60 min the glucose-induced insulin release without and with theophylline (5 mM) was investigated. Islets cultivated at 5 mM glucose and at 20 mM glucose with the inhibitors mannoheptulose or atropine lost the responsiveness to glucose and theophylline whereas such islets cultivated at 20 mM glucose alone or with diphenylhydantoin (DPH) or 5.3 mg Mg++ showed a stimulation of insulin secretion by glucose and theophylline. Compared, however, with freshly isolated islets all cultivated islets were restricted in their maximal glucose response and this defect was not evoked alone by quantitative changes in islet insulin content. Nevertheless, culture conditions which facilitate a net increase of insulin (content and release) during cultivation influenced also positively the glucose-induced insulin release without and with 5 mM theophylline in the following short-term experiments.


The ribitol-phosphate-containing lipopolysaccharide from Proteus mirabilis, strain D52. Investigations on the structure of O-specific chains. A soluble hydrophilic lipopolysaccharide, termed lipopolysaccharide II, isolated from Proteus mirabilis, strain D52 contained N-acetylglucosamine, glucose, galactose, ribitol phosphate and ethanolamine phosphate as constituents of the O-specific polysaccharide. Periodate oxidation studies were carried out on the polymer before and after dephosphorylation with hydrofluoric acid and on oligosaccharides derived from the polymer by partial acid hydrolysis. The results obtained indicate that the polysaccharide chain consists of the chemical repeating unit Gal-1,3(4)-GlcNAc-1,3-Glc-1,3-GlcNAc-, where GlcNAc stands for N-acetylglucosamine. Whereas the galactose residue is substituted at C-3 by ribitol phosphate, the glucose is substituted by ethanolamine phosphate at C-6.


Physical training in man. Skeletal muscle metabolism in relation to muscle morphology and running ability. The metabolic and morphologic adaptation to physical training in skeletal muscle tissue of eleven middle-aged, physically untrained men was studied. Muscle biopsies were taken from the vastus lateralis before, after 8 weeks and after 6 months of physical training for analysis of metabolic and morphologic variables. Glucose tolerance test indicated increased insulin sensitivity after 6 months of physical training. The activities of glycogen phosphorylase, hexokinase and glucose-6-P-dehydrogenase were increased but other enzymes involved in glycogen turnover and glycolysis were unchanged after 6 months of physical traning. The activities of citrate synthase and cytochrome-c-oxidase, representing the oxidative capacity were significantly increased already after 8 weeks of physical training. The incorporation rate of palmitate-carbon into CO2 and triglycerides increased, and the incorporation rate of leucine-carbon into CO2 decreased with 6 months of physical training. The fiber diameter of both Type 1- and Type 2-fibers increased, while the mitochondrial volume increased predominantly in Type 2-fibers. Significant correlations were found between metabolic, physiologic and morphologic variables before and after physical training. The results indicate an increased oxidative capacity, mainly located to Type 2-fibers, and an increased utilization of fatty acids in response to this type of physical training.


Studies of the interaction between aminoacyl-tRNA synthetase and transfer ribonucleic acid by equilibrium partition. The partition behavior of isoleucyl-tRNA synthetase, leucyl-tRNA synthetase and tRNA in aqueous two-phase systems composed of the polymers poly(ethyleneglycol) and dextran was investigated. From the results of this investigation a two-phase system could be derived which can be employed for the study of the interactions between synthetases and their cognate tRNAs by equilibrium partition. These measurements show that in each case one molecule of cognate tRNA is bound per molecule of enzyme. The binding constants were in the range 1-5micronM-1. It could be demonstrated that equilibrium partition is a useful method for the study of interactions between macromolecules.


Interacting binding sites of isoleucyl-tRNA synthetase from Escherichia coli studied by equilibrium partition. The binding of tRNAIIe to isoleucyl-tRNA synthetase in the presence of isoleucine or ATP was investigated using the equilibrium partition method. Isoleucine decreased the affinity of tRNAIIe for the enzyme by a factor of about 5. For the free standard energy of interaction a value of about 1 kcal/mol (4.2 kJ/mol) was calculated. ATP exhibits qualitatively the same effect as isoleucine. A binding of two molecules isoleucine per molecule of enzyme could not be demonstrated even in the presence of ATP and pyrophosphatase.


A nuclear elongation factor of transcription from Physarum polycephalum in vitro. Homogenates of Physarum plasmodia contain a factor which stimulates UMP incorporation on native DNA by solubilized homologous RNA polymerases in vitro. The factor is a heat-sensitive protein and has been located in nuclei. It does not alter the template activity of DNA nor the initiation frequency of transcription. The factor interacts with free or bound RNA polymerase molecules (only 37 degrees C and at low ionic strength) and yields larger transcripts in vitro. The level of the factor in vitro fluctuates: it is gradually reduced during spherulation and reaches its maximum in mid S phase of the cell cycle of Physarum.


Lipopeptidophosphoglycan from Trypanosoma cruzi. Amide and ester-linked fatty acids. Lipopeptidophosphoglycan, extracted from whole cells of epimastigote forms of Trypanosoma cruzi, has now been shown to contain 12.6% of fatty acids in addition to the previously identified content of neutral sugars (60%), glucosamine (0.8%), peptide (9.5%) and acid-hydrolyzable phosphate (2%). The main fatty acids are palmitic (6.9%) and lignoceric (4.6%) acids. Stearic (0.55%), oleic (0.15%) and myristic (0.18%) acids were also found. One third of the fatty acids are bound in the lipopeptidophosphoglycan as esters (14 mmol%) and two thirds as amides (28 mmol%). Lignoceric acid was found to be bound only as amide. Two ninhydrin-positive compounds, obtained by chloroform extraction of a total acid hydrolysate of the lipopeptidophosphoglycan, were tentatively identified as sphingosine bases.


Aminopeptidase N from Escherichia coli. Unusual interactions with the cell surface. The subcellular localization of aminopeptidase N (previously called aminoendopeptidase) has been investigated. This enzyme was found to be partially released (30-40%) by osmotic shock or by converting Escherichia coli K10 cells to spheroplasts. However, in all other E. coli strains (K12, B/r, MRE 600, ML 308) tested, this enzyme is not released at all by these procedures and thus behaves like a cytoplasmic enzyme. The crypticity of aminopeptidase N is surprisingly low, 75-85% of the enzyme activity is directly assayable in intact cells of any E. coli strain. Various inhibitors of transport systems do not interfer with this assay. Aminopeptidase activity could also be assayed in spheroplasts, even when an insolubilized substrate was used, which suggests a surface location of this enzyme. As well, N-ethylmaleimide (0.4 mM), under conditions which do not allow penetration in the cytoplasm, caused 70% inhibition of aminopeptidase N. Binding of 125I-labeled antiaminopeptidase N antibody to spheroplasts (from K12 strain) was used to assay the orientation of aminopeptidase N in the membrane. This enzyme is exposed on the outer surface of the cytoplasmic membrane. Confirmation of this orientation was obtained by comparing the accessibility of aminopeptidase, alkaline phosphatase and beta-galactosidase to fluorescamine in intact cells. Only 16% of the total beta-galactosidase was labeled with this fluorescent reagent whereas 44-45% of the aminopeptidase N and 59% of the alkaline phosphatase were labeled. Electron microscopic visualization of insolubilized reaction products of aminopeptidase N within the cells showed that these products are located at the poles of the cells. Neither mutant cells which were devoid of aminopeptidase N activity nor parental strains with the enzyme activity inhibited with phenylmercuric chloride contained the characteristic black caps. Thus, it appears that the periplasm is enlarged at the poles of the cells and that the reaction product is mainly located in these places. Investigation of the type of interactions of aminopeptidase N with the plasma membrane only revealed that aminopeptidase N has mainly an electrostatic interaction with the outer surface, probably mediated by magnesium ion bridges. Additional interactions are involved since disruption of the integrity of the cytoplasmic membrane is required to totally release this enzyme.


Poly(4-thiouridylic acid) as messenger RNA and its application for photoaffinity labelling of the ribosomal mRNA binding site. Poly(4-thiouridylic acid) [poly(s4U)] synthesized by polymerization of 4-thiouridine 5'-diphosphate with Escherichia coli polynucleotide phosphorylase (EC 2.7.7.8) acts as messenger RNA in vitro in a protein-synthesizing system from E. coli. It stimulates binding of Phe-tRNA to ribosomes both in the presence of EF-Tu-Ts at 5 mM Mg2+ concentration and nonenzymatically at 20 mM Mg2+ concentration. It codes for the synthesis of polyphenylalanine. Poly(s4U) competes with poly(U) for binding to E. coli ribosomes. Light of 330 nm photoactivates poly(s4U) thus making it a useful photoaffinity label for the ribosomal mRNA binding site. Upon irradiation of 70-S ribosomal complexes, photoreaction occurs with ribosomal proteins as well as 16-S RNA. Ribosomes pre-incubated with R17 RNA are protected against the photoaffinity reaction. The labelling of 16-S RNA can be reduced by treatment of ribosomes with colicin E3.


Chemical studies on yeast hexokinase. Specific modification of a single tyrosyl residue with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. 1. Of the 15 tyrosyl residues/subunit of yeast hexokinase A (ATP:D-hexose 6-phosphotransferase) only one residue is specifically modified at pH 8.0 with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. 2. The acylation of this single tyrosyl residue leads to the loss of the enzyme activities (hexokinase and ATPase) by a first-order process, which can be fully reversed by treatment with hydroxylamine. 3. ATP does not protect the enzyme against chemical modification and inactivation; however, glucose exerts a noticeable though indirect protection effect against chemical modification and inactivation. 4. The chemically modified enzyme, purified by column chromatography, has 14% of the activity of the native enzyme, but the Km for ATP-Mg or glucose remains unchanged as does the pH optimum of activity. Results of conformational studies (ultracentrifugation, fluorescence, thermostability and chemical reactivity of the sulfhydryl groups) indicate that the decrease of enzyme activity due to the modification of the tyrosyl residue is related to a localized perturbation of the enzyme active-center region.


Methionyl-tRNA synthetase from Escherichia coli: substituting magnesium by manganese in the L-methionine activating reaction. While Mg2+ can be efficiently replaced by Ni2+, Co2+ and Mn2+ in the ATP-PPi isotopic exchange reaction catalysed by methionyl-tRNA synthetase from Escherichia coli, the latter ion was selected for detailed analysis of the L-methionine activation reaction. In order to avoid artefactual results due to the slow aggregation of Mn2+ with pyrophosphate, this process was investigated by electron paramagnetic resonance and conditions were determined where it does not interfere with enzymic experiments. The thermodynamic parameters derived from steady-state (ATP-PPi isotopic exchange, fluorescence at equilibrium) or prestationary (fluorescence stopped-flow) experiments are compared to those obtained in the presence of Mg2+ [Hyafil et al. (1976) Biochemistry, 15, 3678-3685]. While the standard deltaG for the reaction (E-Met-ATP-Me2+equilibriumE-Met approximately AMP-PPi-Me2+) is close to zero in the case of Mg2+, Mn2+ slows down the rate of adenylate reversion and thus shifts the reaction towards the latter species. The deltaG for the formation of the E-Met approximately AMP complex does not depend on the metal used, suggesting that the divalent ion does not participate in the structuration of this complex. Substituting Mn2+ for Mg2+ decreases notably the dissociation constant of PPi-Me2+ from the E-Met approximately AMP-PPi-Me2+ species and from its abortive analog E-Met-Ado-PPi-Me2+. Similarly the dissociation constant of ATP-Me2+ from another dead-end analog E-methioninol-ATP-Me2+ is decreased by Mn2+. Involvement of the purine N7 atom in the binding of the metal ion to the active site of methionyl-tRNA synthetase is ruled out by the use of 7-deaza-adenosine. The role of the metal in the catalytic process of methionine activation and its relevance to the specificity of the reaction is then discussed in the light of the results obtained without metal and with Mg2+ and Mn2+.


Mitochondrial heredity of resistance to 3-(3,4-dichlorophenyl)-1,1-dimethylurea, an inhibitor of cytochrome b oxidation, in Saccharomyces cerevisiae. 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron), an inhibitor of cytochrome b oxidation, has been used for the selection of three resistant mutants (diur) of Saccharomyces cerevisiae. The mutant diur-64 exhibits in vivo cross-resistance to antimycin A while diur-34 and diur-1 are more sensitive to antimycin A than the parental strain. The three mutants exhibit mitochondrial inheritance according to the following criteria: mitotic segregation of diuron-resistant and diuron-sensitive diploids is obtained among the diploid progeny of a cross between diur and dius; non-Mendelian segregation of diuron resistance (4:0) is observed in spores of tetrads issued from diuron-resistant diploid; extensive ethidium bromide treatment leads to the formation of Q- mutants which no longer transmit diur and dius alleles. Evidence for two distinct diuron-resistant loci were obtained by allelism tests. Recombination analysis shows that diuron-resistance is not located in the polar region of the mitochondrial genome. The diur loci are not linked to the erythromycin locus since the upper limit in recombinants frequency (26%) for a non-polar region is obtained between diur and eryr. A low recombinants frequency (3%) is observed in crosses between diur-34 mutation and the two mutants cob1 and cob2 suggesting that diur-34 might be located between these two cytochrome-b-deficient loci. The resistance to diuron is also expressed in vitro since the oxidation rates of succinate by sonicated submitochondrial particles from the mutants are clearly less sensitive to diuron than that of the wild type.


Cooperative and antagonistic interactions of peptidyl-tRNA and antibiotics with  bacterial ribosomes. There is a single-site interaction of [methylene-14C]thiamphenicol and [methylene-14C]chloramphenicol with run-off ribosomes with dissociation constants Kd = 6.8 micronM and Kd = 4.6 micronM respectively. Similar affinities for the antibiotics are observed in polysomes totally deprived of nascent peptides, or bearing nascent peptides on the A-site. However, two types of interaction are observed in endogenous polysomes with some ribosomes bearing nascent peptides on the P-site and other in the A-site. The lower-affinity bindings (dissociation constants Kd = 6.4 micronM and Kd = 1.5 micronM for thiamphenicol and chloramphenicol respectively) are due to the ribosomes bearing nascent peptides on the A-site. The higher-affinity bindings (dissociation constants Kd = 2.3 micronM and Kd = 1.5 micronM for thiamphenicol and chloramphenicol, respectively) are due to the ribosomes bearing nascent peptides on the P-site. Therefore binding of nascent peptides to the A-site does not affect the affinities of thiamphenicol and chloramphenicol for the ribosome. On the other hand interaction of the nascent peptides with the P-site of the ribosomes increases the affinities of both antibiotics for the ribosome. Thiamphenicol and chloramphenicol are thus good inhibitors of peptide bond formation in ribosomes and polysomes. Their affinities are increased precisely when the peptidyl-tRNA is placed in the P-site preceeding the peptide bond formation step, which is specifically blocked by the antibiotics. There is a single-site interaction per ribosome for [35S]thiostrepton, which does not appear to be affected by the attachment to the ribosomes of mRNA, tRNA and nascent peptides either to the A or the P-site. [N-methyl-14C]Lincomycin, [N-methyl-14C]erythromycin, [G-3H]streptogramin B and [G-3H]-streptogramin A bind to run-off ribosomes and polysomes totally free from nascent peptides. However, these antibiotics do not interact with ribosomes bearing nascent peptides either in the A or the P-site and therefore are not active on preformed polysomes. Thus lincomycin and streptogramin A only interact with free ribosomes and 50-S subunits and block the early rounds of peptide bond formation prior to polysome formation. Erythromycin and streptogramin B do not inhibit either initiation or the first round of peptide bond formation. However, erythromycin and streptogramin B, prebound to the ribosome, block peptide elongation probably by steric hindrance with the growing oligopeptide chain when this reaches a certain critical length.


Synergistic interaction of the streptogramins with the ribosome. Quantitative binding studies of [G-3H]streptogramin A and [G-3H]streptogramin B with high-salt-washed ribosomes were carried out in the presence of a minimum of 10% (v/v) ethanol because of the antibiotic insolubility in water. It was observed that the presence of streptogramin A increases the affinity of [G-3H]streptogramin B for the ribosome. Thus the dissociation constant for [G-3H]-streptogramin B interaction with the ribosome is Kd=13.3 nM in the presence of streptogramin A and Kd=59 nM in its absence. Furthermore the values for the dissociation constants for [G-3H]-streptogramin B interaction in the presence of 50% (v/v) ethanol, were Kd=0.13 micronM in the presence of streptogramin A and Kd=0.70 micronM in its absence. This increased affinity of [G-3H]streptogramin B in the presence of streptogramin A can explain the synergistic effects of mixtures of streptogramins A and B at the ribosome level.


Viral antibodies in the sera from patients with Parkinson disease. An assay of antibodies to 15 various viruses and mycoplasma pneumoniae was performed on the serum specimens from 441 patients with Parkinson disease and from 443 healthy controls matched by sex, age, and place of residence, or from a representative group of these matched pairs. The main finding was a higher herpes simplex complement-fixing antibody level in patients with Parkinson disease than in controls. Patients with Parkinson disease had higher herpes simplex antibody titers more often than did their matched controls, and the matched controls, respectively, had low titers more often than the patients. The mean herpes simplex antibody titer (log2) of the patients (4.9) was significantly higher than that of controls (4.6) (p less than 0.01). This difference was also demonstrable when matched pairs were analysed for paired differences of herpes simplex antibody titers. For other viral CF and HI antibodies studied and for mycoplasma pneumoniae CF antibody, there were no significant differences either in the mean titers or in the distribution of individual titer values between the patients with Parkinson disease and the matched controls.


Abnormal central monoamine metabolism in humans with "true hypersomnia" and "sub-wakefulness". A case of Kleine-Levin syndrome with true hypersomnia and a case of sub-wakefulness are described. In both patients lumbar cerebrospinal fluid homovanillic acid, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol levels have been assayed during episodes of hypersomnia and normal sleep-waking cycles. Besides an increased 5-hydroxytryptamine turnover, mainly an increased dopamine turnover has been detected in both kinds of hypersomnia, and this finding was more remarkable in the case with sub-wakefulness. The probable role of dopamine in abnormalities in the sleep-waking cycle is discussed on the basis of results in experimental animal hypersomnias.


Classification of cells in the cerebrospinal fluid. A review. Comparative ultrastructural findings of meninges, ventricular ependyma and choroid plexus of mammals including man were summarized with the aim of a better understanding as to which cells can play a role as macrophages in the cerebrospinal fluid (CSF) cytology. Differences between phagocytic capacity of pial cells and arachnoid cells were emphasized. Comparative investigations showed that most of the cells in the CSF originate from the blood. Scanning electron microscopy of the subarachnoid space and cytological investigation of the CSF gave the result that haematogenous cells belong to the normal cell population of the subarachnoid space of normal individuals. These cells in the CSF react as their equivalents in the blood, that is, after confrontation with antigens the monocytes transform into macrophages, sometimes into multinucleated giant cells, the T and B lymphocytes transform into blast cells. On the basis of immunological and ultrastructural results, the classification of CSF cells in normal and pathological conditions has been proposed.


Functional independence of donor and recipient cardiac tissues of single and double heart transplant patients revealed by chronobiology. 3 total (single) and 1 double-heart-transplant patients were studied for temporal changes in the electrical events of cardiac function. Results of statistical analyses document the existence of circadian rhythms in the donor and recipient P--P or R--R intervals. However, for 1 total-heart-transplant patient studied at intervals during the year following implant and the double-heart-transplant patient 5 mth after surgery, the period (tau) of the rhythm in the P--P or R--R interval of the recipient tissue deviated greatly from that of 24.0 h. For the total-heart-transplant patient studied 1 mth prior to death, the tau was 32.3 h; for the double-heart-transplant patient, the tau was 29.0 h. In both patients, the donor heart tissue continued to exhibit a 24-h rhythm. These findings imply that changes in tau for the rhythm in P--P or R--R interval may reflect aspects of disrupted physiologic, feedback, regulatory mechanisms or perhaps graft rejection. Although additional study is required, the possibility that alteration in tau is associated with rejection is intriguing since if documented, then the noninvasive monitoring of ECG and subsequent analysis of data for significant deviations of tau from 24.0 h will be useful as an additional tool for monitoring host tolerance for the heart implant.


The assessment of regional abnormalities of the left ventricle by angiography. A method of regional wall motion analysis of left ventricular cineangiograms which does not make assumptions about ventricular geometry is described. The technique measures the movement of the ventricular perimeter in relation to the geometric center of gravity of the endsystolic frame expressing movement as a change in radical length. 10 control patinets each with 3 left ventricular cineangiograms, comprise the group for definition of normal values of movement and permit estimations of reproducibility within and across patient groups. Isolated examples of abnormal wall motion are shown.


Dose-titrated, double-blind, cross-over comparison of a selective beta-blocker and methyldopa in the treatment of hypertension. The efficacy and toxicity of tolamolol and methyldopa in hypertensive patients has been compared by a dose-titrated, double-blind, cross-over study. Thirteen patients completed the trial. Within the dose ranges investigated (tolamolol - 300 mg/day - 900 mg/day; methyldopa - 750 mg/day - 2250 mg/day)both drugs produced significant falls in laying and standing, systolic and diastolic blood pressures. Although the hypotensive effects of methyldopa were more marked than tolamolol, these only achieved conventional (P less than 0.05) levels of significance for lying blood pressure. There were no objective changes in haematological or biochemical indices during treatment with either drug, but patients complained of tiredness, weak limbs and mouth dryness significantly more during methyldopa treatment, than during either placebo or tolamolol therapy.


Studies on the depletion of brain amines by m-tyrosine. The biochemical basis of the well-known physiological and pharmacological actions of m-tyrosine was examined by a detailed study of its effect on the brain biogenic amines. m-Tyrosine was injected i.p. and rat brain monoamine levels were measured. Endogenous levels of dopamine, norepinephrine and serotonin all showed approximately 50% reductions 1 h after the administration of L-m-tyrosine at 150 mg/kg. These actions of L-m-tyrosine could be blocked by the inhibition of the central dopa decarboxylase. Depletion of brain monoamines was also observed with the D-isomer of m-tyrosine, although this effect was less pronounced than that of the L-isomer. In vitro experiments with rat brain homogenates showed that L-m-tyrosine, m-tyramine and m-octopamine enhanced in efflux of exogenous labeled monamines from brain particles, whereas D-m-tyrosine was completely ineffective. From these results it is concluded that the observed decreased in brain monamine levels by L-m-tyrosine may be due to a m-tyramine-enhanced release of the amines which are quickly metabolized in vivo.


Physostigmine analgesia and somatosensory evoked responses in man. 14 normal volunteers were given 0.5 mg physostigmine or saline placebo i.v. in a randomized double blind trial. Subjects were pretreated with 0.5 mg methscopolamine i.m. on both days. Pain ratings and average evoked responses were obtained to brief electrical stimuli administered to the forearm. Pain response criterion was significantly higher on physostigmine than on placebo. Average evoked response component P100 was significantly smaller on physostigmine than placebo, especially for higher intensity stimuli. These results are consistent with central cholinergic modulation of pain and arousal systems in man.


The time-scale of radioprotection in mammalian cells. The chain of reactions, resulting in mutation and cell death, initiated when ionizing radiation interacts with mammalian cells is complex and traverses a time-scale from a fraction of a picosecond to a few hours. Recently, progress has been made in identifying some of the more important pathways and potentially damaging free radical intermediates. Protection can, in principle, result from modification at several steps in these reaction chains, each with its distinctive time-scale. To date we have demonstrated that radio-protection can be effected in mammalian cells by the modification of processes at three quite different times. In this paper, the temporal sequence of radiation-initiated events are reviewed and the potential for or measurement of radioprotection of each is discussed. Such an understanding of cellualr radioprotection has become possible by our improved understanding of cellular radiation mechanisms derived from recent studies of its chemistry [1-4].


Effects of ethidium bromide in diploid and duplication strains of Aspergillus nidulans. Unstable duplication and diploid strains of Aspergillus nidulans were treated with ethidium bromide, and it was shown that this drug reduces the number of sectors produced by such strains. The mechanisms which could be responsible for the partial stabilization of the strains are discussed and it is suggested that a similar mechanism is responsible for the production of sectors in both strains. It is also suggested that ethidium bromide could be useful for the reduction of instability of industrial strains.


A comparative study of the differentiation of dissociated nerve cells under different culture conditions. In vitro differentiation of chick embryo brain cells was compared under several culture conditions. Morphological observations and acetylcholinesterase histochemical staining revealed that the development was similar in all conditions tested if cells have been derived from 7 days embryos. Considering the cultures from 11 days embryos, the cell dissociation by trypsin and the plastic surface proved to be the most favourable conditions in contrast to mechanical dissection and collagen surface.


Conversion of psoralen DNA monoadducts in E. coli to interstrand DNA cross links by near UV light (320-360 nm): inability of angelicin to form cross links, in vivo. Both angelicin and psoralen monoadducts formed in vivo in E. coli by near UV light produce lethal and mutagenic effects. However psoralen monoadducts are converted to cross links by higher doses of UV; angelicin monoadducts are not. The relevance of these results to psoralen photosensitization is discussed.


[Pyrazole sulfanilamides. XV. Nitroderivatives of 1-phenyl-4-sulfanilamidopyrazole]. The research on the change of antibacterial activity due to the introduction of a nitro group in the benzene nucleus linked at the heterocyclic nitrogen of N-phenylsulfanilamidopyrazoles is continued with the preparation of 1-(2'-nitrophenyl)-4-sulfanilamidopyrazole (IIa: -NO2 in 2'; R=-H), 1-(3'-nitrophenyl)-4-sulfanilamidopyrazole (IIb: -NO2 in 3'; R=-H) and 1-(4'-nitrophenyl)-4-sulfanilamidopyrazole (IIc: -NO2 in 4'; R=-H). By analogy with the results obtained for the derivatives of 4-sulfanilamidopyrazole (I) previously prepared, enhancement of the bacteriostatic activity in vitro against S. aureus and E. coli, have been observed in almost all the cases, especially with 1-(3-nitrophenyl)-4-sulfanilamidopyrazole (IIb).


Design of neurohypophyseal peptides that exhibit selective agonistic and antagonistic properties. Within the spectrum of the characteristic pharmacological activities (oxytocic (O), milk-ejecting (ME), antidiuretic (A), pressor (P) associated with the known natural and synthetic analogs of oxytocin and vasopressin it is possible to discern patterns of selectivity of these types: 1) interpeptide-like (a) O/A, (b) O/P; 2) intraoxytocin-like (a) O/ME; (b) ME/O; 3) intravasopressinlike (a) A/P, (b) P/A. Consideration of structural modifications of oxytocin or vasopressin, which individually or in combination give rise to peptides possessing enhanced selectivity of a given type, can in some cases provide a rational basis for the design of peptides with even greater selectivity. [1-Deamino-4-valine-8-D-arginine]vasopressin, the most highly specific antidiuretic peptide known to date, was designed in this fashion. By contrast, intraoxytocin-like selectivity, is manifested to only a minor degree in all peptides studied to date. Enhanced interpeptide-like selectivity of the type 1a (O/A; O/P) is readily attainable by specific single substitutions at positions 4 or 7 in oxtocin. Substitution of threonine in the 4 position of the oxytocic antagonist [1-deaminopenicillamine]oxytocin brought about a threefold enhancement in oxytocic inhibitory activity. Thus [1-deaminopenicillamine-4-threonine]oxytocin (dPTOT) is the most potent antagonist of the in vitro oxytocic response to oxytocin known to date. Thus analysis of the pharmacological data from over 300 analogs of oxytocin and vasopressin allows the delineation of those structural modifications that can optimize selectivities. The potential and limitations of this approach for the design of peptides possessing desired agonistic or antagonistic selectivity for potential clinical use and for studies on oxytocin and vasopressin receptors is discussed.


Vascular smooth muscle and neurohypophyseal hormones. Experimental studies relating to the direct peripheral vascular actions of neurohypophyseal hormones and their synthetic variants are reviewed. In addition, the available data on the comparative pharmacologic actions of these peptides on mammalian vascular smooth muscle are reviewed. Experiments relating to mechanisms by which neurohypophyseal peptides induce contraction of blood vessels are discussed. Neurohypophyseal peptide hormones appear to be able to contract and relax vascular smooth muscle, the exact type of response being dependent on species, vascular bed, and region within a vascular bed. Receptors that subserve both contraction and relaxation may exist on different blood vessels within a species, with a preponderance of receptors that subserve contraction being present in most blood vessels. Concentrations of vasopressin that can be considered physiologic (i.e., 10(-13) to 10(-11) M) are capable of evoking responses on a variety of microscopic as well as large blood vessels. Arginine-vasopressin appears to be, relatively, the most potent contractile substance on rat blood vessels investigated to date; angiotensin is not. Preservative-free oxytocin is a contractile agent on all mammalian arterial and arteriolar vessels so far investigated. A great deal of the controversy surrounding the exact vascular actions elicited by these peptide hormones can be attributed to many factors that were not controlled in older experiments. Moreover, rat pressor assays cannot be utilized to determine structure-activity relationship for neurohypophyseal peptides on vascular smooth muscles. Nuerohypophyseal peptide-induced contractions of vascular smooth muscles can be markedly affected by sex, sex hormones, alcohols, [Ca2+]0, [mg2+]0, oxygen deficit, and glucose-deprivation. Extracellular sodium and potassium ions appear to play relatively little role in vasopressin-induced contractions of rat arterial smooth muscle. The terminal amino group, phenolic hydroxyl, aromatic ring and basicity in positions 1, 2, 3, and 8, respectively, of the neurohypophyseal hormones are important for optimizing hormone-receptor affinity and intrinsic contractile activity on vascular smooth muscle. Basicity in position 8 of these peptide hormones is not an absolute requirement for contractile activation of these smooth muscles. Alterations in molecular structure can result in neurohypophyseal peptides with unique, and selective, microcirculatory effects that may be beneficial in the treatment of low-flow states.


Interrelationships of mycotoxins with nutrition. Mycotoxins interact with lipid, protein, carbohydrate, and vitamin nutrition. Diets high in lipid have a mortality-sparing effect against aflatoxicosis and, if high in unsaturated fatty acids, a growth-sparing effect. Aflatoxicosis causes a lipid malabsorption syndrome coupled with decreased digestive enzymes and bile salt excretion, a decreased synthesis of fatty acids, and impaired transport. Deficiencies of vitamins A, D, or riboflavin make animals more sensitive to aflatoxin while a thiamin deficiency has the opposite effect. Interaction with vitamins E and K has not been clearly demonstrated as yet. Mycotoxins increase the protein requirements of animals and apparently alter the enzymes that regulate glycogen catabolism and neogenesis.


The first two decades of vitamin E.

The first two decades of vitamin E. This presentation reviews highlights of the first 20 years (1922-1942) of vitamin E. It begins with background information leading to identification of an antisterility factor for rats of both sexes and its acceptance into the vitamin family as vitamin E (1925). Research of the next 12 years revealed a multiplicity of deficiency manifestations: embryonic mortality, testis degeneration, encephalomalacia and exudative diathesis in the chick, and nutritional muscular dystrophy in avian and mammalian species. Toward the close of this period came the isolation of vitamin E from natural sources, determination of its empirical formula, and introduction of the designation alpha-tocopherol for vitamin E (1936). Within the next two years the structural formula of alpha-tocopherol was elucidated, its chemical synthesis accomplished, and its production from natural plant oils by molecular distillation was well established. The existence of other tocopherols with lesser degrees of biological activity became recognized. Also, the concurrent development of a chemical method for determining the vitamin E content of alpha-tocopherol in foods, body tissues and body fluids, which replaced the very laborious bioassay procedure, greatly facilitated later advances in knowledge of the distribution and nature of vitamin E.


Agnes Fay Morgan and early nutrition discoveries in California. Agnes Fay Morgan (1884-1968) and several other California pioneers in nutrition contributed much to the early increase in basic knowledge of nutrition and foods. Dr. Morgan became a member of the faculty in the division of Nutrition at the University of California at Berkeley in 1915. Her academic retirement was in 1954, but she remained active and productive even to the time of her death in 1968. The hallmark of her career was the high standards she established both in training home economists and nutrition investigators and in gaining widespread public recognition of the importance of good nutrition. Also,, she was imaginative and productive in significant research. Such work was directed to the nutrients of California foods and the effects on food values resulting from heat processing and storage. Other major early nutrition scientists in California included Ruth Okey, H. M. Evans, H. S. Olcott, S. Lepkovsky, H. J. Almquist, T. H. Jukes, and E. L. R. Stokstad. Their contributions included major accomplishments in the discovery and/or characterization of vitamin E, vitamin B6, pantothenic acid, and vitamin K.


The founding of the American Institute of Nutrition, including commentaries on the founders. The conception of the American Institute of Nutrition in 1926 culminated in the publication of the first issue of the Journal of Nutrition in September 1928. It was nearly 5 years later--April 1933--before the organizational meeting of the AIN as the future scientific society was convened. At this meeting, 172 persons were declared to be charter members, among whom were the original founders--10 men and 1 woman. These 11 pointers of AIN were rather unique. They had diverse backgrounds, different professional aspirations, and a dissimilarity of scientific objectives. Notwithstanding, they "were motivated by a desire to build a competent science of nutrition out of the rather chaotic mass of fragments of knowledge then in existence."


Factors influencing the dynamics of gonadotropin response following bolus infusion of luteinizing hormone-releasing factor in women with menstrual abnormalities. Thirty-five women with menstrual abnormalities were given 100 microng of luteinizing hormone-releasing hormone (LHRH) by bolus intravenous injection in an attempt to simplify and quantitate the usefulness of this test in clinical management. Peak and total gonadotropin responses are highly correlated. Peak and total LH are significantly related to basal LH but no similar relationship could be established for follicle-stimulating hormone (FSH). There is no association between gonadotropin response and prolactin levels or body weight. Basal estradiol levels are inversely related to FSH response but not to LH response. It is concluded that the use of an intravenous 100-microng bolus of LHRH is of little use as a clinical test for the gynecologic endocrine patient.


Pituitary response to luteinizing hormone-releasing hormone after induced abortion in the first and second trimesters. Luteinizing hormone-releasing hormone (LHRH) (100 microng) was administered subcutaneously to healthy female volunteers 2 and 4 weeks after induced abortion in the first trimester (group A) and the midtrimester (group B). Four patients were studied in each group. The response to LHRH was determined in terms of plasma LH and follicle-stimulating hormone levels. Adequate pituitary response occurred in subjects of group A at both 2 and 4 weeks. In group B pituitary unresponsiveness was found at 2 weeks which persisted to some extent at 4 weeks. These data are in accord with the pituitary unresponsiveness observed after termination of pregnancy at term and suggest that the duration of pregnancy has an influence on the development of this unresponsiveness.


Low-dose combination oral contraceptives: a controlled clinical study of three different norgestrel-ethinyl estradiol ratios. Three doses of norgestrel-ethinyl estradiol in altered ratios were investigated in a double-blind, randomized study. The estrogen content was maintained at 20 microng or less, while the progestogen dose was increased in 100-microng increments. Two pregnancies were reported for the lowest dose. No pregnancies occurred in the two higher doses. Each dosage increase improved cycle control and lessened bleeding irregularities. The incidence of patients reporting intermenstrual bleeding was inversely proportional to the doses studied. Dropouts for cycle disturbances followed a similar pattern.


[Gastrin and blood proteins].

[Gastrin and blood proteins]. With the aid of affinic, ion-exchange- and gel-chromatography, disc- and immunoelectrophoresis, the blood serum of healthy people and animals was shown to contain proteins capable of interaction with gastrin. These proteins form a system including, along with albumins, globulins with electrophoretic mobility of alpha- and gamma-globulins. The immunoglobulins interacting with gastrin are related to the G class. Presence of a number of forms of the labile, spatially organized structural hormonal protein complexes is suggested, which play the functional part of an effective storage and transport of the hormone from the hormone-producing cell to the effector one, and excitation of its membrane's structures. Such overmolecular complexes seem to be easier recognized by the celleffector and to exert a specific action.


Cicatricial pemphigoid with circulating antibasement membrane antibodies. Report of three atypical cases. 3 patients had cicatricial pemphigoid with positive indirect immunofluorescence to basement membrane. 1 patient had remarkably mid disease; another had high titers of autoantibody; and the third was partially responsive to sulfapyridine. All 3 patients were women, as has been true most other reported cases. Antibody titers seemed to correlate with disease activity but not with disease extent.


Prolongation of Bacillus firmus survival on human skin by a spore inoculum. A case report is presented of an individual who carried vegetative cells of Baccillus firmus on multiple sites of his body for over a year. With the aim of investigating the survival mechanisms of Bacillus species on human skin, vegetative cells or spores of this microorganism were applied to the forearms of volunteers. Whereas vegetative cells were rapidly eliminated, the bacillus was recovered up to 2 weeks following an inoculum of spores. Persistence was not passive since germination, growth, and possible sporulation were demonstrated. We observed strong individual differences in the carriage of bacilli.


Cutaneous sarcoidosis treated with levamisole. 16 patients with cutaneous sarcoidosis were treated intermittently over a period of 6 months with levamisole in an open study. The skin lesions cleared in 2 of 13 patients completing the course of treatment. Aggravation of the sarcoidosis was noted in 2 other patients after a few weeks of treatment. Tuberculin sensitivity did not increase during the treatment period. Dinitrochlorobenzene sensitivity increased in 5 patients but the lesions did not clear in any of these patients. It is concluded that levamisole is not useful in the treatment of cutaneous sarcoidosis.


A controlled clinical trial of calcium dobesylate in the treatment of diabetic retinopathy. In a two-year study of 36 diabetic patients with retinopathy, proliferative in 18, first six months (period A) were spent in baseline. The patients then received calcium dobesylate, 250 mg three times a day (period B) and were then entered into the double blind part of the study, receiving either dobesylate for six months followed by placebo for a further six month period, or the reverse, according to a randomised code (period C and D). Cutaneous capillary resistance (CCR) which was abnormal in 26 patients at the beginning of the study had returned toward normal in 11 patients by the end of period B. However, this beneficial effect was not confirmed in the double blind part of the study. Punctate red spots (microaneurysms and microhemorrhages) were counted at the end of each period. No statistically significant differences were noted at any period studied. Retinal angiographic studies also failed to demonstrate any beneficial effect of the drug.


Effects of tetracycline and diazepam on insulin secretion and adenylyl cyclase activity of isolated rat islets of Langerhans. Tetracycline (2 and 20 micronM) inhibited glucose-stimulated insulin secretion from isolated rat islets of Langerhans, although it failed to alter tolbutamide-stimulated insulin release. Diazepam (10 micronM) potentiated tolbutamide-stimulated insulin release and at a concentration of 1 mM increased glucose-stimulated insulin release. Tetracycline (20 and 200 micronM) or diazepam (10, 100 and 1,000 micronM) inhibited adenylyl cyclase activity of islets homogenate. These results suggest that the effect of tetracycline on insulin secretion might be in part due to inhibition of adenylyl cyclase of the islets. However, the effect of diazepam on insulin secretion is not mediated through the adenylyl cyclase system.


[Maintenance hemodialysis and renal transplantation in diabetic patients (author's transl)]. Maintenance hemodialysis and renal transplantation are increasingly used for treating diabetic patients with terminal uremia. Nowadays dialysis techniques may be considered for most of these patients, except those presenting with multiple severe disabling complications. Difficulties in control of glycaemia or of the uremic state or in the management of immunosuppressive drugs in transplanted patients do not, in themselves, constitute special problems in dialysis or transplantation. The high rate of complications and the excess mortality recorded in diabetics, compared with non-diabetic dialyzed or transplanted patients are closely related to the cardiovascular, neurological and microvascular disease that is present to various degress in all diabetic patients. Cardiac and cerebrovascular complications account for most of the deaths. Ocular and neurological status often worsen during dialysis but their stabilization usually occurs after successful transplantation. The choice between therapeutic methods in end-stage uremia must be an individual one for each patient" depending on age, medical and psychological factors and technical feasibility. Renal transplantation gives best results in patients aged less than 50 years and should be carried out early (creatinine clearance 15 - 10 ml/min.) before occurrence of the most disabling complications. If transplantation is not indicated or available, dialysis should be initiated when creatinine clearance is about 10 ml/min. Early multidisciplinary care of uremic diabetics will improve the results of maintenance hemodialysis, the problems and failures of which occur most frequently when treatment is commenced too late in patients with irreversible clinical and/or metabolic conditions.


Plasma insulin and C-peptide levels in cirrhotic and uremic patients. Fifty grams of glucose were administered orally to twelve cirrhotics, twelve uremics and ten normal controls and the plasma insulin and C-peptide responses were measured and expressed as molar concentration. Glucose intolerance, hyperinsulinemia and elevated C-peptide levels were found in cirrhotics after glucose loading and in uremics during the later part of the glucose response. The molar ratio of C-peptide to insulin was lower in cirrhotics and higher in uremics than in controls. It is suggested that insulin is mainly degraded by the liver and C-peptide by the kidneys, and that C-peptide is not affected by the liver damage but is present in raised concentration in subjects with injured kidneys. Elevated C-peptide level in cirrhotics is consistent with hyperfunction of pancreatic B-cells.


The prognostic importance of plasma glucose levels and of the use of oral hypoglycemic drugs after myocardial infarction in men. The relationship of plasma glucose levels to risk of death over a five-year follow-up period was studied in 2,770 male survivors of myocardial infarction in the placebo group of the Coronary Drug Project (CDP). In univariate analyses, a positive association was observed between mortality rates and both fasting and one-hour glucose levels. After adjustment for 38 other baseline characteristics, the strengths of these relationship were substantially diminished; however, an increased mortality persisted in patients with fasting glucose levels larger than or equal to 140 mg./dl. after adjustment for other risk variables. There exists some evidence of an increased mortality risk in users of oral hypoglycemic (OH) agents over that of nonusers at baseline in men with elevated baseline glucose levels. However, the results must be interpreted with great caution both because they are of only borderline statistical significance and also because various factors not recorded in the CDP might have influenced the results.


Synthetic gastric inhibitory polypeptide. Stimulatory effect on insulin and glucagon secretion in the rat. Effect of synthetic gastric inhibitory polypeptide (GIP) on insulin and glucagon secretion was stuied in vivo and in vitro in the rat. Intravenous administration of 1 microng./kg. GIP along with 0.625 gm./kg. glucose caused a more prominent rise of plasma insulin than did 0.625 gm./kg. glucose alone. The suppression of plasma glucagon levels induced by glucose was attenuated partially but not significantly by the concomitant administration of GIP. GIP (1 microng./kg. i.v.) alone raised both plasma insulin and glucago levels. In in-vitro experiments with isolated pancreatic islets, GIP significantly augmented insulin release induced by either 8.3 mM or 16.7 mM glucose, whereas the augmentation of glucagon release was observed at 3.3 mM, 8.3 MM, and 16.7 mM glucose concentrations. Three peptides, consisting of 1-28, 22-43, and 15-43 amino acids of GIP, failed to potentiate insulin and glucagon secretion. These results suggest that synthetic GIP has a stimulating effect on insulin and glucagon secretion.


The value of calcium dobesilate in the treatment of diabetic retinopathy. A controlled clinical trial. The effect of calcium dobesilate on capillary resistance and background retinopathy was compared with placebo in a double-blind cross-over trial on 18 diabetics. Each treatment lasted 8 months. The trial produced no evidence in favour of a significant beneficial effect of calcium dobesilate on the capillary resistance in diabetics or on the course of the diabetic retinopathy.


Histone synthesis and replacement during spermatogenesis in the mouse. Separation of labelled nuclei by sedimentation velocity at unit gravity (Staput method) was used to study the timing of histone synthesis and replacement by testis-specific basic nuclear protein (TSP) during spermatogenesis in the mouse. Animals were injected (intratesticularly) with 1.25 micronCi per testis 3H-arginine or 2.5 micronCi per testis 3H-lysine, testis nuclei were separated, and the acid extract of each nuclear fraction was analyzed by acrylamide gel electrophoresis. The distribution of labelled histones and TSP in separated nuclei was assessed 2 h after incorporation. Changes in the labelled histone and TSP content of nuclei during subsequent differentiation (1--34 days post-label) was followed in fractions of separated testis cell nuclei and in nuclei of cauda epididymal spermatozoa. Analysis of total histone and (TSP) content indicated quantitative changes during development. Nuclei from primary spermatocytes had relatively larger amounts of histones H1 and H4. Spermatid nuclei showed a relative reduction in histones H1 and H4, coincident with the appearance of TSP in these nuclei. These results suggested that synthesis and/or removal of certain histones must occur in late primary spermatocyte and early spermatid stages of spermatogenesis. Results of labelling experiments indicated several periods of histone synthesis during spermatogenesis: (1) closely associated with the last DNA synthesis(i.e., in early primary spermatocytes), (2) late in meiotic prophase (i.e., in pachytene primary spermatocytes) and (3) simultaneous with TSP synthesis (i.e., in late spermatids). Histone H1 was more heavily labelled toward the end of the primary spermatocyte period. Histone H4 was more heavily labelled in the early primary spermatocyte period, and again at the time of TSP synthesis in spermatids. Histones synthesized before the pachytene primary spermatocyte stage appeared to be replace, but histones synthesized later in spermatogenesis appeared to be at least partially retained in epididymal spermatozoa. These results suggested that repeated specific alterations in the protein complement of the nucleus are an integral part of spermatogenic differentiation in the mouse.


Identification of lymphocytes in percutaneous liver biopsy cores. Different T:B cell ratio in HB sAg-positive and -negative hepatitis. The lymphocytes infiltrating the liver were isolated and characterized as T or B cells in three groups of patients: 20 patients with hepatitis B surface antigen (HB sAg)-positive acute and chronic hepatitis, 8 patients with HBsAg-negative chronic hepatitis with prior evidence for hepatitis B virus (HBV) infection, and 5 patients with HBsAg-negative chronic hepatitis without prior evidence for HBV infection. The predominant cell infiltrating the liver was shown to be a T cell in all categories; however, the ratio of T:B cells was significantly lower (1.96) in the patients without evidence for HBV infection than in the patients who were HBsAg-positive at (7.86), or before (8.85) the time of study. The significantly (P less than 0.001) higher number of B cells in the patients with chronic hepatitis of unknown etiology suggests that a different immunopathogenetic mechanism is operative in this group. A peripheral T lymphocytopenia was observed in patients with both antecedent and existent HBs-antigenemia, but not in the patients without evidence for HBV infection.


[Endometrial cancer and extraglandular oestrogen biosynthesis (author's transl)]. An increasing incidence of endometrial cancer caused by a higher life expectancy and a number of other facters (i.e. obesity, diabetes, hypertension, lower pregnancy rate) as well as the unfavorable location for early detection when compared with cervical cancer has initiated this review in order to single out women with increased risk. Clinical characteristics of patients with endometrial cancer represented by age, menstrual disorders, reduced fertility, obesity, diabetes, hypertension, hirsutism, hyperplasia of the ovarian stroma or hilus cells in connection with an increased oestrogen effect in the vaginal smear and proliferative changes of the endometrium can be explained by extraglandular respectively peripheral aromatization of androgens to oestrogens, particular by the conversion of androstenedione to oestrone. This is supported by an increased plasma oestrone/oestradiol-ratio and increased conversion rate with age and overweight. In vivo- and in vitro-investigations have demonstrated the participation of adipose tissue in peripheral oestrogene production. The compiled data point towards the importance of the extraglandular oestrone production for the etiology of endometrial cancer by effecting the endometrium over a long period of time. The counter action of the normally cyclic changes of oestradiol and progesterone is lacking. Therefore, a dysoestrogenic effect of oestrone upon the endometrium can be fully effective, depending on the hormone receptor content of the respective endometrium. Based upon these data including recent publications, pre- and postmenopausal oestrogen therapy has to be critically reevaluated.


Comparative study of the value of the calcium, secretin, and meal stimulated increase in serum gastrin to the diagnosis of the Zollinger-Ellison syndrome. To evaluate the usefulness of provocation tests in the diagnosis of the Zollinger-Ellison (ZE) syndrome stimulation tests with calcium, 15 mg/kg. 3 h, and secretin GIH, 1 U/kg.30 s, were performed in 15 patients with histologically proven or suspected ZE syndrome. Nine of these 15 patients were without previous gastric surgery and in them meal stimulated serum gastrin levels were measured as well. These tests were also performed in normal subjects and in patients with duodenal ulcer, antrectomy, total gastrectomy, and achlorhydria. All tests were considered to be positive if a more than 50% increase in serum gastrin was found. The results indicate that secretin stimulation is the provocation test of first choice in the diagnosis of this syndrome. This test is most valuable for the following reasons: (1) there were few (two out of 15) false-negative test results in ZE patients; (2) there were no false-positive tests in 69 patients without gastrinoma; (3) it was easy and quick to perform; and (4) there were no adverse reactions. The two ZE patients with negative secretin stimulation tests had negative calcium provocation tests as well, in spite of histologically proven gastrinoma. In 11 patients with suspected or proven ZE syndrome and basal serum gastrin levels of less than 1000 pg/ml a rather good correlation (r = 0-841;  P less than 0-01) was found between the percental increase in serum gastrin after stimulation by calcium and secretin. Meal stimulated serum gastrin levels are helpful only in patients without previous gastric surgery.


24-hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine. Cimetidine markedly inhibits gastric acid secretion, but from the therapeutic point of view it is important to know whether concurrent treatment with an anticholinergic increases its effect. This possibility has been investigated by measuring the 24 h intragastric acidity and nocturnal output of acid in four duodenal ulcer patients, each receiving on separate occasions cimetidine 1 g/day and placebo, atropine 2-4 mg/day and placebo, cimetidine and atropine, or two placebos. Cimetidine alone decreased mean hourly hydrogen ion activity by 63% of control values, decreased mean hourly hydrogen ion concentration (total acid) by 41%, inhibited nocturnal acid secretion by 83% and resulted in half the nocturnal samples being anacidic. Atropine alone had no effect when compared with control and combined treatment with both drugs was not superior to cimetidine alone. Atropine did not affect the absorption or urinary excretion of cimetidine. Fasting serum gastrin concentrations were not changed by any of the treatments. At the doses studied, the combination of cimetidine with an anticholinergic appears to offer no advantages over treatment with the H2-antagonist alone. Cimetidine is the only potent anti-secretory drug that does not cause acute side-effects and this important advantage would be lost if it were given with a maximal dose of an anticholinergic.


Immunoprophylaxis and therapy of grafted rat colonic carcinoma. Two independent lines of chemically-induced colonic carcinoma, serially graftable in syngeneic rats, have been used to investigate the effects of immunoprophylaxis and immunotherapy. Rats were immunised by various procedures, including BCG, irradiated tumour grafts, and cancer cells treated by mitomycin and neuraminidase. A partial inhibition of tumour growth was observed in one of the four protocols. On the other hand, a significant enhancement of tumour growth was obtained in two other experiments.


Heparin, heparin-activated enzymes and platelets. This review summarises evidence supporting the view that the therapeutic anticoagulant properties of heparin are related to its physiological function in the organism, especially its activation of lipoprotein lipase and lecithinase. The conflicting results obtained from studies of the effect of heparin on platelet function are discussed, together with reasons for these differences of opinion. Finally, a hypothesis which links heparin, heparin-activated enzymes and platelet function is proposed, this hypothesis being complementary to the current views concerning the activation by heparin of the inhibitor of activated factor X.


[Disorders of the blood circulation in the gastrointestinal tract]. Blood flow disturbances in the gastrointestinal tract can lead to serious illness. They can be acute or chronic, their cause may be arterial or venous occlusion or hypotonia. Lesions of the gastrointestinal tract caused by ischemia depend on localisation, acuteness and degree of the blood flow disturbance. They may reach from focal and segmental ischemic lesions to extensive necroses of the entire intestinal tubes. The most serious ischemic disease is the embolic and thrombotic occlusion of the arteria mesenterica superior due to previous arterosclerotic damage. Infarction of a large part of the intestines and peritonitis can be the consequence. These patients' only chance of survival is early diagnosis--as a rule exclusively via angiography--and immediate surgery. Chronic occlusion of the arteria mesenterica superior leads to angina abdominalis which mainly occurs after food intake and can last for hours. The reason may also be a general arteriosclerosis. Men are affected more frequently and at a younger age than women. As a consequence of lowered intestinal blood flow these patients suffer from malabsorption and heavy weight loss. Conservative therapy is not effective. These patients, too, will have to be treated surgically after previous angiography. Vascular disease with decreased blood flow as its consequence can be found in a number of inflammatory diseases, in malign hypertensian, in collagen disease and in other more rare diseases as pseudoxanthoma elasticum or Ehlers-Danlos-syndrome. In the case of ischemic colitis arterial and more rarely venous occlusions cause decreased blood flow in the big bowel. A frequent consequence is colitis in the left colon which is characterized by acuteness, pain in the left side of the abdomen and by heavy rectal bleeding. Diagnosis is established by means of endoscopy, barium enema and angiography. Primarily therapy of ischemic colitis is of the conservative type. In severe cases with gangrene and peritonitis the colon has to be resected.


"To select better--to shunt better" prerequisites for better shunt therapy in liver cirrhosis. Review. Essentially 3 facts are responsible for the poor clinical outcome after porta-caval shunt in liver cirrhosis today: 1. Further reduction of hepatic blood flow, 2. total or nearly complete deprivation of the liver of portal venous blood supply with essential substances and functions and 3. insufficient criteria for selection. Since there exists no alternative procedure in decompressing bleeding varices in the end, porta-caval anastomoses will have to be performed also in the future. Therefore all efforts must be undertaken to improve the operative and longterm results, including a better preoperative selection and a better shunting. Determination of "functional" liver volume, knowledge of hepatic arterial reaction and preoperative determination of the intrahepatic shunt-flow might be very promising aspects in the selection today. In porta-caval surgery a differentiated choice of the available shunting methods to be applied, especially techniques for selective decompression and liver arterialization, may improve the results. Finally, the aim in each case should be a porta-caval shunt adapted to the individual situation of the cirrhotic patient.


Characterization of the collagen synthesized by cultured human smooth muscle cells from fetal and adult aorta. Smooth muscle cells were grown from explants of the tunica media of fetal and adult human aorta. Collagen was isolated after incubation with [14C]glycine and was characterized by ion-exchange chromatography. All cells investigated synthesized two types of collagen: Type I (chain composition [alpha1(I)]2alpha2) and type III (chain composition [alpha1(III)]3). The collagen made by cells from adult donors contained approximately 70% type I and 30% type III collagen. This corresponds to the collagen composition in teh original tissue. No age-relate change in the type I/type III ratio was found with cells from donors between 9 and 67 years of age. On the other hand, the type III portion of the collagen made by fetal cells was markedly less (about 15-20% of total collagen).


A review of lobular, portal, and periportal hepatitis. Interpretation of biopsy specimens without clinical data. This representation, in which a recently adopted terminology is used, represents a compilation of clinical diagnoses that must be considered whenever a morphologic diagnosis of lobular, portal, or periportal hepatitis has been made. Also described are the morphologic findings that may enable the pathologist to list, without knowledge of clinical data, the suspected clinical conditions in an order of likelihood.


Malakoplakia in a cadaver renal allograft: a case study. Malakoplakia is an uncommon chronic inflammatory disease characterized by histocytes with intracellular Michaelis-Gutmann bodies. The etiology is uncertain, but it is thought that depressed macrophage phagocytosis of bacteria is important. This presentation describes a case of malakoplakia arising in a cadaver renal transplant. The association of long term immunosuppression and repeated E. coli urinary tract infections is discussed.


Preferential derivation of abnormal human G-group-like chromosomes from chromosome 15. The marked binding of antibodies specific for 5-methylcytidine to the short arm of chromosome 15 distinguishes this chromosome from the other human acrocentrics. This method has been used to study over 60 individuals including 12 who did not have Down's syndrome, but who did have an extra G-group sized acrocentric chromosome. In six cases the extra chromosome did not show intensive binding of anti-5-methylcytidine. In the other six cases, the extra chromosome contained a 5-methylcytidine rich band at each end indicating that both ends were derived from chromosome 15 and contained centromeric heterochromatin normally present on the short arm of chromosome 15. The duplication of short arm material in the abnormal chromosomes was confirmed in all cases by quinacrine staining, nucleolar organizer (Ag-AS) staining or C-banding. In three cases, the abnormal chromosome appeared to arise from two different chromosomes 15. Several possible mechanisms for the production of the abnormal chromosome are discussed. The individuals with this abnormal chromosome all showed some degree of mental retardation, but few common physical findings.


Origin of the translocated segment of the 14q+ marker in non-Burkitt lymphomas. The cytogenetic findings by G-banding in two histiocytic lymphomas are described. Both tumors had a stemline with a 14q+ marker. The origin of the extra segment on No. 14 was determined, and it was different in the two cases. These observations, and those from non-Burkitt lymphomas with 14q+ markers reported in the literature, indicate an inconsistent pattern for the origin of the extra material on No. 14. The only feature in common for all cases is instability of the distal region of the long arm of No. 14, and liability of this region to be involved in structural rearrangements, particularly translocations.


Heat-labile enterotoxin produced by Escherichia coli serogroup O149 isolated from diarrheic calves. Nine strains of Escherichia coli serogroup O149 isolated from diarrheic calves were found to produce a heat-labile enterotoxin. The heat-labile enterotoxin activity was destroyed by heat (85 degrees C/30 min) and was neutralized by rabbit anti-heat-labile enterotoxin. One of the strains also produced a heat-stable enterotoxin.


Biological properties of Shigella flexneri 2A toxin and its serological relationship to Shigella dysenteriae 1 toxin. A toxin extracted from heat-inactivated, alkaline-treated Shigella flexneri 2a showed biological properties similar to those of Shigella dysenteria 1 toxin. The S, flexneri 2a toxin was lethal to mice, enterotoxic for ileal loops of rabbits, and cytotoxic for HeLa cells. A serological relationship between S. flexneri 2a and S. dysenteriae 1 toxin was shown with cross neutralization tests.


Evaluation of serum opsonic capacity by quantitating the initial chemiluminescent response from phagocytizing polymorphonuclear leukocytes. Phagocytically activated polymorphonuclear leukocytes produced a chemiluminescence that could be correlated metabolically with the stimulated oxidation of glucose via the hexose monophosphate shunt, The chemiluminescence observed was considered to originate from the relaxation of electronically excited carbonyl groups produced during singlet molecular oxygen-mediated microbicidal oxidation of the ingested microbe. With adequate adjustment of leukocyte and bacterial concentrations, the rate of chemiluminescence increase was nearly constant for the first minutes after initiation of phagocytosis. This rate was dependent on the quantity of bacteria phagocytized by the leukocytes. If both leukocytes and bacterial concentrations were held constant, this initial rate of chemiluminescence reflected the opsonic capacity of the sera used for opsonization. The prior absorption of opsonins from serum resulted in a decresed rate of chemiluminescence related to the quantity of bacteria used for absorption. Heating of sera to 56 degrees C for 30 min resulted in a great decrease in the chemiluminescent responses and may reflect the role of complement in the opsonization process.


Growth inhibition of Candida albicans by rabbit alveolar macrophages. Normal rabbit alveolar macrophages were infected in vitro with Candida albicans. Early after infection, germ tube formation of phagocytized C. albicans was inhibited in contrast to extracellular (nonphagocytized) C. albicans. Over and 8-h period, plate counts of C. albicans incubated with alveolar macrophages revealed a decrease in colony-forming units in contrast to C. albicans alone. In addition, an assay was developed which specifically measured C. albicans [3H]leucine incorporation in the presence of alveolar macrophages. Using this assay, we observed a 71 to 93% inhibition of macromolecular synthesis in C. albicans when incubated with alveolar macrophages. Autoradiographic studies showed that the inhibition of leucine incorporation was restricted to the ingested Candida.


In vitro response of rabbit alveolar macrophages to infection with Nocardia asteroides. The interaction of Nocardia asteroides with cultured "normal" nonimmune rabbit alveolar macrophages was studied by light and electron microscopy. It was shown that the alveolar macrophage response to the more virulent strain (N. asteroides 14759) was quite different from the response to the less virulent organism (N. asteroides 10905). N. asteroides 14759 elicited a dramatic in vitro response of the macrophages toward the nocardial infection. Within a few hours postinfection, there was a migration of macrophages toward other cells actively infected with viable nocardia, so that at 6 h considerable macrophage aggregation on the cover slips had occurred. Many of the macrophages within these aggregates exhibited tight cell-to-cell contact, whereas others were observed to fuse, forming multinucleate giant cells, with many containing more than 10 nuclei. Upon continued incubation, these giant cells appeared to destroy the intracellular nocardia, so that, at 24 h postinfection, gram-positive, ultrastructurally intact bacteria could not be observed. At the same time, some of the macrophage aggregates that did not fuse appeared to be unable to stop the intracellular growth of nocardia. At 12 to 24 h large numbers of gram-positive, acid-fast filaments were observed growing out from within these macrophage aggregates. The macrophage response seemed dependent upon the strain of Nocardia infecting them, since N. asteroides 10905 did not induce a similar response within the macrophage population.


Role of zinc in the abatement of hepatocellular damage and mortality incidence in endotoxemic rats. Intraperitoneal administration of zinc (ZnIP) as zinc chloride prior to or simultaneously with a lethal quantity of intraperitoneally administered Salmonella typhimurium endotoxin significantly protected rats against toxin-induced mortality and hepatocellular damage. Pretreatment with amounts of zinc chloride ranging from 0.4 to 2.0 mg/100 g of body weight resulted in 80 to 100% survival compared with 10% survival in untreated control rats at 24 h after endotoxin treatment. Zinc chloride treatment in excess of 2.0 mg/100 g of body weight appeared to be toxic and provided diminished protection. In contrast with the protection obtained with ZnIP, intravenously administered zinc did not provide protection. The effectiveness of ZnIP to enhance survival if it was given after endotoxin was greatly diminished as a function of time after endotoxin. The extent of hepatocellular damage was assessed at various times after endotoxin administration in ZnIP-treated and untreated rats by measurement of plasma ornithine carbamoyltransferase activity and histological examination of liver sections. Endotoxin absorption from the peritoneal cavity and hepatic uptake were studied by using 51Cr-labeled endotoxin. ZnIP pretreatment significantly reduced 51Cr-labeled endotoxin content of blood and liver when compared to untreated controls, and effectively prevented endotoxin-induced elevations in plasma ornithine carbamoyltransferase activity and hepatic tissue necrosis. These data indicate that protection afforded by ZnIP treatment results as a consequence of the ability of zinc to diminish absorption of the toxin from the peritoneal cavity and subsequent hepatic uptake.


Enterotoxigenic Escherichia coli in Sweden. The adrenal cell test for detection of heat-labile enterotoxin-producing Escherichia coli was performed on faecal specimens collected over a period of six months from 648 patients with diarrhoea. The patients came from all parts of Sweden. A total of 72 enterotoxigenic strains were found in 27 patients. Enterotoxigenic strains do not seem to be an important cause of diarrhoea in Sweden, since 70% of the patients with enterotoxin-producing strains had been abroad. Enterotoxigenic enterobacteria were the cause of traveller's diarrhoea in 11% of the patients who had been abroad with a peak incidence in July and August when traveller's diarrhoea was associated with enterotoxigenic strains in 17% of the patients. A simplified method for screening a large number of specimens for enterotoxin production was evaluated and found to be useful.


[Microbiological diagnosis of septicemia (author's transl)]. To detect microorganisms in the blood it is necessary not only that the microbiologist uses reliable methods, but also that the clinician takes a sufficient number of blood samples at the right point in time using a correct method for drawing the blood. The best results are obtained if the blood sample is transferred to the culture media at the bedside. The media should contain anticoagulants, osmosis stabilizers and preparations to neutralize the microbial action of the blood (caused by intrinsic and extrinsic factors). Up until now sodium polyanetholsulfonate ("Liquoid") has proved to be the most suitable additive. The procedure used for blood culturing must enable growth of aerobes, anaerobes and microbes with cell-wall damage. Today, modern methods such as radiometry, impedance measurement and microcalorimetry are used or are in the process of being developed which facilitate screening for positive cultures. Antigens, cell-wall constituents and metabolites of bacteria and fungi present in the blood stream can be detected by means of counter-immunoelectrophoresis, the Limulus test and gas chromatography, without culturing being necessary. Concentration techniques such as filtration and centrifugation are also being refined to enable a more reliable and earlier detection of septicemia.


Effect of thymic factor on human lymphoid cells of umbilical cord blood and of children with T cell deficiency. We report on the in vitro effect of a thymic factor (TF) extracted from pig thymuses, on human lymphoid cells from umbilical cord blood and from peripheral blood of 8 T cell-deficient patients. E rosette formation was not affected by TF when tested on cells from peripheral blood of normal adults. With cells from umbilical cord blood of 13 healthy, full-therm newborn babies, the difference between the percent (mean) of ERFCs before (16.31 +/- 11.13) and after (28.85 +/- 17.10) incubation with TF was statistically significant (p less than 0.05). In most samples, TF transformed about 10-20% of the cells. In the T cell-deficient group the increase in ERFCs of the peripheral blood lymphocytes, though consistent, was variable in degree from case to case. Our data indicate that precursor cells in some individuals with T cell deficiency are very sensitive to TF. Patients with highly responsive precursors appear to be the best candidates for a therapeutic approach with TF when thymus transplant is not possible.


T and B cell populations in the peripheral blood of rhesus monkeys. B and T cell populations in the peripheral blood of rhesus monkeys are comparable to those of normal human beings. B cells of monkeys, like those of human beings, also have receptors for IgM, IgG and IgA.


Diagnosis of reaginic allergy with house dust, animal dander and pollen allergens in adult patients. II. A comparison between skin tests and provocation tests. The results of skin tests (ST) were compared with those of 2,055 provocation tests (PT) in 403 patients with asthma and/or allergic rhinitis. The overall agreement between ST and PT results was 77%. Various correlation figures were found for different allergens. In patients with pronounced allergy in the shock organ the prportion of positive ST was higher than in those with low-grade allergy. It is concluded that only strong ST reactions should be relied upon. In other cases additional diagnostic methods are reccommended. The diagnostic precision of ST is of the same order of sizes as that of the radioallergosorbent test.


Importance of the spleen for the immuno-inhibitory aciton of linoleic acid in mice. Certain immuno-inhibitory effects of a polyunsaturated fatty acid, linoleic acid (C18:2), no longer occur after splenectomy of young adult CBA mice. This observation suggest that the spleen is a major intermediary in the action of C18:2 on the lymphoreticular system. Pathways of this action remain to be elucidated. Possibilities include C18:2-stimulated suppressor cell generation in the spleen, or excess biosynthesis of immuno-inhibitory prostaglandins by splenic macrophages.


On errors related to the use of expert estimates. The use of expert estimates has become a normal procedure for many applied problems, usually reduced to testing statistical hypotheses. A typical example is the problem of medical diagnostics, when experts are asked, for instance, to estimate the probability of appearance of different symptoms of different diseases. This paper treats the problem of the influence of the accuracy of expert estimates on the properties of the statistical tests used, that is, changes of their critical levels and powers are considered.


Subjective phenomena in drug trials.

Subjective phenomena in drug trials. Three types of problem arise from subjective phenomena in drug trials: problems of control, measurement, and analysis. Examples are given in order to illustrate these three aspects and to present some recent advances in clinical pharmacology. The author discusses the control of drug compliance, the validity of questionnaires, the subjectivity of the observer and that of the observations. Drug side-effects and the statistical analysis of qualitative data are presented in more detail.


Controlled evaluation of the antitussive activity of viminol p-hydroxybenzoate. A double-blind cross-over trial was carried out to evaluate the antitussive activity of viminol p-hydroxybenzoate; the comparison was done with three preparations: a placebo and the drug at two doses, 70 and 140 mg respectively. The responses were scored hourly up to 4 hours after the administration of single doses in the morning to subjects with persistent cough. The highest dose of viminol showed a definite antitussive activity, whereas the lowest did not differ from the placebo. The antitussive effect appears clinically useful for the treatment of cough, but further studies are indicated to define optimal dosage schedules.


Photodynamic action of thiopyronine on polyribosomes and cell-free protein synthesis in yeast. The treatment of yeast with thiopyronine (TP) caused a degradation of polyribosomes, even if the cells were not illuminated. In contrast, no differences in the polyribosome profiles of illuminated and unilluminated cells could be seen. Likewise, in in vitro experiments, there was no degradation of polyribosomes caused by dark effect or photodynamic action. Cell-free protein synthesis was inhibited up to 75 per cent by the photodynamic effect when the complete system was treated, but only up to 40 per cent when the polyribosomes or enzyme fraction were treated. Since the enzyme fraction contained aminoacyltRNA-synthetases and tRNA, it was necessary to investigate separately the effect of TP on the enzyme and the tTNA. It was shown that the aminoacyl-tRNA-synthetase and not tRNA was effected by the photodynamic action in its biological activity.


Unscheduled DNA synthesis in diploid yeast after X-irradiation in diffent phases of the cell-cycle. The uptake of radioactive 5'-dTMP into the DNA of diploid yeast cells was measured in the G1 and S-phase of the cell-cycle. In control cells, the uptake is zero in G1 and increases with time in the S-phase. Cells irradiated in early G1 show an uptake (unscheduled DNA synthesis) which is higher than if irradiation is performed later in G1. An analysis which takes into consideration the incomplete synchronization of the cell population shows that, at the end of G1, no uptake would be present in an ideally-synchronous population. At the end of G1 the shoulder in the dose-effect curve for cell survival also disappears. This provides additional evidence that the shoulder in a dose-effect curve might be due to repair reactions in living cells.


Radiosensitization of hypoxic cells by a nitrofuran; dose-modifying and shoulder effects. The radiosensitizer nifurpipone dihydrochloride (5-nitro-2-furaldehyde N-methyl piperazino acetyl hydrazone dihydrochloride) sensitizes hypoxic V79 mammalian cells by at least two mechanisms. Sensitization is by a reduction of ñ in addition to an increase in slope. Both these affects are absent under oxygenated conditions. When hypoxic V79 cells are irradiated in the presence of nifurpipone dihydrochloride combined with Ro-07-0582, sensitization greater than that due to air alone is observed; this effect is due to a reduction in ñ and an increased slope. Again this effect is absent under oxygenated conditions. Rapid-mix studies using Serratia marcescens show that full senitization occurs with a pre-irradiation contact time of 4 msec; this contrasts with data for V79 cells where a pre-irradiation contact time of 40 msec is insufficient for any sensitization to occur. This sensitizer also exerts a differential toxic effect, being more toxic to hypoxic cells than to oxygenated ones. It is concluded from these results that nifurpipone dihydrochloride sensitizes by at least two mechanisms, one of which resembles that of the electron-affinic type.