[Classification and diagnosis of ankle injuries]. A new method for the classification of the injuries of the ankle is recommended by the author. The main types according to his classifixation are the following: pronation-flexion, pronation-extension, supination-extension, supination-flexion and supination-extension types. His classification is compared with Lauge-Hansen's and Weber's classification. Critical analysis of these two last classifications is given. The aim of the author's classification is to render help to the doctors for their every-days' curative work. The characteristic symptoms of the pronation and supination, resp., injuries are described. Attention is drawn to "Weber's lace"--this denomination is proposed by the author, since the first description is due to Weber. On the basis of the author's examinations described in his candidate's dissertation "syndesmolysis trigonum"--pathognostic for syndesmolysis--is dealt with. The "reclined" roentgenograms are dealt with. The so-called pronation reclined roentgenogram visualize the rupture of the deltoid ligament and the syndesmolysis in the same time. The sagittal reclined roentgenogram is dealth with separately, by means of which the "table-drawer" symptom may be produced.


[The effect of ligament calcification following syndesmolysis on pseudoarthrosis of the median malleolus]. The development of the false joint of the medial malleolus of 16 patients has been followed by the authors at the least for 13 years. It was found that in the cases, in which the fracture of the medial malleolus was concomitant with syndesmolysis, recovery of the false joint occured in the cases, in which in the place of the syndesmolysis calcification appeared, which brought the lateral cutting effect in the talo-crural joint to an end.


[Conservative and surgical treatment of open fractures of the forearm]. On the basis of the 10 years' material of the Hugarian National Institute of Traumatology the possibilities of treatment of the open fractures of the forearm are discussed. It is stated by the authors that operative treatment of the open fractures of the forearm is more and more frequent, and--chiefly in the last time--the surgeon strives to obtain rigid internal fixation. If the individual and objective conditions of the internal fixation are not given or the operation seems risky for other reasons--intramedullary splinting--completing the conservative treatment--or wire fixation are the method of choice. In connection with fractures of different type the authors' method is discussed and a few cases are reported.


Helix-coil stability constants for the naturally occurring amino acids in water. 11. Lysine parameters from random poly(hydroxybutylglutamine-co-L-lysine). The synthesis and characterization of water-soluble random copolymers containing L-lysine with N5-(4-hydroxybutyl)-L-glutamine, and the thermally induced helix-coil transitions of these copolymers in water, are described. The incorporation of L-lysine was found to decrease the helix content of the polymers at neutral pH. The Zimm-Bragg parameters sigma and s for the helix-coil transition in poly(L-lysine) in water were deduced from an analysis of the melting curves in the manner described in earlier papers. The computed values of s indicate that, in the temperature range of 0-60 degrees C, lysine has a tendency to destabilize helical sequences, this tendency being minimal at approximately 25 degrees C and increasing at lower and higher temperatures.


[Substitution of the frontal bone with silicon]. The good results obtained with silicon implants used in the frontal region are reported by the authors. After the correct primary treatment the reconstructive operations have been performed at the least 6 months after the lesion, if the environment of the defect was free from any reaction during this time. 14 implantations have been performed in 2 years. Satisfactory functional and cosmetic results were obtained and the implant was to be removed in no case.


[Treatment of injuries of the penis and scrotum complicated by total skin loss]. In connection with two healed cases the free transplantation of semi-thick skin is recommended by the authors for the treatment of the above-mentioned injuries, on the basis of the following reasons: 1. The most ideal results may be expected from this method. 2. The objective conditions (dermatome, Humbey's knife, sponge etc.) age generally given. 3. The semi-thick skin plasty is one of the mostly used and well-known methods. 4. In the case of failure the method may be repeated or other method may be chosen. 5. Semi-thick skin plasty is the easiest way to observe the principle: "Nil nocere".


[Acute arteria mesenterica superior syndrome caused by severe electric injury]. The case of acute arteria mesenterica superior syndrome--occurred in a boy aged 10, as rare complication of high voltage electro-trauma--is reported. The aetiology of the syndrome, as well as a possible new pathogenic factor are discussed. The clinical picture and the therapeutic principles are dealt with.


[Substitution of an injured finger joint by silicone rubber prosthesis]. Between 1973 and the first semester of 1975, on the injured and destroyed digital articulation 27 patients have been operated on by means silicon rubber prosthesis of Swanson type. The prosthesis plasty and the field of its use are shortly resumed, pointing out the importance of its adaptation on the injured articulation. The operative technique is described, as well as the results obtained and the aspects of the evaluation are discussed. The results obtained with the silicon rubber prosthesis are very promising. In the case of failure arthrodesis may be performed at any time.


[Phlebography of the talus following fracture and dislocation (preliminary report)]. After dislocation or dislocated fracture of the talus late arthrosis is a frequent complication, in which primary bone and cartilage damage play a role. For the demonstration and preclusion, resp., of the vascular damage phlebography performed 3--6 months after the injury is recommended by the authors--by means of which favourable initial experiences could be obtained.


Pharmacotherapy of myocardial ischemia.

Pharmacotherapy of myocardial ischemia. The cornerstones of pharmacotherapy for myocardial ischemia are the nitrites and the beta-adrenergic blocking agents. These drugs not only inhibit cardiac mechanical activity (and therefore energy requirements) in a variety of ways but also redistribute available blood flow to the potentially ischemic segments of cardiac muscle. The least effective dose of nitroglycerin and the most tolerated (or blocking) dose of propranolol provide the optimum in management. There is increasing evidence that certain orally administered nitrates at larger than usual dosage can further increase the tolerance to effort. Amelioration of hypertension or congestive failure may play a significant role in selected patients.


Principles in selection of therapy.

Principles in selection of therapy. The physician today is presented with a plethora of possibilities in the therapy of each of the aspects of ischemic heart disease (Fig. 15-5). There is the temptation to recommend complex and impossible dietary prescriptions coupled with several pharmaceutical agents for control of anginal pain, hypertension, arrhythmias, hypercholesterolemia, and clinical congestive heart failure. While each of the objectives may be in part valid, the burden on the patient of following such a constraining and difficult life may make it virtually impossible either to enjoy life or to follow the physician's recommendations explicitly. Often a compromise must be reached between theoretically optimal therapy and that which is reasonable and acceptable to the patient. Again, a review of each aspect of the program with the patient may aid in establishing that which is possible rather than that which is ideal.


Triacetylated insulin: biologic activity and resistance to degradation. Tritiated N-hydroxysuccinimide acetate was prepared with specific activities up to 5 Ci/mmole and utilized to prepare tritiated triacetyl insulin. Binding of triacetyl insulin to liver plasma membranes was measured by its capacity to displace 125I-monoiodoinsulin. At low concentrations, less than 10 ng/ml triacetyl insulin appears to be as effective as native insulin in reducing the binding of 125I-monoiodoinsulin to plasma membranes. At concentrations of 20 ng/ml and higher, triacetyl insulin is significantly less effective than native insulin in displacing binding of 125I-monoiodoinsulin to plasma membranes. The properties of triacetyl insulin in this system are not ascribable to deacetylation and conversion of the substituted product to native insulin. Biologic activity of triacetylated insulin was studied in two other in vitro systmes. A comparison was made of the capacity of native beef insulin and its triacetyl derivative to stimulate glucose oxidation by epididymal fat pads. At all three concentrations tested (2, 6, and 18 ng/ml), triacetyl insulin exerted considerable activity, although its potency was significantly less than that of native insulin. Similar effects were observed when biologic activity was measured by induction of tyrosine-alpha-ketoglutarate transaminase in a cultured liver cell system where significant activity of triacetyl insulin was found at concentrations of 10(-9)-10(-7) M. In all systems tested, the activity of triacetylated insulin could not be accounted for by deacetylation and conversion to native insulin. In all systems studied, triacetyl insulin was more resistant to degradation than was monoiodoinsulin.


Effects of arginine infusion in infants: increased urea synthesis associated with unchanged ammonia blood levels. Infusion of L-arginine hydrochloride in infants and children (ages ranging from 1 day to 12 yr) at a dosage of 0.5 g/kg body weight resulted in a dramatic increase in the arginine plasma concentration, with highest values of approximately 7 mmole/liter immediately after the end of the infusion; 120 min later the mean plasma level of the amino acid had decreased to mean values of 1 mmole/liter. These fluctuations were paralleled by increased ornithine concentrations, although the mean plasma levels of this amino acid remained far below those of arginine, i.e., 0.73 and 0.22 mmole/liter after 30 and 90 min, respectively. When expressed on a molar basis, arginine administration resulted in an almost stoichiometric rise in urinary urea excretion. These findings indicate that arginine is rapidly metabolized via urea and ornithine, the latter being transformed to glucose, as evidenced by a significant rise in the blood glucose concentration. Blood gas analyses and serum urea and blood ammonia concentrations determined after the load showed no significant deviations from preinfusion levels. Thus, in contrast to the effects to be expected form studies with tissue culture homogenates, even when administered to newborn infants, arginine does not impair the turnover of the urea cycle.


Effect of hydrogen ion buffers on photosynthetic oxygen evolution in the blue-green alga, Agmenellum quadruplicatum. The photosynthetic oxygen evolution capacity of Agmenelium quadruplication suspended in four hydrogen ion buffers (pH 7.4, 0.05 M) and its synthetic marine growth medium was measured with an oxygen electrode. High rates of oxygen evolution were obtained in the growth medium and N-tris(hydroxymethyl)-methylglycine (Tricine) buffer. Compared to oxygen evolution in the growth medium, rates in phosphate buffer and N-tris(hydroxymethyl)-2-aminoethanesulphonic acid (TES) buffer were sometimes reduced by up to 30% and rates in tris (hydroxymethyl) amino-methane (Tris) were consistently reduced by 50%. An incubation-rinsing procedure caused inhibition of oxygen evolution in TES, phosphate, and Tris by 50 to 100%. Oxygen evolution could be restored to cells rinsed in TES or phosphate by resuspension in growth medium or in buffer plus magnesium and calcium ions. Bezoquinone-supported oxygen evolution was not affected by rinsing with any buffer tested except Tris. Ferricyanide was photoreduced at a low rate by cells rinsed in Tes but at a high rate in TES plus magnesium and calcium ions. We interpreted our results to mean that, in Agmenellum quadruplicatum, inhibition of photosynthetic oxygen evolution by Tris occurs at the level of photosystem 2 while the effects of TES and phosphate are on electron-transport occurring after the rate-limiting reaction.


A new form of antihistamine--the H2-receptor antagonist. A new group of drugs, the histamine2 (H2)-receptor antagonists, act on receptors in the stomach to reduce acid secretion when this is stimulated by histamine, pentagastrin, the vagus nerve or food. The reduction in acid secretion is profound and may approach the degree of reduction brought about by gastric surgery. The H2-receptor antagonist metiamide, administered orally, has been used successfully in the treatment of duodenal ulcer and the Zollinger-Ellison syndrome, but it has been shown to cause agranulocytosis. Trials are in process with an analogue, cimetidine (Tagamet, SKF), which has a different chemical structure from metiamide and has not caused haematological changes in animals or man. These drugs offer the prospect of successful medical management of duodenal ulcer, while a study of their effects on H2-receptors elsewhere in the body may reveal other therapeutic benefits.


Streptococcal sore throat in general practice--a controlled study. A controlled study was undertaken to determine the incidence of Group A haemolytic streptococci and other bacterial pathogens in throat swabs from patients presenting with sore throats. The isolation rate (38-8%) of Group A haemolytic streptococci from patients with acute tonsillitis was significantly higher than the isolation rate (8-9%) in a control group, but there was no significant difference in the isolation rates in patients diagnosed as having acute pharyngitis compared with the control group. There was no difference in the isolation rates of the other bacterial pathogens in the patient and control groups. In-vitro antibiotic studies were performed, and a comparison was made of the results of these tests and the treatment prescribed.


Reflex increase in coronary vascular resistance in patients with ischemic heart disease. To assess possible coronary vasoconstriction in patients with ischemic heart disease, we measured coronary vascular resistance in 12 patients with normal hearts and 12 with coronary disease before and during the initial 50 seconds of cold pressor test, a stimulus known to produce systemic vasoconstriction. Control coronary vascular resistance was similar in the two groups, and although it did not change in patients with normal vessels, it rose by 27 per cent (P less than 0.005) in the group with coronary disease during the cold pressor test. In three of 12 patients with coronary disease coronary flow actually declined despite an increase in arterial pressure; in four, angina was precipitated. Phentolamine abolished increases in arterial pressure and coronary vascular resistance during the test in three patients with coronary disease. Adrenergically mediated coronary vascular tone may be an important determinant of coronary blood flow and may contribute to ischemia in patients with coronary disease.


Proteolytic activity in liver cells from mouse, rat, Ehrlich ascites carcinoma bearing mouse and in Ehrlich ascites carcinoma cells. The activity of intracellular proteinases from Ehrlich ascites carcinoma bearing mice were compared with that from liver cells of normal mice and rats. The activity of intracellular proteinases was measured in the supernatant of Ehrlich ascites carcinoma cells homogenate. The activity of intracellular proteinases in normal mouse and normal rat liver were different at pH 3.5, pH 6.0 and pH 7.5. The activity in liver cells from Ehlrich ascites carcinoma bearing mouse at pH 3.5 was not significantly changed from normal mouse or rat liver cells, however at pH 6.0 and pH 7.5 the activity in the affected liver significantly decreased. The proteolytic activity in the supernatant of Ehrlich ascites tumor cell homogenate was 0.110 E750 mmu/mgN at pH 7.5, 0.154 E750 mmu/mgN at pH 3.5. The proteolytic activity at pH 6.0 was not detected in any experiment.


Correlation of the oxytocin challenge test with perinatal outcome. A total of 234 oxytocin challenge tests (OCT) were performed on 100 high-risk patients. The results were negative (N) in 68 of these 100 patients, suspicious (S) in 22, and positive (P) in 10. The incidence of late decelerations during labor was N, 5%; S, 40%; P, 86%; and meconium staining of the amniotic fluid was N, 4%; S, 5%; and P, 30%. The cesarean section rate was N, 16%; S, 36%; and P, 60%; and of these the cesarean section rate for fetal indications was N, 9%; S, 25%; and P, 67%. The overall perinatal mortality in the study group was 2% (N, 1.5%; S, 0%; P, 10%). The results confirm the negative OCT as innocuous and positive OCT as the most ominous. They also indicate that the majority of patients with positive OCT can be delivered vaginally without endangering the fetus if fetal scalp blood pH determinations can be performed.


Microstructure of the solder-casting zone in bridges of dental gold alloys. The composition and structure were studied in the cast and in the solder of bridges which had failed clinically. Both materials were gold alloys but with different contents of Pt, Ag and Zn. The metallographic investigation revealed defects mostly in the solder, situated in the subsurface layer. SEM studied of the fracture surface revealed large porosites and a structure of dense parallel lines--striations--, indicating that the material had failed from fatigue. The materials in the fractured bridges were identified by micro-probe measurements. It was stated that cast material and solder material used together, were of different composition.


Gingival crevicular fluid: a new diagnostic aid in managing the periodontal patient. On the whole, the studies on GCF have demonstrated that the flow of this fluid is sufficiently indicative of the inflammatory state that it can be used under a variety of clinical conditions to monitor and control gingival inflammation. Since gingivitis is extremely common, and since some cases of gingivitis presumably do not progress to periodontitis, the question could be posed whether or not a concerted effort to control inflammation (i.e. trying to achieve a GCF flow as near to zero as possible) would be clinically significant. Until there is evidence to the contrary, the answer must be "yes", since few cases are known where periodontitis occurs without being preceded by gingivitis. In other words, the control of all gingivitis, if feasible, should prevent most cases of periodontitis. Although control of all gingivitis would mean the treatment of many cases that would not progress to periodontal breakdown, such efforts would be worth-while if most periodontal destruction were prevented. Even the early destructive lesion exhibiting little or no inflammation may soon be identified, mainly because the minute volume of fluid collected from the gingival crevice can now be measured accurately. Accordingly, the concentration of various constituents in the GCF can be determined, which should lead to the development of tests to differentiate between pockets undergoing active destruction with minimal inflammation from the majority of active lesions that are intimately involved with frank inflammation. Thus, a clinician would measure sub-clinical gingival inflammation by measuring GCF flow, then differentiate destructive from quiescent lesions by analyzing the GCF sample for some constituent(s), chemical or microbial (Listgarten et al. 1975) indicative of the periodontal destructive process. Monitoring the flow of GCF might be of value in other clinical situations. For example, one could monitor the response of gingival tissues to various restorative and prosthetic procedures (Strauss et al. 1975) to ensure that these procedures do not aggravate the periodontal tissues and induce gingivitis or periodontitis. The education of the patient should be easier since patients can read their own numbers on the GCF meter at each examination and self-evaluate their personal periodontal condition and the effectiveness of their home care. Even the education of the dental student should be easier since he or she would have the means of self-evaluating the effectiveness of treatment, and not be as dependent upon the subjective assessment of his efforts by an instructor. Finally, monitoring GCF for various components could provide the dentist with a valuable means of easily screening patients for systemic disease. Obviously, this area of investigation is in its infancy, but does promise an exciting future for the oral diagnostician.


[Neuroaminergic control of anterior pituitary secretions (author's transl)]. The demonstration and identification of monoamines and of aminergic tracts in the central nervous system has permitted a study of their role in the control of the liberation of hypothalamic releasing hormones. Knowledge of the role of these hypothalamic neurohormones in the release of pituitary hormones is at present under study. The role of monoamines in the control of pituitary hormone functions depends narrowly on pharmacological methods intervening either in the synthesis of neuroamines or in their action on a specific receptor. The authors consider successively the implication of monoamines in the control of liberation of ACTH, GH, TSH, prolactin and gonadotropic hormones. The role of aminergic mechanisms in the physiology of pituitary releasing hormones forms an integral part of homeostasis. Knowledge of these mechanisms leads to a clinical study of their role in disorders of hypothalamo-pituitary function.


Diagnosis and treatment of duodenal ulcer in infancy and childhood. An awareness of the modes of presentation in childhood duodenal ulcer disease is necessary for prompt diagnosis and treatment. Therapy should be based on the rationale of decreasing acid secretion and providing adequate buffering of gastric acid throughout the day. Because of the high incidence of recurrence in children, aggressive diagnosis and treatment of duodenal ulcer are indicated in any child suspected of having the disease.


Genetic variation of lysosomal acid lipase. Lysosomal acid lipase (LAL) activity was measured using a new fluorometric assay in cultured skin fibroblasts from eight control subjects, two obligate heterozygotes for Wolman's disease (WD), one patient with WD, and one patient with cholesteryl ester storage disease (CESD). The LAL activities (mean+/-SD) were 25.8+/-8.2, 13.2+/-0.1,1.1, and 1.4 nmol 4-methylumbelliferyl oleate (4-MUO) hydrolyzed/min/mg protein, respectively. These results compare favorably with those obtained using standard radioassays. The LAL activities of two cultures of amniotic fluid cells were 12.1 and 10.5. The LAL activity (mean+/-SD) of peripheral leukocytes obtained from 34 laboratory volunteers (19 females, 15 males) was 4.0+/-1.8. Partially purified lymphocytes contained about 25 times as much LAL activity as did granulocytes. Cellogel electrophoresis, followed by staining with 4-MUO, showed at least two bands of LAL (A and B) from normal fibroblasts, amniotic fluid cells, and lymphocytes. Band A was absent from WD and CESD fibroblasts and was reduced in fibroblasts of the WD heterozygotes.


Influence of low extracellular pH upon the Ca inward current and isometric contractile force in mammalian ventricular myocardium. In isolated papillary muscles of cats the changes in Ca inward current and isometric contractile force following a decrease of extracellular pH from 7.4 to 5.5 were studied. The Ca current was analyzed (a) by measuring the upstroke velocity of Ca-mediated action potentials and (b) in voltage clamp experiments using the double sucrose gap technique. 1. At a pH of 5.5 the upstroke velocity of the Ca-mediated action potential decreased to 65% of the control, while overshoot and action potential duration remained almost unchanged. Furthermore, the relative refractory period was prolonged and in some cases, a "Wenckebach-like" phenomenon occurred. In voltage clamp experiments, the slow inward current was found to be diminished to 50-60% of the initial control value and over a broad voltage range the current voltage relationship curve was shifted to weaker currents. Acidosis did not influence the steady state inactivation but altered the kinetics of inactivation of the slow inward current and induced an increase of tauinactivation and taurecovery. This indicates that acidosis exerts a complex effect on the slow membrane channel. 2. The normal response of the Ca current towards variations of the extracellular Ca concentration (0.5-4 mM) or towards the addition of the beta-stimulating compound isoproterenol (2 mg/l) was not altered by the lowered extracellular pH. 3. In the acid medium, isometric contractile force declined to 40% of the control value within 25 min and, thus, reacted stronger than the Ca current. This indicates that those forms of acidosis used in the present experiments caused their negative inotropic effect not exclusively via a depression of the Ca current. Rather an additional intracellular effect has to be assumed which finally leads to a reduced activity of the contractile system. 4. At pH 5.5 excess Ca (4 mM) induced the same quantitative response of the contractile system as obtained at normal pH. In contrast, the positive-inotropic effect of 2 mg/l isoproterenol was more pronounced, whilst the sensitivity of the Ca inward current towards this beta-stimulating compound remained unchanged.


[Acute kidney failure during periarteritis nodosa]. In 9 patients aged 16 to 71 years with acute renal failure, histological examination disclosed polyarteritis nodosa. Symptoms of rapidly progressive glomerulonephritis (GN) were present in 7 cases. Hypertension was a constant feature. Fever and muscular articular and cutaneous signs occured at times simulating Henoch-Schönlein purpura. Necrotizing angiitis was a constant finding, with perivascular granuloma in 7 cases. Lesions affecting smaller arteries were associated with diffuse or segmental extracapillary GN, and lesions of larger arteries with ischaemic appearance of the glomeruli. Diagnosis was obtained during life by percutaneous renal biopsy in 5 patients and muscular or cutaneous biopsy in 2 other patients, whereas the evidence was only obtained on post mortem examination in the 2 remaining patients. In the 6 renal biopsies examined by immunofluorescence, fibrinogen was always present in glomeruli and/or arteries. In one patient there was a linear deposit of IgG along glomerular basement membrane (GBM) and there were circulating antibodies directed against GBM. Arteries of different sizes may be damaged in various organs, as showed by arteriography and autopsy. Steroid therapy and immunosuppressive drugs had no effect on renal symptoms. 8 out of 9 patients died rapidly, in 6 the death was due to extrarenal localization of the disease, even though uraemia was controlled by haemodialysis. The last patient died 2 years after onset of the disease, while being on maintenance haemodialysis treatment.


Treatment of angina pectoris. Pharmacologic approaches. The short-acting nitrite sublingual nitroglycerin is the cornerstone of drug treatment of angina pectoris. It is most useful when given two to three minutes before activity that may precipitate an anginal attack. If disabling angina persists despite medical management and there is no contraindication, the beta-adrenergic blocking agent propranolol should be tried before coronary artery surgery is considered. Newer bera-adrenergic blocking agents do not appear to be more effective than propranolol. Digitalis may be beneficial in patients with congestive heart failure or with cardiac arrhythmias responsive to digitalis and in some patients with radiographic evidence of left ventricular enlargement or with nocturnal angina resulting from increased left ventricular end-diastolic volume. If bypass graft surgery is done, medical management must be continued postoperatively.


An eighteen months' study of the clinical response to metoprolol, a selective beta1-receptor blocking agent, in patients with angina pectoris. Following an initial dose response study, metoprolol, a selective beta1-receptor blocking agent, was compared with equipotent dosages of propanolol in a double blind cross-over study, including exercise tolerance tests, on fourteen patients with angina pectoris. Long term therapy with metoprolol then followed until the seventy-second week. Patients performed 8% more total work on metoprolol with 15% more work recorded up to the onset of S-T depression, in comparison with propranolol. In the long term, ther was no significant difference in work performed when the daily dosage of metoprolol was changed from a q.i.d. to a b.d. regime. Metoprolol was shown to be an effective anti-anginal compound with good tolerance and safety, with gradual improvement in underlying myocardial ischaemia during long term treatment.


Piperazine derivatives of dimethylxanthines. IV. Reaction of beta,gamma-epoxypropyldimethylxanthines with piperazines. In the reaction of 7-resp. 1-beta,gamma-epoxyproplderivatives of theophylline (Th) or theobromine (Tb) with piperazine and N-monoalkyl or monoarylpiperazines the corresponding 7-resp. 1-beta-hydroxy-gamma-piperazinopropyl-Th (1-8) resp. Tb (9-16) were formed. In preliminary screening some of the new compounds showed strong antagonism with histamine H1 receptor and with endogenous histamine.


Pneumococcal antigen in pneumonia. A post-mortem study with the histological and bacteriological findings. Pneumococcal capsular antigens can be detected in lung tissue by counter-current immunoelectrophoresis even when, following antibiotics, post-mortem bacterilogy suggests that Escherichia coli has replaced pneumococci. The results suggest that antipneumococcal therapy would benefit at least 55% of patients critically ill with lung infection and that the potentially toxic drugs directed at coliform bacteria may be unnecessary.


The stability of N-pyrrolidinomethyltetracycline in solutions. In aqueous solution N-pyrrolidinomethyltetracycline (PTC) undergoes decomposition into tetracycline, epitetracylcine, anhydroepitetracycline and ynhydrotetracycline. The decomposition products were identified and separated  by TLC and their activity was estimated microbiologically.


Catecholamine-stimulated cyclic GMP accumulation in the rat pineal: apparent presynaptic site of action. Guanosine 3':5'-cyclic monophosphate (cGMP) increased 7-fold in rat pineal glands incubated in the presence of l-norepinephrine. This response consisted of two components-one was stereospecific and inhibited by alpha-adrenergic antagonists while the other was not stereospecific and not readily inhibited by antagonists. Although l-isoproterenol was more potent than l-norepinephrine it had less intrinsic activity and its action was not stereospecifc. The increase in cGMP caused by these catecholamines, unlike that of adenosine 3':5'-cyclic monophosphate (cAMP), was dependent upon extracellular calcium. Ouabain and high levels of potassium produced a marked, calcium-dependent increase in pineal cGMP, without affecting cAMP. There was no effect of cholinergic agonists on cGMP. Surgical denervation markedly reduced the cGMP response to stimulation by l-norepinephrine, potassium, or ouabain. This was in contrast to the enhanced response of cAMP in denervated glands. The nonspecific increase in cGMP caused by l-isoproterenol, however, was not affected by denervation. These data demonstrate the existence of a calcium-dependent presynaptic mechanism for the generation of cGMP which may be mediated by an alpha-adrenergic-like receptor. In addition, the mechanisms regulating pineal cGMP appear to be physiologically distinct from those regulating cAMP.


Erythrocyte membranes undergo cooperative, pH-sensitive state transitions in the physiological temperature range: evidence from Raman spectroscopy. We have examined the Raman scattering from erythrocyte ghosts at 2700 to 3000 cm-1 (CH-stretching region). Plots of the intensity (I) of the 2930 cm-1 band relative to the intensity of the thermally stable 2850 cm-1 band, i.e., the [I2930/I2850] ratio, as a function of temperature reveal a sharp discontinuity, which at pH 7.4 has a lower limit of 38 degrees and is irreversible above 42 degrees. [I2930/I2850] is stable between pH 7.0 and pH 7.4, but increases or decreases sharply below pH 7.0 or above pH 7.5, respectively. Reduction of pH to 6.5 lowers the transition temperature by about 16 degrees, and a shift to pH 6.0 drops the transition range to 0 to 7 degrees. The above effects of temperature and pH on Raman scattering closely correspond to those detected by studies on the interaction of membrane protein fluorophores and lipid-soluble fluorescence quenchers [Bieri, V. and Wallach, D.F.H. (1975) Biochim. Biophys. Acta 406, 415-423]. Taken together, these results suggest that the transitions represent concerted process, involving hydrophobic amino acid residues and lipid chains at apolar protein-lipid boundaries.


Central regulation of sympathetic neuron development. The sixth lumbar (L-6) ganglion has been used to study the central regulation of peripheral sympathetic neuron development. During post-natal ontogeny, tyrosine hydroxylase [tyrosine 3-monooxygenase, L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] activity increased 60-fold, while total protein rose 10-fold in the ganglion. Transection of the spinal cord at the fifth thoracic (T-5) segment in neonatal rats prevented the normal developmental increase in tyrosine hydroxylase activity of the L-6 ganglion. However, spinal transection did not alter the ontogeny of tyrosine hydroxylase in the superior cervical ganglion, which derives its innervation from spinal segments rostral to the surgical lesion. Thus, spinal transection interfered with the maturation of sympathetic neurons distal to, but not proximal to, the lesion. The effect of transection on the L-6 ganglion persisted for at least one month, the longest time tested. Our observations suggest that trans-synaptic regulation of adrenergic maturation in the periphery is governed by suprasegmental mechanisms in the central nervous system.


[Purification and properties of L-glutamine and L-asparagine deaminase from Pseudomonas aurantiaca IBPM-14]. An enzymic preparation of L-glutamine and L-asparagine deamidase was obtained from Pseudomonas auractiaca IBPM B-14. The preparation was purified 100--150-fold by thermal treatment and chromotography on columns with biogel P-150 and DEAE-cellulose. The enzymic activity was measured by the methods of hydroxylaminolysis and direct nesslerization. The deamidase preparation had an activity of 51 i. u. by glutamine and 15 i. e. by asparagine. Evidence on the pH effect on the deamidase activity was accumulated.


Use of thyrotropin and cholera toxin to probe the mechanism by which interferon initiates its antiviral activity. Thyrotropin (10 muM) inhibited the antiviral activity of interferon. When added after interferon, thyrotropin (TSH) had no effect on antiviral activity. There was also no inhibition of interferon action in cells washed with medium between incubations with TSH and interferon. 125I-Labeled TSH and 125I-labeled cholera toxin could bind to preparations of mouse L-cell plasma membranes. The binding was specific in that it was prevented by unlabeled thyrotropin or cholera toxin, but not by insulin, glucagon, prolactin, growth hormone, human chorionic gonadotropin, or luteinizing hormone. Mouse interferon inhibited 125I-labeled TSH binding to L-cell plasma membranes. The effect of mouse interferon on 125I-labeled cholera toxon binding was more complex, inhibition occurring only after an initial enhancement at low interferon concentrations. A 10-fold higher concentration of interferon was required to inhibit 125I-labeled TSH binding. Mouse interferon was also able to displace bound 125I-labeled TSH, but not bound 125I-labeled cholera toxin. The interferon interaction with cell membranes was temperature-sensitive. Human interferon could induce changes in binding of 125I-labeled TSH and 125I-labeled cholera toxin to mouse L-cell plasma membranes similar to those induced by mouse interferon. Mouse interferon induced similar changes in plasma membranes of human KB-3 cells, which are insensitive to both human and mouse interferons. In view of these results, the species specificity of interferons does not appear to reside solely at the point of the initial interaction with their binding sites.


Multiple factor analysis of the action of local anesthetics. The pH jump data of Bianchi and Strobel [(1968) Trans. N.Y. Acad. Sci. Ser. II, 30, 1082-1092] on desheathed frog sciatic nerve are fitted to rate equations. A general quantitation of synergism, summation, and antagonism of anesthetics and of excitation is given.


Rumen function in red deer, hill sheep and reindeer in the scottish highlands. Red deer, sheep and reindeer grazing on their normal hill ranges were examined at intervals over a period of four years. Samples from the digestive tract were taken at different seasons and processed in the field. The Red deer and reindeer were killed before samples were taken; rumen samples from the sheep were taken by stomach tube, but a number of animals were also killed at different seasons to correlate stomach tube and whole rumen samples. The animals sampled were representative of the general condition of the herds. Examinations were made for parasites and any pathological conditions. In most instances parasitic infections were slight. Apparent seasonal changes were found in the compositions of the diets. The Red deer and sheep ate principally heather and grass, the proportion of heather increasing in the winter. The reindeer ate mainly grass in the summer, with lichens and grass forming the winter diet, and these animals seemed to have a higher nutritional status in the winter than did the other two species. The weights of the animals and of their rumen contents, the concentrations of rumen ammonia and volatile fatty acid, and the rates at which different dietary components were fermented are recorded. Rumen fermentation was low in winter and the diets were generally inadequate for the animals. A lack of nitrogen seemed to be a major factor. Some data on caecal contents are also given.


Modulation of cycloheximide-resistant memory by sympathomimetic agents. Amphetamine overcomes the amnesia caused by cycloheximide (CXM) provided it is administered closely following the learning trial. In day-old chickens with one trial passive avoidance learning, there is a short-term, labile memory existing for 90 min following training under the influence of CXM. Amphetamine has been shown to keep the memory at precisely the level exhibited by the labile, cycloheximide-resistant memory trace at the time of injection. Norepinephrine, methoxamine (an alpha adrenergic stimulant) and isoprenaline (a beta adrenergic stimulant) each mimic the amphetamine effect in CXM-pretreated chickens. That the action of amphetamine could be due to its release of norepinephrine is supported by the finding that it could be blocked by both alpha adrenergic (piperoxane) and beta adrenergic antagonists (propranolol). It has been suggested that this labile memory trace depends on the functioning of a sodium pump. Norepinephrine may be modulating memory formation by an action on the sodium pump since in preliminary biochemical assays norepinephrine stimulated the sodium pump (Na+/K+ ATPase) activity in chicken forebrain total homogenate.


Studies on the polymorphism of carbromal. Specimens of carbromal obtained by crystallization from various solvents were analyzed. After a 9-month storage period, the occurrence of three polymorphic forms (I, II and III) was ascertained. The metastable form III obtained by crystallization from dimethylformamide showed a reasonably high stability. Preliminary pharmacological tests revealed clear-cut differences in the therapeutic effect between a commercial specimen and the polymorphic modification III. The results presented here indicate the importance of polymorphism of carbromal for medicinal use.


Treatment of depression with tricyclic drugs--pharmacokinetic and pharmacodynamic aspects. A series of studies on the pharmacokinetic and pharmacodynamic properties of some tricyclic antidepressants is reviewed. During treatment with the same oral dose of these drugs, patients develop widely differing plasma levels. The importance of this variability for the clinical effects has been studied in detail for the monomethylated compound, nortriptyline. There is an association between side-effects and high plasma levels of this drug. In endogenously depressed patients, the relationship between plasma level and effect appears to be curvilinear. The tricyclic antidepressants differ in their capacity to inhibit transmitter uptake into noradrenaline- and serotonin neurons respectively. Nortriptyline is a preferential noradrenaline uptake inhibitor, while the dimethylated compound, chlorimipramine also has a profound influence on serotonin neurons. These differential effects are also reflected in changes in the levels of the transmitter metabolites in cerebrospinal fluid (CSF). The CSF studies have also supported the hypothesis of a biochemical heterogeneity of the depressive syndrome. The levels of the serotonin metabolite, 5-HIAA were bimodally distributed in CSF. In patients with a low level of 5-HIAA there was a significant correlation between the CSF metabolite level and the severity of the depression, and these patients also appeared to be more suicide-prone than those with higher 5-HIAA levels. These patients seemed to be less amenable to treatment with nortriptyline. The effect of chlorimipramine treatment in this subgroup of depressives is presently being explored.


The contribution of drug research to investigating the nature of endogenous depression. A relationship between brain monamines and endogenous depression is suggested by observations on the mode of action of drugs producing or alleviating depressive symptoms. For example, reserpine is capable of faithfully mimicking the clinical picture of endogenous depression, which may be related to monoamine depletion. On the other hand, antidepressant drugs, e.g. the monoamine oxidase inhibitors, the tricyclic antidepressants and the monoamine precursors appear to increase the availability of monoamines at postsynaptic receptor sites. The different classes of antidepressant agents in general appear to potentiate each other's actions, according to animal data and clinical observations. Studies on the mode of action of tricyclic antidepressants with different profiles and on monoamine precursors suggest that 5-hydroxytryptamine is primarily involved in the control of mood, and noradrenaline in psychomotor activity. Clincial investigations initiated by the drug studies have demonstrated changes in monoamine metabolism in endogenous depression. The available evidence thus suggests a causal relationship between disturbances in monoamine metabolism and depression.


Indications for long-term pharmacological treatment of schizophrenic syndromes. The practice of long term pharmacological treatment of schizophrenic syndromes has become widespread and seems to be currently recommended. The concept appears, however, to be poorly defined, and the assumptions underlying this therapeutic approach are scarcely discussed. In the present paper possible differences as concerns the hypotheses which might motivate a long term pharmacological treatment are schetched and their possible implications discussed. A short review of factors which might influence the decision for long term pharmacological treatment is also presented. Finally some recommendations for an appropriate management of long term psychopharmacological treatment are suggested.


Critical study of the use of long acting neuroleptics (depot neuroleptics) in France. Long acting neuroleptics (L.A.N.) represent 11% of the medical prescription of neuroleptics in France (about 40,000 patients in 1974). Some psychiatrists remain reluctant to prescribe long acting-neuroleptics and many problems related to their use are still solved empirically:1) relation between the posology of the standard Neuroleptic and the corresponding L.A.N. 2)the problem of dose-interval. 3) the necessary prescription of an parkinsonian. The superiority of N.A.P. over the Neuroleptic Standard has received no experimental confirmation in France, but the L.A.N. appear to us as an original therapy, the "pivot chemotherapy" around which psychotherapy and sociotherapy can be arranged without anarchical and ceaseless changes of neuroleptic compounds and of posology.


Unwanted effects of long-term medication in schizophrenia and depression. Medicine is an experimental science which proceeds by trial and error, and with pharmacotherapy doctors must continually review the drugs at their disposal for both effectiveness and adverse effects. These adverse effects must be assessed not only in relation to the therapeutic effect, but also, of course, in relation to the severity of the patient's illness and the likely prognosis in the absence of treatment. In this review I will select one or two side effects in each of the major group of drugs for consideration.


Malaria of the orang-utan (Pongo pygmaeus) in Borneo. The primary objective of this project was to study the life cycle and ecology of Plasmodium pitheci, a malaria parasite of the orang-utan. The field work was based on the orang-utan rehabilitation centre in the Sepilok Forest Reserve of eastern Sabah. Two visits were made to Sepilok, the first in February and March, 1972, and the second (by W.P.) in January 1974. On the first visit two species of "surrogate host" were taken to Sabah, i.e. chimpanzees and Aotus monkeys for experimental work. The arboreal habitat of the orang-utan in the dipterocarp forests of eastern Sabah is described. In the Sepilok Forest Reserve dwell gibbons and leaf-monkeys, in addition to a small population of semi-domesticated and wild, free-ranging orang-utans of various ages. Although numerous species of anopheline mosquitoes have been collected in eastern Sabah, longitudinal studies are not available. Anopheles balabacensis was caught both attracted to orang-utans and to man at Sepilok. This species which is the main vector of human malaria in the north of Borneo, is suspected also of transmitting orang-utan malaria in this part of Sabah. Repeated blood examinations have been made on a number of orang-utans in the centre since 1966 and a high prevalence of infection was recorded with Plasmodium pitheci. In 1966 10 out of 19 animals had demonstrable parasitaemia. Detailed case histories are presented to show the course of parasitaemia in several orang-utans. Infections of P. pitheci were found to run a very chronic course. During the 1972 expedition a second, previously undescribed malaria parasite of the orang-utan was discovered, and was named P. silvaticum. The new parasite was successfully transmitted both by blood inoculation and, later, by sporozoite inoculation, into splenectomized chimpanzees. Although both species of malaria parasite may cause transitory signs of illness, orang-utans in general appear to be little discomforted by the infection. The animals do however suffer from other infectious diseases such as amoebic and balantidial dysentery, and melioidosis is a serious natural hazard which may have accounted for several deaths of wild orang-utans. An unidentified, intraerythrocytic structure that appeared in the blood of one chimpanzee, which had been inoculated with blood from an orang-utan, may have contributed to its death. Detailed descriptions and illustrations of P. pitheci and P. silvaticum are given. All stages of the life cycle of P. silvaticum are known (the tissue stages having been described in the liver of a "surrogate host", the chimpanzee) but only the blood and sporogonic stages of P. pitheci have been seen. This species was not infective to a chimpanzee, although there is an earlier report of a transient infection in this host by other workers. In the blood both parasites showed a tertian periodicity. From the appearance of the tissue schizonts on the seventh day it was estimated that the complete pre-erythrocytic cycle of P. silvaticum in the chimpanzee would occupy 8 days. P...


Different susceptibilities to intracellular proteases of hemoglobin and hemoglobin-haptoglobin complex. The susceptibilities of hemoglobin and hemoglobin-haptoglobin complex to intracellular proteases differ significantly. Hemoglobin and hemoglobin-haptoglobin complex are degested in the regions of pH 5.5-2.5 and 4.0-2.5 respectively, having pH optima at pH 4.0 and 3.0 respectively, by intracellular proteases from rat and mouse liver or spleen. The difference in proteolytic susceptibility is found to be due to the different stabilities to acid among hemoglobin derivatives as evidenced by the measurements of their helical contents in acidic pH.


Mechanoelectrical transduction in hyaluronic acid salt solution is an entropy-driven process. An electrical potential develops between the ends of a column of hyaluronic salt solution displaced from a resting position by gentle pressure. A previous study demonstrated that such displacement changes the optical rotary dispersion properties of the salt, either increasing the rotation in the direction already shown by the salt before displacement or changing and increasing the rotation in the opposite direction, depending on the direction of the displacement. The present investigation demonstrates that the loss of bound water component across a membrane separating the solution and water is corelated with the extent of the column displacement. In addition, a return of the column to the position before displacement is correlated with a return of the water component across the membrane-but not at the same rate as the exodus. The data seem consistent with the hypothesis that the hyaluronic acid salt, when strained, adopts a less entropic configuration, releasing bound water and thus increasing the  entropy of water component. This change in the distribution of entropy is reversible; i.e., Eddington's "time's arrow" is reversible with respect to the water component of the solution.


Necroqizing enterocolitis with pneumatosis intestinalis in systemic lupus erythematosus and polyarteritis. Pneumatosis intestinalis was encountered in association with fatal necrotizing enterocolitis in systemic lupus erythematosus (SLE) and polyarteritis nodosa. The radiologic identification of mottled, bubbly, and linear collections of intramural intestinal gas distinguish this ominous complication from benign pneumatosis cystoides intestinalis. In the setting of intestinal vasculitis due to SLE or polyarteritis nodosa, these characteristic radiologic features indicate necrotizing enterocolitis. Since corticosteroids may mask clinical progression of the intestinal lesion, radiologic evaluation is essential in the overall management of the patient with intestinal vasculitis.


Biochemical properties of the prostaglandin/thromboxane synthetase of human blood platelets and comparison with the synthetase of bovine seminal vesicles. The enzyme system which  synthesizes prostaglandins and thromboxanes in extracts of washed human platelets has been characterized with respect to kinetic parameters, pH and cofactor dependence, and inhibitor potencies. Arachidonate and dihomo-gamma-linolenate were shown to be mutually competitive substrates, thus providing biochemical support for the assumption that both substrates are metabolized by the same cyclooxygenase, although they are ultimately metabolized to different patterns of products. Products of the synthetase of human leucocytes qualitatively resemble those obtained with human platelets. The prostaglandin synthetase of bovine seminal vesicles was studied under similar conditions, and kinetic parameters and inhibitor potencies were compared with those of platelet extracts.


Tardive dyskinesia and depressive illness. Tardive dyskinesia has been regarded as a long-term complication of neuroleptic administration to patients with the diagnosis of schizophrenia. However, nine of the first fourteen patients evaluated for an investigation of tardive dyskinesia met diagnostic criteria for depression. Neuroleptics produce blockade of post-synaptic dopaminergic receptors. Tardive dyskinesia occurs when neuroleptics are discontinued, and is regarded as a manifestation of super-sensitive post-synaptic dopaminergic receptors. Tardive dyskinesia occurs when neuroleptics are discontinued, and is regarded as a manifestation of super-sensitive post-synaptic dopaminergic receptors. Chronically decreased neurotransmission in the synapse of a patient with depression may contribute to the development of a super-sensitive receptor and could explain the high proportion of patients with depression seen in this sample of patients with tardive dyskinesia.


Weight-bearing deficiency of the 1st metatarsal ray. The authors have analysed a special disturbance of the statics and dynamics of the forefoot - deficient weight-bearing on the first metatarsal ray whilst walking. From the clinical point of view, the condition resulted in the development of a dorsal bunion and metatarsalgia. Forty-nine cases were treated and seven causative factors were discovered: Club foot, Paralysis, Congenital deformity, Fracture-dislocation of Lisfranc's joint, Sequelae of surgery for hallux valgus, Sequelae of subtaler arthrodesis, "Functional" abnormality.


Measurement of glycolytic rates in cell suspensions using a recording pH meter. A method for measuring continuously glycolytic rates in cell suspensions, using a recording pH meter, is described. Under the described conditions the method is very exact, sensitive and reproducible. The method can be applied to different cells and different conditions of assay calibrating in each case the pH range, cell concentration range and the ratio of delta protons to delta lactic acid.


Characterization and induction of aryl hydrocarbon (benzo(a)pyrene) hydroxylase in rabbit bone marrow. Benzo(a)pyrene hydroxylase activity was found in the bone marrow of control and 3MC-induced New Zealand white rabbits. This activity was localized in the microsomal fraction, was NADPH dependent and CO sensitive. The reaction was inhibited by 7,8-benzoflavone indicating that it was mediated by the 3MC-inducible form of cytochrome P-450. BP hydroxylase activity in rabbit bone marrow was located primarily in white cells, and was considerably higher than that previously reported for cultured human lymphocytes and monocytes. A possible role for the bone marrow mixed-function oxygenase in the production of hemopoietic toxicity is considered.


NADPH dependent lipid peroxidation of calcium bound microsomes. Rat liver microsomes prepared by a calcium aggregation method have been found capable of readily undergoing NADPH induced lipid peroxidation. Malonic dialdehyde production of calcium bound microsomes is equivalent to that attained by microsomes prepared by ultracentrifugation. In addition these calcium bound microsomes can be quickly removed from suspension by means of ultrafiltration.


Molecular complexes of cocaine, its active metabolites and some other stimulants with thiamine. Cocaine, its pharmacologically active metabolites, norcocaine benzoylnorecgonine, benzoylecgonine and other central nervous system stimulants e.g. dextrococaine, nicotine, caffeine and p-hydroxy norephedrine formed molecular complexes with thiamine. The possible implications of such an interaction are discussed.


[Immune status of indefinitely surviving rat renal allograft recipients after short course of ALS-treatment Detection of a serum blocking factor by allorosette formation inhibition test (author's transl)]. 53 LBNF1 kidneys were grafted into L-rats. 24 untreated recipients served as control and survived 16.1 +/- 1.7 days. 14 recipients were treated with 4 ml alloantiserum (ADS) each, and the other 15 animals with 4 ml ALS each. 9 and 10 of these 14 and 15 animals survived for more than 4 months. We performed GvH-reaction with spleen cells of these 19 animals. It showed normal cellular immune response. After splenectomy first donor specific skin was transplanted, 18 days later second skin of same origin (LBNF1) and 18' days after third party skin (LBufF1). The first grafts survived 13.1 +/- 1.9 days in the recipients of ADS treatment and 12.2 +/- 1.2 days in the recipients of ALS. Second skin grafts were rejected delayed in the former recipients as the first grafts, in the later more accelerated than the first grafts. The third grafts survived as the controls. Before and after skin grafting we could not detect lymphocytotoxin and hemagglutinin. The sera of animals with ADS therapy inhibited the spontaneous allorosette formation to 46.0 +/- 4.4% and of ALS therapy 37.7 +/- 9.2%. Our results suggest that after ALS treatment blocking antibodies were produced in the recipients and they cause the enhancement of kidney allograft.


[The Göttinger minipig as a laboratory animal (author's transl)]. Blood pictures, serumelectrolytes, acid-base- and bloodgas-values of the arterial blood were determined from two juvenile and one adulte collectives of minipigs (Gottingen strain), which were kept under SPF-conditions. The results were compared with the corresponding values of human blood and should be regarded as base- or orienting values for further investigations.


[Studies on the pH-dependence, inhibition and reactivation of angiotension II-amide splitting enzymes in human erythrocytes (author's transl)]. Aminopeptidase activity of three fractions of human erythrocytes (membranes free of hemoglobin; hemolysate free of membranes; enzyme protein fraction made free of hemoglobin by DEAE-cellulose) was measured by a NADH dependent optical test using asparaginyl1-angiotension II-amide as substrate. 1. From the enzyme protein fraction 6 subfractions were obtained by (NH4)2SO4 precipitation. By measuring enzyme kinetics at three different pH-values (pH 5,0; 7,0; 8,0) with and without addition of the effectors Na2EDTA and Ca++ the existence of 6 different enzymes could be demonstrated. 2. The aminopeptidase activity of the hemolysate made free of membranes could be inhibited by diisopropylfluorphosphate and p-chloromercuribenzoate at three different pH-values (pH 5,0; 6,5; 7,0; 8,0 and 6,5; 7,0; 8,0 respectively). 3. A reduction of enzymatic activity of 20% was found after incubation at 37degreesC for two hours.


Carbonic anhydrase inhibitor in trout plasma. A manometric assay has been constructed such that carbonic anhydrase dehydration activity can be determined utilizing intact erythrocytes. It was found that unwashed whole trout blood lacks any dehydration activity quite in contrast to whole rat blood. Removal of the plasma and replacement with physiological saline results in pronounced dehydration activity with inhibition restored by replacing the saline with the original plasma. An inhibitor residing in the plasma (probably a protein but not yet fully characterized) is capable of limiting in vivo dehydration activity. The inhibitor could work at the level of the enzyme per se or by inhibiting erythrocytic HCO3 influx, or both. The lack of erythrocytic dehydration activity presumably would alter CO2 excretion patterns; possible implications are discussed.


Intracellular pH in cold-blooded vertebrates as a function of body temperature. Intracellular pH (pHi) was measured in vivo in tissue of frogs (Rana catesbeiana) and turtles (Pseudemys scripta) using the DMO technique. Animals were permitted 3-8 days to come to a new steady-state body temperature (Tb) which ranged 5-32 degrees C. Least squares regression equation for pHi data are: frog blood, 8.184-0.0206 Tb; frog striated muscle, 7.275-0.0152 Tb; turtle blood, 8.092-0.0207Tb; turtle muscle, 7.421-0.0186 Tb; turtle heart, 7.452-0.0122 Tb; turtle liver, 7.753-0.0233 Tb; turtle esophageal smooth muscle, 7.513-0.0141 Tb. Only turtle cardiac muscle deltapHi/deltaT was significantly different from deltapH/deltaT of blood. Results have been interpreted in terms of protein charge state alterations; in the physiological pH range, histidine residues of proteins are the principal dissociable groups (HPr+ = H+ + Pr) affected by pHi and Tb changes. Constancy of protein charge state can be assessed by monitoring alpha imidazole, alphaIM = Pr/(HPr+ + Pr). A uniform pKIM of 6.85 (20degreesC) and a deltaHO of 7 kcal/mol are assumed in calculating alphaIM. Intracellular alphaIM is preserved in the tissues studied as body temperature changes. These results indicate that ectotherm acid-base balance, alphastat control, regulates not only extracellular blood proteins, but also intracellular compartment proteins in such a way as to preserve functions dependent upon protein net charge states.


Model studies of intracellular acid-base temperature responses in ectotherms. Measurements of intracellular pH (pHi) in air-breathing ectotherms have only been made in the steady state; these pHi indicate that protein charge state, measured as alpha imidazole (alphaIM), the fractional dissociation of protein histidine imidazole groups, is preserved when ectotherm tissues change temperature in vivo, with related changes in pHi and PCO2. In partial answer to the question of how such tissues are able to avoid disrupting transients to functions sensitive to protein charge states, model studies were carried out to assess the passive intracellular buffer system response to a combined change in body temperature and CO2 partial pressure as occurs in vivo in these species. The cell compartment was modeled as a closed volume of ternary buffer solution, containing protein imidazole (50 mM/1); phosphate (15 mM/1) and CO2-bicarbonate buffer components, permeable only to CO2 and permitted no change in buffer base. Excursions from a steady-state non-equilibrium pHi were computed to a step-change in temperature/PCO2. Computations for frog (Rana catesbeiana) striated muscle show that the calculated pHi response on the basis of estimated composition and concentration of cell buffer components, moves along the curve describing the steady-state temperature relationship. No transient away from steady-state alphaIM and carbon dioxide content need be postulated. Applications to turtle (Pseudemys scripta) striated muscle are also explored. These calculations show that ectotherm cells may be capable of responding without appreciable time for adaptation to intracellular acid-base state changes incurred by sudden alteration of body temperature in vivo, given the observed adjustments of blood PCO2 with temperature.


Intracellular buffering of heart and skeletal muscles during the onset of hypercapnia. Changes in the total CO2 content of tissues were determined in order to characterize variations in intracellular acid-base parameters during the onset of hypercapnia. Within two minutes after an increasement in the CO2 tension of the inspired air of rats, there were large increases in the intracellular bicarbonate concentrations of both cardiac and skeletal muscles. Greater changes occurred in the heart, and its intracellular pH remained near normal during the first hour of hypercapnia; whereas there was an intracellular acidosis in skeletal muscle. This greater capacity of the heart to buffer excess CO2 has been linked to an increased movement of bicarbonate ions into and/or hydrogen ions out of cardiac cells during hypercapnia (Lai et al., 1973c). Yet, the buffer capacity of the heart was not compromised by metabolic acidosis during which there was a greatly reduced extracellular bicarbonate ion concentration and a greatly increased extracellular hydrogen ion concentration. The intracellular pH of the cardiac ventricle was stable following the imposition of a noncarbonic acid load on normocapnic rats.


The effect of hepatectomy on the energy state and on acid-base variables of the rat brain. The influence of hepatectomy on cerebral energy metabolism was studied in rats in which an end-to-side portacaval anastomosis had been performed one week earlier. The hepatectomy gave rise to an exaggeration of the increase in tissue ammonia content resulting from the shunt. Three hours after the hepatectomy there was a fall in tissue glutamate content but no change in alpha-ketoglutarate. The energy state of the tissue, as evaluated from the concentrations of ATP, ADP, and AMP, was unchanged. There was a significant increase in cerebrospinal fluid pH but no change in intracellular pH.


Microcalorimetric measurements of heat production in human erythrocytes. Heat effect during methylene blue stimulation. The metabolic activity in human erythrocytes during stimulation with 10(-4) mol/l methylene blue has been studied by a microcalorimetric method. Simultaneous measurements were performed on cells from the same preparation suspended in different media. Mean values for the ratios between heat effect values were 7.1 +/- 1.0, 7.4 +/- 0.8, and 10.2 +/- 1.7 (+/- S.D.) for cells suspended in plasma, serum, and glucose phosphate buffer, respectively. All heat effect values were corrected to pH 7.40 using the correction factor found in the present work (0.4 % per 0.01 pH unit). The present calorimetric results are in qualitative agreement with previous reports of other investigators concerning the stimulating effect of methylene blue and the influence of pH on the pentose phosphate pathway.


Effect of the histamine H2-receptor antagonist, cimetidine, on gastric secretion and serum gastrin during insulin infusion in Man. Cimetidine infusion (100 mg h-1) reduced the acid secretory response to insulin infusion (0.03 units Kg-1h-1) when compared to paired control tests in 6 healthy volunteers. There was no significant difference between cimetidine and control tests in terms of pepsin output or serum gastrin concentrations. Cimetidine also reduced the acid secretory response when administered after 90 minutes of insulin had established a secretory response in extended tests in 3 additional volunteers. Cimetidine may have therapeutic potential in the peptic ulcer diathesis.


Effect of gastric hypersecretion on the canine duodenum. The neutralization of acid introduced into the duodenum has been found to be less intensive in patients with duodenal ulcer than in controls. The present work studied the possibility that chronic gastric hypersecretion injures the duodenal mucosa and thereby influences the neutralization system. Gastric hypersecretion was provoked for 3 weeks in 3 dogs by a daily injection of a gastrin preparation with prolonged effect. After a subcutaneous injection of this preparation given together with a test meal the acidity of both gastric and duodenal contents was found to increase significantly. After the 3 weeks of gastric hypersecretion the pancreatic bicarbonate response to exogenous secretin was unchanged, while the bicarbonate response to duodenal acidification was decreased from 2.03 mEq/30 min to 1.27 mEq/30 min (p less than 0.05), compatible with an impaired secretin release. Also the concentration of lactase, maltase, sucrase, and alkaline phosphatase in mucosal biopsies from the second part of the duodenum was significantly reduced (p less than 0.001). These results indicate that gastric hypersecretion causes mucosal damage in the duodenum and thereby reduces the release of secretin.


Enkephalin-induced depression of single neurons in brain areas with opiate receptors--antagonism by naloxone. Enkephalin, applied microiontophoretically, depressed spontaneous and glutamate-induced firing of single neurons in frontal cortex, caudate nucleus, and periaqueductal gray matter, where enkephalin and high concentrations of opiate receptors are found. Many of the depressions were blocked by the specific narcotic antagonist naloxone. The data are compatible with a neurotransmitter or neuromodulator role for this new brain pentapeptide.


Structural studies on des-pentapeptide (B26-30)-insulin. III. State of aggregation, tyrosyl environment, and peptide backbone conformation in solution. The three-dimensional structure of des-pentapeptide (B26--30)-insulin (DPI) in solution has been studied by several methods in view of the obvious fact that such knowledge would have much to bear on an understanding of the structure of the receptor-binding site of insulin. (1) The molecular weight of DPI has been studied by the gel filtration method. The results demonstrate that DPI exhibits no self-association behaviour but exists as monomers under the experimental conditions. This enables us to deduce that insulin binds its receptor in the monomeric form; its functional unit is the monomer. (2) The pH difference spectra, denaturation difference spectra, and temperature effect curves have been examined. The results indicate that all three tyrosyl side chains of DPI are unmasked and situated on the surface of the molecule. (3) The UV CD curves of DPI have also been studied. The far UV CD curve of DPI at pH 7.0 is similar to that of insulin, except that the negative value for [iota]220 decreases. This probably demonstrates that the peptide backbone conformation of DPI is very similar to that of insulin, except that it is slightly extended for the former. The near UV CD curve for DPI differs from that for insulin and has an extremum at 266nm as well as a low negative value of [iota]. The assignment of this extremum to Phe and/or -S-S- has been discussed. Taking into consideration the results given in the following papers, it may be concluded that the results of conformation research obtained support our previous working hypothesis that the hydrophobic surface in between the two monomers making up dimeric insulin constitutes a part of the receptor-binding site of insulin.


beta-Adrenergic receptor involvement in 6-hydroxydopamine-induced supersensitivity in rat cerebral cortex. The intraventricular administration of 6-hydroxydopamine, a procedure which destroys noradrenergic nerve terminals in the central nervous system, caused an increase in the density of beta-adrenergic receptors in rat cerebral cortex, without affecting their affinity for isoproterenol. The results suggest that changes in the density of adrenergic receptors are involved in 6-hydroxydopamine-induced supersensitivity at central noradrenergic synapses.


Structural studies on des-pentapeptide (B26-30)-insulin. IV. A preliminary investigation on the hydrophobic region by employing a fluorescence probe, 1-p-toluidinylnaphthalene-8-sulphonate. The fluorescnece porperties of 1,8-TNS in relation to the polarity and viscosity of the solvents have been studied and found to be just as useful as those of its positional isomer 2,6-TNS in the capacity of being a fluorescent probe. The properties of the hydrophobic region of insulin, des-pentapeptide (B26-30)- insulin (DPI), bovine plasma albumin, lysozyme, and ovalbumin have been investigated by employing this fluorescent probe. It has been shown that there is a small but definite hydrophobic region in DPI just as in insulin. This suggests that removal of the C-terminal pentapeptide does not impair seriously the hydrophobic structure related to the binding with insulin receptor. However, at physiologic pH, the hydrophobic region of DPI becomes more exposed than that of insulin and its conformation is less stable. As the pH is increased, the local conformation of the DPI molecule probably suffers some distortion, which damages the conformation of the hydrophobic region to a certain extent. In comparison with insulin, the DPI molecule is relatively loose and unstable.


Structural studies on des-pentapeptide (B26-30)-insulin. V. High resolution NMR studies. Preliminary studies have been made of the 250 MHz nuclear magnetic resonance spectra of both insulin and DPI. Differences have been found between DPI and insulin spectra, which indicate that the splitting off of the B-chain C-terminal pentapeptide from insulin has brought about local changes in the conformation of the protein molecule in solution. It seems that these conformational changes have little effect on the biological activity of the hormone. Many studies have revealed that for insulin molecules in solution, an equilibrium exists between aggregation and dissociation, their state of aggregation bearing a close relationship to the concentration as well as pH of the insulin solution. Changes in the concentration and pH value of DPI solutions do not significantly affect the NMR spectra. But as the concentration and pH of the solution are increased, the methyl regions for valine, leucine, and isoleucine and aromatic regions of the insulin spectra are broadened. All these show that zinc-free DPI molecules probably exist as monomers in solution.


Ovum aging and pH imbalance as a cause of chromosomal anomalies in the hamster. Using female hamsters mated in estrus, we have produced triploid embryos as manifestations of pregnancy wastage by combining delays of 3 to 4 hours in ferilization with exposure of the animals to hypoxia. Among the triploid embryos only XXX and XXY karotypes occurred, indicating derivation from XX-containing ova. These findings have relevance to human reproduction.


Choline administration: activation of tyrosine hydroxylase in dopaminergic neurons of rat brain. The administration of choline in doses previously shown to elevate brain acetylcholine concentrations also increases the activity of tyrosine hydroxylase in rat caudate nuclei. This response can be blocked by atropine, a muscarinic antagonist. These findings indicate that choline-induced increases in acetylcholine concentrations may be associated with parallel changes in the amount of the neurotransmitter released into synapses.


[Capillary sample and blood gas analysis. Technic and validity]. The authors have developed a technique of sampling and analysis of capillary blood which they describe here. Applied to 34 patients, it gives excellent correlations, both for PO2-PCO2 and pH. The advantages of capillary methods and their disadvantages are discussed.


Skin changes in graft-vs-host disease.

Skin changes in graft-vs-host disease. In this review of the clinical and histopathologic manifestations of the graft-vs-host reaction, the characteristic changes in the skin are given particular emphasis, since they are among the earliest and most obvious signs of this syndrome. The acute and chronic forms of graft-vs-host disease are distinguished, with notation of their different dermatologic presentations. The distinctive histopathologic and immunopathologic findings of the graft-vs-host reaction in the skin are presented. Finally, the possible pathogenetic mechanisms which produce the clinical picuture of graft-vs-host disease are discussed. Both T cells and B cells apparently are involved, as are macrophages, but what is primary and what is secondary in the reaction remains to be delineated, as do the respective contributions of donor and host cells.


The introduction of SI units and the standardisation of laboratory reports: recommendations of the South African Association of Clinical Biochemists. The change of SI units in laboratory reporting is occurring in South Africa. To assist this process and to ensure uniformity among laboratories, the Recommendations of the South African Association of Clinical Biochemists are presented. Controversial points are discussed and subunits selected. A standardised format of laboratory reports is suggested.


The effect of microaggregates in stored blood on canine pulmonary vascular resistance. Microaggregates have been implicated as a contributory cause of respiratory distress syndrome. Blood flow and resistance changes are compared between the right and left lungs following the selective administration of stored autologous heparinized blood into the left pulmonary artery. Eight dogs were bled 1,160 +/- 47 c.c. over 3 days. Following storage for 5 days the volume, number and size of microaggregates were measured by multichannel particle size analyzer and compared to 14-day-old human blood. Distribution of blood flow and resistance were calculated from data derived from injection of radioactively tagged microspheres into the right atrium and determination of cardiac output and pulmonary artery and wedge pressures. These measurements were made during a control period, following resuscitation from a 2 hour hemorrhagic shock period with the stored blood and 3 hours after resuscitation. Despite the administration of stored blood with massive amounts of microaggregates into the left pulmonary artery, the distribution of blood flow immediately and 3 hours following resuscitation was the same as in the control period. The pulmonary vascular resistance increased across both lungs but the increase was the same on the left as the right. These data suggest that microaggregates may not be important in the development of the respiratory distress syndrome.


Purification and properties of human factor IXa. Human factor IXa was purified 5,000-fold from serum by ion exchange chromatography. The preparation was free from other clotting factors. Both pH sensitivity and heat stability of purified factor IXa appeared to be different from those of factor IX in the plasma. The molecular weight of human factor IXa is 80,000 as estimated from gel-filtration experiments. Modification of seryl or histidyl side chains abolished the activity of factor IXa.


Reactivity of fibrinogen crosslinking sites in the absence of thrombin. The reactivity of fibrinogen crosslinking sites with thrombin-free, preactivated factor XIII (F. XIIIa) was investigated under different conditions such as increased ionic strength, presence of urea, protamine sulfate (PS) or of varying concentrations of monodansylcadaverine (MDC). Crosslinking and incorporation of MDC into fibrinogen or fibrin gamma- and alpha-chains were evaluated by SDS-polyacrylamide gel electrophoresis. According to our results, rates of crosslinking of, and of MDC incorporation into, both gamma- and alpha-chains of fibrinogen were low under physiological conditions; they were not significantly influenced by the presence of either 1.0 M NaCl or 1.0 M urea. In contrast, 0.01% PS precipitated fibrinogen, and, simultaneously, significantly increased the rates of crosslinking and of MDC incorporation into both gamma- and alpha-chains. MDC, at concentrations above approximately 6 mM, also precipitated fibrinogen, and, up to a concentration of about 9 mM, markedly enhanced the reactivity of acceptor crosslinking sites. Our results suggest that solubility of fibrinogen and the conformational arrangement of its subunit chains are closely interdependent; the reactivity of crosslinking sites with F. XIIIa seems to be a function of this conformational state.


Aggregation of platelets and inert particles induced by thrombin. Thrombin-induced platelet aggregation and release were investigated in washed platelet suspensions and in suspensions of inert particles in order to evaluate the role of fibrinogen-fibrin transformation in aggregometer tracings. Thrombin (0.25-2.0 U/ml) produced two waves of light transmission increase (LTI) in both platelet and inert particle suspensions containing fibrinogen, and concomittantly aggregates were observed under phase microscopy. Without fibrinogen, thrombin induced rapid release of platelet ADP but failed to cause second wave of LTI. The kinetics of LTI in platelet and inert particle systems were related to both thrombin and fibrinogen concentrations. A rapid second wave of LTI could be produced by direct interaction of thrombin-treated platelets or inert particles with polymerizing fibrin, and was inhibited by sodium sulfite and low pH of 5.1 which prevent fibrin monomer polymerization. No fibrin strands were noted in platelet aggregates fixed at the completion of the second wave of LTI. Apyrase and PGE1 inhibited the rate of first but not that of second wave LTI. The results suggest that the release of platelet ADP induced by thrombin primarily affects the first phase aggregation, and the second phase may result from interaction of thrombin-exposed platelets and polymerizing fibrin. Thus, the blood coagulation mechanism may be directly involved in platelet aggregation.


Human immunity to rat antigens. II. Immune responses in dialysis patients. The immune status of 35 patients with renal failure was studied shortly after they had commenced treatment by chronic haemodialysis to see if a group with poor immunological responses could be identified. Of 27 patients who were unimmunised to start with, only two developed lymphocytoxic antibodies after a year of treatment. The routine immunological tests that were carried out on these patients failed to predict which of them would develop antibodies, and the values that were obtained for the group of cytotoxic negative patients were no different from those obtained for the two patients who became immunised and six others who had previously rejected a kidney transplant. By using a new test that measured cellular immunity to rat antigens, eight patients could be identified as "poor responders." These individuals had in addition failed to develop cytotoxic antibodies during dialysis, had serum IgG levels that were significantly lower than normal, and were uniformly unresponsive to purified protein derivative. This group of patients might be a favoruable one to transplant.


Studies on a systemic xenogeneic graft-versus-host reaction model in newborn mice. A xenogeneic graft-versus-host reaction model is described, evoked in neonatal mice by injection of rat spleen cells, and registered as splenomegaly at day 7. The following arguments are given as support for the idea that the reaction is indeed a graft-versus-host reaction: only living rat cells can give the reaction; rat cells treated with antilymphocyte serum cannot do so. The reaction is of almost the same strength in mice which have thymus dysplasia and are probably incapable of mounting a host-versus-graft reaction. Pretreatment of the grafted cells with mitomycin C, which abolishes the cells' capacity for DNA synthesis and proliferation, also eliminates their capacity to cause splenomegaly. This is probably because the grafted cell clone, reactive to mouse antigens, is small and has to be expended in order to be effective. Dividing rat cells have been demonstrated by chromosome studies in the enlarged mouse spleens 2--6 days after grafting.


Correlation of graft-versus-host mortality and positive CML assay in the mouse. GVH mortality was encountered in each of six parental-F1 hybrid combinations with antigenic disparity sufficient to cause strong positive CML. Mortality was encountered in only one of nine combinations in which CML is negative (or weak). The CML assay may thus be useful, but is not perfect, in prediction of GVH mortality. Of the eight CML-negative, GVH nonlethal combinations, three were MLC positive and also activated donor T-cell proliferation in vivo.


Properties of 3',5'-cyclic-AMP phosphodiesterase from Paragonimus africanus metacercariae. 3',5'-Cyclic-AMP 5'-nucleotidohydrolase (cAMP phosphodiesterase, EC 3.1.4.17) was partial purified from metacercariae of Paragonimus africanus. The enzyme activity absolutely depends on Mg2 or Mn2+. The pH-optimum of the cAMP phosphidiesterase was found at pH 8.0. The Michaelis constant for cAMP was determined to be 5 X 10(-6) M. Papaverine deoxyadenosine, theophylline and adenosine were found to be competitive inhibitors of the enzyme activity. The inhibitor constants were calculated to be 13 X 10(-6)M, 25 X 10(-5)M, and 35 X 10(-5)M, and 85 X 10(-5)M,respectively. The molecular weight of the cAMP phosphodiesterase was estimated to be about 40 000 by gel filtration.


[Hydrogen ion activity in the cell].

[Hydrogen ion activity in the cell]. Literature data and results of our experiments evidence for a heterogenous hydrogen distribution in cells. Intracellular pH should be regarded as a mean activity of hydrogen ions which is the sum of activities in different phases of a cell. Intracellular pH value does not depend on the transmembrane action potential difference, and is resistant to respiratory and metabolic disorders of acid-base equilibrium in the body. It also slightly changes with changing the electrolyte composition and pH of the medium and is not influenced by metabolic inhibitors. A low hydrogen activity in the cell has a certain functional significance. The pH stability is ensured by a number of regulatory mechanism: the buffer properties of the protoplasm itself, and the active hydrogen transport into the medium. Hydrogen released from cells is supposed to be connected with functioning of a specific respiratory chain of superficial protoplasmic membranes.


In situ dissolution of ureteral calculus. An obstructing uric acid calculus was successfully managed by dissolution in situ. The methods used are described in detail. Perhaps not applicable in all cases, the ease of the procedure makes it worth considering especially in patients at high risk for open operative intervention.


[Activity and variability of aminopeptidases and gamma-glutamyl transpeptidase of the cutaneous mucous membrane in the cow's rumen]. The authors studied the activity, chromatographic and electrophoretic distribution of leucylarylamidase, cystinamino peptidase, and gamma-glutamyl transpeptidase of the cytoplasmatic fraction of cow's rumen mucous membrane homogenate. The results of comparative analysis draw attention to the existence of a certain number of the molecular forms of the enzymes studied, to the activation of leucylarylamidase by Co2+, cystinamino peptidase by Co2+ and Ca2+. The possible functions of the amino peptidases and transpeptidase of glutamic acid in the metabolism of nitrogen compounds of the type of peptides, amino acids, and their amides, are discussed in the study.


[Effectiveness of various barbiturates in chickens of different ages]. Phenobarbital, allobarbital, and pentobarbital in the doses of 40 and 80 mg per 1 kg body mass were applied intramuscularly to groups of the cockerels of the WL breed at the age of two days, one, two, and six weeks (each group had ten birds) and to eight-week-old WL cockerels in groups of five birds. The methods of clinical observation and repeated determination of the response of the animals to sonic stimuli and contact stimuli, and the evaluation of the quality of some reflexes (particularly the spontaneous position of the body and the correction of the lateral position) were used for the study of suppression evoked by the applied barbiturates. Sleep occurred first after the application of pentobarbital (sooner in younger age groups). The latest beginning of sleep was observed after phenobarbital; in the latter case, sleep was hard to evaluate because it was not very deep. The time of sleep had the longest duration after allobarbital (only in the eight-week-old sleep was longer after pentobarbital), and the shortest after phenobarbital; there were also differences in the duration of sleep between the age groups of birds. The pentobarbital dose of 80 mg kg-1 of body mass killed birds in the three youngest age groups )in the two-day-old it killed nine of ten birds, in the one-week-old eight of ten birds, and in the two-week-old two of ten birds). The differences in the effectiveness of the applied barbiturates in two doses per unit of body mass were related to the age of the animals, even in the cases of the shortest age intervals between individual groups. Very high interspecies differences ensue from a comparison with the doses of these barbiturates usually applied to man.


Microsomal styrene mono-oxygenase and styrene epoxide hydrase activities in rats. 1. Styrene epoxide formation and styrene epoxide hydration have been studied in liver, lung, kidney, heart, spleen and brain of female and male rats. 2. Styrene epoxide formation is NADPH-dependent although it is enhanced when NADH is added together with NADP. This enzymic activity is inhibited by metyrapone and SKF 525-A but not by the effective inhibitors of epoxide hydrase, 1,2-epoxy-3,3,3-trichloropropene and cyclohexene oxide. 3. Known inducers of liver microsomal mono-oxygenases show a different activity on the two enzymes. Phenobarbital increases both formation and hydration of styrene epoxide; and carbamazepine increase the hydration but not the formation of styrene epoxide; a steroid contraceptive combination (lynestrenol+ mestranol) increases styrene epoxide formation while it inhibits epoxide hydrase; 3-methylcholanthrene does not affect either of the activities.


[Absorption, distribution and excretion of (quinuclidinyl-3 methyl)-10-phenothiazine (LM 209), a new antihistamine]. 1. The absorption, distribution and elimination of 10-(3-quinuclidinylmethyl)-phenothiazine (LM 209) were studied in the rat and dog after oral or intravenous administration of the 35S-labelled molecule. 2. Determinations of radioactivity in the rat and dog confirmed absorption and showed that the blood levels increase in proportion to the dose but remain very low compared with tissue concentrations. These were highest in the liver and lung and persisted at high level for more than 6 h after dosage. 3. Excretion of radioactivity was by the urinary and faecal routes. The high level of radioactivity in faeces resulted mainly from biliary excretion which was accompanied by much entero-hepatic circulation. 4. The prolonged retention of LM 209, due to binding to blood and tissue proteins and to entero-hepatic circulation, did not lead to noticeable accumulation of the drug after repeated doses. 5. The difference in the intracellular distribution of LM 209 and phenothiazine shows the importance of the quinuclidine N-subsitution on the phenothiazine ring, and results in a greater affinity to sub-cellular particulate fractions (nuclei, mitochondria, microsomes).


Metronidazole (Flagyl): degradation by the intestinal flora. 1. Metronidazole (Flagyl) is reduced exponentially by the contents of the rat caecum in the absence of oxygen. The rate of removal is highest at pH 7 and 37 degrees. 2. Reduction of the drug is inhibited by boiling of the caecal contents, CHCl3, Cu2+, Ag+, azodicarboxylic acid bis-dimethylamide, p-chloromercuric benzoate, N-ethylmaleimide and 4,4,4-trifluoro-1,2-thienyl-1,3-butanedione. Nitrate, ethanol (3%), CO, phenol and amytal did not affect the rate of reduction. 3. It is concluded that iron-sulphur systems are involved in degradation of the drug.


Mechanism of 2-naphthylamine oxidation catalysed by pig liver microsomes. 1. In pig liver microsomes 2-naphthylamine-dependent NADPH oxidation, oxygen reduction, and hydroxylamine formation are linear with time for several minutes. A sharp increase in NADPH oxidation and oxygen uptake then coincides with an abrupt loss of hydroxylamine from the medium. 2. The initial rate of 2-naphthylamine N-oxidation correlates with the microsomal concentration of mixed-function amine oxidase and the extent of linear accumulation of hydroxylamine is dependent on microsomal NADPH-cytochrome c reductase activity and concentration of lipid (microsomes). 3. Antisera to NADPH-cytochrome c reductase markedly decreased hydroxylamine accumulation during incubation but had no effect on the rate of 2-naphthylamine N-oxidation. 4. A system duplicating all of the kinetic properties of the microsomal 2-naphthylamine oxidase was constructed with two purified flavoproteins, (mixed-function amine oxidase and NADPH-cytochrome c reductase) and a lipid phase (erythrocyte ghosts or synthetic lecithin liposomes). 5. By independently varying the concentrations of each component in the reconstituted system, the contribution of each to the observed kinetics was defined. 6. In addition to the initial N-oxidation of 2-naphthylamine, at least six other reactions contribute to the kinetic patterns of 2-naphthylamine oxidation catalysed by the reconstituted system.


Production physiology and properties of a novel fungal fibrinolytic enzyme. A potent extracellular fibrinolytic enzyme was obtained from cultures of the imperfect fungus Fusarium semitectum under certain growth conditions. Nitrate addition to cultures increased enzyme production. The enzyme showed a versatile proteolytic activity against several protein substrates including casein, gelatin, haemoglobin, bovine serum albumin, and fibrin from both buffalo and human sources. Optimal fibrinolysis occurred at pH values around 7.0. The fibrinolytic activity exhibited marked heat stability in enzyme samples heated at 60 degrees C, and retained more than 40% of its activity in samples heated to 100 degrees C for 10 min. Fibrinolysis proceeded optimally in the temperature range between 50--60 degrees C. Copper ions significantly activated the enzyme. Other biochemical properties are also reported.


[Cleavage of alpha-L-arabinofuranoside, beta-D-glucopyranoside and beta-cellobioside of 4-nitrophenol by enzymes of various fungi - a contribution to increase the selectivity of tumor therapy]. To carry out long-term experiments as part of a therapy concept of malignant tumours using inactive transport forms of cancerostatic substances and their specific cleavage in the acidic pH region of the tumours by application of extraneous enzymes, we require enzymes with similar catalytic and pharmacokinetic properties which differ from each other in immunological respect. In the search for such enzymes, the alpha-L-arabinofuranosidases from 12 different fungi, among them 9 basidiomycetes, were studied. The enzymes mentioned were demonstrable in all fungi. Optimum pH values ranged between 2.5 and 5.5. The Km values for the cleavage of alpha-L-arabinofuranoside were, in most cases, 0.5 to 1.8 moles-liter-1-10(-3). With regard to pH dependence, the alpha-L-arabinofuranosidases of most of the fungi investigated proved adequate for the long-term trials envisaged. 4-nitrophenyl-beta-D-glucopyranoside and -beta-cellobioside were also cleaved by enzyme preparations of all the 11 fungi investigated. The beta-D-glucopyranosidases showed a less favourable pH dependence than the alpha-L-arabinofuranosidases. The cleavage of 4-nitrophenyl-beta-cellobioside, on the contrary, showed mostly a comparatively favourable pH dependence. On the basis of the coinciding optimal pH values and the occurrence of 4-nitrophenyl-beta-D-glucopyranoside as an intermediate product in the cleavage of the corresponding cellobioside, we assume that both substrates are cleaved by beta-glucosidase. Because the occurrence of the glucoside during the cleavage of cellobioside is undesirable for the therapeutic trial, a method is proposed for selection of an appropriate cellobioside splitting enzyme basing on the present studies and the relevant literature.


[On the age dependence of the intracellular proteolysis (author's transl)]. We report the age dependent changes of the proteolytic capacity of the rat liver at pH 3.0 and pH 6.0. The total proteolytic activity increases during the whole cycle. During the weanling period the specific activity (mug substrate split x min-1 X mg liver protein-1) rises up to values about 30% higher than those of the remaining lifetime. We found the specific activity in old male animals (18 months) to be lower than in younger ones (5 months). These findings are correct for the liver homogenate as well as for the cell fractions.


[Study of resistance to physical stress in pregnant women: influence of standardized work on cardiovascular system, ventilation, gaseous interchange, carbohydrate metabolism and acid-base balance (author's transl)]. 10 women in the 12th week of pregnancy were tested with 50 and 60 watts on the bicycle ergometer; 16, in the 38th week of pregnancy and 12 weeks after delivery. Heart rate, blood pressure, O2 intake, CO2 elimination, respiration rate, respiratory volume per minute, lactate, pyruvate, glucose, pCO2, base excess and pH were measured at rest and under stress. Already in the 12th week of pregnancy (SSW), O2 intake and calorie consumption for the same work was significantly higher than in the nonpregnant subjects. Heart rate and blood pressure behaved the same during and outside of pregnancy. In the 38th week of pregnancy, the steady-state was reached later. O2 intake and calorie consumption were significantly increased. In pregnant women, the glucose level decreased about 11 mg% under stress while it remained constant in nonpregnant subjects. In pregnant women, lactate production is significantly higher (26%) during work. Metabolic acidosis cannot be compensated by respiration. The base deficit was significantly larger; pH was reduced. In pregnant women, physical stress produces increased respiration, CO2 consumption and calorie consumption are increased, CO2 deficit is greater and metabolic acidosis develops.


[Relationship between thermal treatments of milk and molecular hysteresis of the milk protein system (author's transl)]. The potentiometric titration curve of milk does not show an equilibrium curve but a hysteresis loop between pH 6.2 und pH 4.8. Hysteresis means thermodynamic metastability and cooperative changes within a structural domain. The structural domain involved in these changes is the casein micelle. Cooperative conformation changes and thermodynamic metastability appear on the resolution of the casein micelle caused by the action of protons. The charge condition of the polypeptide chains is not synchron with the charge supply. The lag depends on the thermal treatment. Therefore the milk protein system can serve as a memory for physical datas.


[Different deoxyribonuclease-activities in bull seminal plasma (author's transl)]. By means of the in situ assay of deoxyribonucleases in DNA-containing polyacrylamide gels after separation by micro-disc-electrophoresis different deoxyribonucleases are detectable in bull seminal plasma. There are two groups of acid deoxyribonuclease-activities with a pH optimum at pH 5.0, one with a pH optimum at pH 7.4 and an additional one with a pH optimum at pH 8.5.


[Effect of pregnancy on the functional state of the upper respiratory tracts]. The author studied the condition of various components responsible for the protective function of the upper respiratory tract mucous membrane as well as the olfactory sensibility in 439 pregnant women. She found certain regularities in the change of the motor, absorbing and secretory activity of the mucous membrane and olfactory sensibility, the calorific effect and the active reaction of the secrete being less characteristic. She emphasizes that the above changes cause the development of respiratory disorders in women during the period of pregnancy.