Bilirubin acidity. Titrimetric and 13C NMR studies. Acidimetric titration of bilirubin IX-alpha, dissolved in excess aqueous sodium hydroxide, showed that two protons are dissociated with pK values well below 7 and that one or several additional acidic groups titrate with pK around 12.9. Precipitation of the nearly insoluble acid precluded determination of the two lower pK values by titration in aqueous solution. In dimethyl sulfoxide solution, four acidic protons were demonstrated, titrating two by two without precipitation. 13C NMR spectra of bilirubin IX-alpha were recorded and complete assignments were made by comparison with the spectra of bilirubin XIII-alpha and mesobilirubin etc. Such spectra, recorded after addition of 2 and 4 mol of base per mol of bilirubin IX-alpha, showed that both carboxyl groups are titrated by the first 2 mol of base, and both lactams by the following 2 mol of base. Cotitrations of bilirubin IX-alpha with other acids, o- and m-hydroxybenzoic acid and 2-pyridone, were used to determine relative pK values in dimethyl sulfoxide solution, and pK values for the four acidic protons of bilirubin IX-alpha in aqueous solution were calculated from the Born equation. Both carboxyl groups exhibited pK = 4.4, and both lactams pK = 13.0, in good agreement with values expected from the chemical structure of the bilirubin molecule. The implications of these findings for understanding the mechanism of bilirubin neurotoxicity are discussed.


The effect of duodenal acidification on plasma secretin and gastrin and pancreatic bicarbonate secretion in man. Plasma secretin, plasma gastrin and pancreatic bicarbonate output were measured in three healthy youths before and after a 10 min period of duodenal infusion of 50, 75 and 100 ml 100 mmol/1 HCl. Plasma secretin rose to a shortlived peak within 10 min, whereas plasma gastrin fell gradually to values significantly below the basal level 60 min after the start of duodenal acidification. Pancreatic bicarbonate output showed a more sustained increase following duodenal acidification. Significant positive correlations were obtained between plasma secretin and infused dose of HCl, between pancreatic bicarbonate output and infused dose of HCl and between plasma secretin and pancreatic bicarbonate output. The calculated maximal pancreatic bicarbonate output (Vmax) of 30.6 mEq/h and the calculated dose of secretin to elicit half maximal pancreatic bicarbonate output (S50) of 0.2 CU/kg-h following duodenal acidification were comparable to that seen after intravenous infusion of secretin. No significant correlation was found between plasma secretin and plasma gastrin. It is suggested that the pancreatic stimulation subsequent to duodenal acidification is mainly effected by release of secretin, and that the fall in plasma gastrin may be caused by a HCl-induced inhibition of gastrin release from the duodenum.


Increased duodenal alkali load associated with the interdigestive myoelectric complex. In six healthy volunteers the interdigestive motor activity and the secretory pattern were recorded in the duodenum by open tip catheters and intraluminal titration, respectively. The duodenal part of the interdigestive myoelectric complex (IDMEC) was regularly associated with a significantly increased alkali load to the duodenum amounting to 2.4 +/- 0.4 mmol per IDMEC. Thus, the intestinal "housekeeper" function of the IDMEC may be brought about by a coupled action of propagated motility and flushing secretion.


Male hypospadias, 625 cases, associated malformations and possible etiological factors. Records from 625 patients with hypospadias have been reviewed, with reference to associated malformations. Cryptorchidism was found to be the most common associated malformation and was present in 6% of cases with hypospadias. The highest incidence of cryptorchidism was found in the more severe forms of hypospadias. Other concomitant genital malformations, such as bifid scrotum, hypoplasia of penis and remnants of the Müllerian system showed the same pattern. The recorded incidence of bifid scrotum and hypoplasia of the penis was 4% and 8% respectively. A high incidence of abnormalities in the lower urinary tract was found; 50% of 84 patients investigated. The hypothesis of hypospadias being a result of testicular hormone insufficiency is discussed.


Therapeutical significance of clopimozide in the treatment of chronic psychotic patients. This report, which concerns both an open and a double-blind study, describes the activity profile and optimum daily dose of clopimozide (R 29 764) investigated in 40 chronic psychotic patients. The results of the open study indicated that clopimozide represents an equal, if not superior, choice versus the other neuroleptics which the patients had been receiving before the open study. Patients sought more contact with those surrounding them, were less preoccupied with their delusions and hallucinations, and showed a better adapted social behaviour. However, these results were not confirmed by the data from the double-blind study-showing that clopimozide was less superior to the placebo than expected on the basis of the open trial. Two hypotheses are advanced to explain this discrepancy: first, the difference in investigational method and second, possible over-dosage of the drug at an average optimum daily dose of 13.95 mg.


Effects of some neuroleptic drugs on aggressive behavior in isolated mice. Effects of some neuroleptic drugs on aggressive behavior in isolated mice. Acta Physiol. Pol. 1979, 30 (2): 295--298. Albino-Swiss male mice were isolated for 28 days and their isolation-induced aggressive behavior was tested after housing them in groups. The effects of the following neuroleptics were investigated: spiroperidol (0.2 mg/kg i.p.), pimozide (1 and 2 mg/kg i.p.), and clozapine (2 and 5 mg/kg i.p.). Among the drugs examined the strongest inhibitory action on the isolation-induced aggressive behavior was inserted by spiroperidol. Primozide and closapine had weaker, but significant anti-aggressive effect.


Effect of synthetic prostaglandin PGF2 alpha on the volume, acidity, and proteolytic activity of the abomasum juice in sheep. Effect of synthetic prostaglandin PGF2 alpha on the volume acidity, and proteolytic activity of the abomasum juice in sheep. Act Physiol. Pol., 1979, 30 (2): 299--304. The investigations were carried out in 3 male sheep on the effect of Estrumate (a synthetic analogue of PGF2 alpha) on the secretion and composition of juice from the "small" abomasum. After intramuscular injection of optimum doses of the preparation (3.0--4.0 micrograms/kg of body weight) it was observed that the volume of the juice, its free HCl content, the total acidity the specific activity (expressed in Anson milliunits/ml) and the total activity (specific activity X volume of juice secreted in a given sample) increased significantly (p less than 0.01). Thus, the synthetic prostaglandin PGF2 alpha stimulates the secretory activity of abomasum glands in sheep.


Vasospastic phenomena in patients treated with beta-adrenoceptor blocking agents. Twenty-one patients developed Raynaud's phenomenon during treatment with beta-adrenoceptor blocking agents. The vasospastic symptoms were obviously related to the treatment, but their pathogenesis is still controversial. A decrease in cardiac output might explain the phenomenon. According to our very preliminary data an alpha-adrenergic dominance caused by a direct effect on the peripheral circulation seems more probable. Vasospastic symptoms may arise after treatment with both cardioselective and non-selective beta blocking agents. Cautious prescription of beta blocking drugs to patients with preexisting peripheral vascular disease is recommended.


Impairment of glucose metabolism during treatment with antihypertensive drugs. A reversible deterioration of the oral glucose tolerance has been reported in subjects with initially impaired glucose tolerance when starting to take oral diuretics. This does not seem to be the case in subjects with an initially unimpaired glucose tolerance. A deterioration in the diabetic state is commonly seen when diuretics are given to subjects with clinical diabetes. Our knowledge about the effect of beta-blockers on the glucose tolerance is limited. As for diuretics there seems to be an overrepresentation of diabetics among subjects taking beta-blockers. This overrepresentation can probably be explained by an association between diabetes and disturbances in which diuretics and beta-blockers are commonly used such as arterial hypertension and ischaemic heart disease.


Elevated serum uric acid levels during treatment with antihypertensive drugs. An increase in serum uric acid levels has been observed both during treatment with diuretics and beta-blockers. The increase during treatment with beta-blockers seems in most cases to be of no clinical importance and is not a reason for serum uric acid determinations of subjects who have no symptoms indicating hyperuricaemia. During treatment with diuretics in those doses which have been commonly used previously, e.g. hydrochlorothiazide or chlorthalidone greater than or equal to 50 mg/d, an increase on an average of about 90 mumol/l is to be expected. When low-dose diuretics are used (e.g. hydrochlorothiazide or chlorthalidone less than or equal to 25 mg/d) about half of this increase might be anticipated. It is recommended that serum uric acid levels should be studied after starting antihypertensive treatment with diuretics.


The rationale of treating high blood pressure in the elderly. The elderly are at risk from stroke and cardiac complications of hypertension. There is strong circumstantial evidence to indicate that these risks may be reduced by hypotensive therapy. However, the decision to treat must be taken after careful appraisal of the patient and, because the risks of therapy are higher in this age group, the choice of drugs should be restricted.


Irritant actions of unphysiological pH values. A controlled procedure to test for topical irritancy. The abdominal skin of juvenile white mice was used. Topical application was accomplished by intracutaneous injection. The solutions tested were thoroughly standardized. By using a special buffer system, a mixture of histidine glutamate and lysine glutamate, each pH value could be tested with the same buffer capacity. The pH values varied from pH 3 to pH 11, the solutions being always iso-osmolalic with plasma. Two criteria were used to judge the irritancy: (a) the edematous reaction for the first 6 h and (b) the macroscopic aspect after 24 h. A very special procedure enabled us to obtain objective numerical values for criterion (a). The results disclose that irritation becomes manifest at pH 4 and pH 10, becomes clear-cut with pH 3 and even more so with pH 11, and depends strongly on the buffer capacity employed. With two substances-amidosulfuric acid and (tri) sodium phosphate--it was exemplified how the procedure could be used to routinely screen for topical irritancy in an informative, inexpensive and decent manner.


Reactivity of isolated canine bronchus and pulmonary blood vessels to autonomic, autacoid agents and antigen. Adult dogs were sensitized to horse plasma. Reactivity of isolated bronchus and pulmonary blood vessels to antigen and some selected autonomic and autacoid agents were studied. Pulmonary veins contracted to bradykinin, 5-HT, PGF2alpha, PGE2, histamine, carbachol and antigen (Schultz-Dale reaction). Pulmonary arterial strips contracted to 5-HT and histamine, but only weakly to horse plasma. Bronchial strips contracted to carbachol, 5-HT, histamine and horse plasma, relaxed to isoprenaline, PGE1 and PGE2. Subsequent antigen challenge produced 'desensitization'. Allowing the tissues to 'rest' for 1 and 2 h resulted in partial 'recovery' of the anaphylactic response. This investigation suggests that the contractions of sensitized pulmonary vein and bronchus to specific antigen may contribute to the patho-physiology of pulmonary hypersensitivity in dogs.


A critique of the U.S. standard for industrial exposure to sodium hydroxide aerosols. Published studies of the toxicity of sodium hydroxide aerosols are few. These studies were generally marred by inadequate characterization of particle size and chemical compositon and of the ambient humidity. Because NaOH aerosols can readily undergo reaction with carbon dioxide to form sodium carbonate, a much less alkaline (and less hygroscopic) compound, these shortcomings may warrant a reconsideration of the NaOH standard and the consideration of a Na2CO3 standard.


Intravenous prophylhexedrine (Benzedrex®) abuse and sudden death. Propylhexedrine was implicated in 15 deaths investigated by the Dallas County Medical Examiner since 1973. Twelve of the deaths were attributable to intravenous abuse of the contents of the Benzedrex® inhaler. Each death could be defined as sudden. Pulmonary edema, foreign body granulomas, fibrosis and evidence of pulmonary hypertension were frequent postmortem findings. Right ventricular hypertrophy was present in nine of the 12 subjects who died of intravenous propylhexedrine abuse. Two homicides and one suicide were propylhexedrine-related. Intravenous propylhexedrine abuse should be considered in the differential diagnosis of right ventricular hypertrophy and/or pulmonary hypertension, and it should be suspected in cases of sudden death involving young adults displaying evidence of intravenous drug abuse.


The relationship of heart rate patterns and tissue pH in the human fetus. The relationship between different FHR patterns and fetal tissue pH in 68 high-risk gravidas in labor was analyzed. A tissue pH electrode was placed in the fetal scalp and tissue pH recorded on a fetal monitor every 15 seconds along with uterine contractions and continuous fetal heart rate. The tissue pH changes correlated with the FHR patterns in a manner consistent with current concepts of fetal stress. Trend monitoring of fetal tissue pH in labor may prove useful in the management of high-risk patients in labor.


Fetal heart rate variability: an approach to automated assessment. Three hundred seventy-five hours of fetal heart rate (FHR) data derived from the direct fetal electrocardiogram (ECG) were studied. This data had been stored on magnetic tape from 83 intrapartum patients. By means of a computerized technique, the FHR variability was assessed quantitatively. The degree of variability was then related to: (1) state of labor, (2) fetal scalp pH values, and (3) the 1-minute Apgar score. FHR variability was computed from differences between consecutive R-R intervals measured from the R wave of each fetal ECG. A trend of increasing variability was seen with advancing labor, defined by either time prior to delivery or cervical dilatation, but values were not statistically significant. Significantly less FHR variability was encountered when fetal scalp pH values below 7.20 were compared to higher values. FHR variability assessed during the 20 minutes immediately preceding delivery was significantly lower in infants with 1-minute Apgar scores less than 7. Machine assessment of FHR variability thus could be correlated with fetal condition as determined by scalp pH and neonatal outcome determined by Apgar score.


Irrigation of the anterior chamber for the treatment of alkali burns. A 31-year-old man had sodium hydroxide blown into his amblyopic left eye after an explosion caused by placing solid sodium hydroxide cleanser into a plugged drain. The eye was treated with topical and intraocular irrigation, and lactated Ringer's solution and the patient was given topical antibiotics, systemic and topical corticosteroids, and carbonic anhydrase inhibitors. Acetylcysteine drops were administered, and a contact lens was placed. The patient subsequently developed severe pain, hypopyon, and hyphema. The cornea was ulcerated and perforated 27 days after injury, and the eye was enucleated 70 days after injury.


Case report. Immunological studies in a case of hepatitis following methyldopa administration. Jaundice with evidence of hepatocellular damage of moderate severity was observed in a patient who received methyldopa. The diffuse mononuclear infiltration of the liver tissue was found to consist of 90% E-rosette-forming cells. Peripheral lymphocytes gave a markedly positive macrophage migration inhibition (MIF) test against methyldopa. The number of T lymphocytes in the peripheral blood was at the lower limit of normal but they proved to be functionally inactive, as demonstrated by the results of a local xenogeneic graft-vs-host reaction test. The liver disease was associated with hyperglobulinemia, a decrease of the third and fourth components of complement and the presence of incomplete erythrocytic antibodies, leukoagglutinins, antinuclear factor, and smooth muscle antibody. Follow-up after discontinuation of the drug revealed a gradual return to normal of liver function and MIF tests, normalization of cellular immunity, and disappearance of the humoral antibodies. It is assumed that sensitization by methyldopa triggered the autoaggressive phenomena and their ultimate manifestation in the liver.


Histopathologic sequence of events in adult mice undergoing lethal graft-versus-host reaction developed across H-2 and/or non-H-2 histocompatibility barriers. The sequence of histologic events in graft-versus-host reaction (GVHR) caused by major and/or minor histoincompatibilities was studied. It was discovered that GVHR may manifest itself in the form of two distinct multiphasic disease entities, depending on whether the donor cells are incompatible with the host for both major and minor histocompatibility antigens ("major GVHR") or for minor histocompatibility antigens alone ("minor GVHR"). The acute or major GVHR has four phases: 1) a transient phase of aplasia, 2) a repopulation phase, 3) a proliferative phase involving lymphoid, presumably immunocompetent, cells, and 4) a phase of acute organ rejection (terminal). The chronic or minor GVHR is characterized by six phases, namely: 1) a transient phase of aplasia, 2) a repopulation phase, 3) a phase of proliferation and tissue infiltration by lymphoid, presumably immunocompetent cells, 4) a phase of major immunologic injuries, 5) a phase of repair, and 6)a terminal phase with advanced sclerosis and proliferative glomerulonephritis. In acute or major GVHR the disease was manifested by the tissue reactions characteristic of acute organ rejection. Lesions were seen in the kidney, liver, bone marrow, lymph nodes, spleen, thymus, intestine, and skin. In the chronic or minor GVHR, tissue injuries were more widespread, affecting the collagen, vessel walls, adipose tissue, renal glomeruli, heart muscle, fascias of skeletal muscles, lymph nodes, spleen, thymus, bone marrow, intestine, skin, esophageal mucosa, and urinary tract. A pronounced plasma cell proliferation was a striking feature in the minor GVHR. Its evolution coincided with advanced thymic epithelial atrophy. It is suggested that the destruction of thymic epithelium resulted in depletion of suppressor T cells and, consequently, in an unopposed proliferation of plasma cells.


The endodermal origin of digestive and respiratory tract APUD cells. Histopathologic evidence and a review of the literature. Twenty-seven small cell carcinomas of the lung and three tumors of the large intestine with combined adenocarcinomatous and small cell and/or anaplastic carcinoid-type histologic features were studied by light and electron microscopy. It was shown that the small cells have morphologic characteristics of APUD cells. Also presented are the histologic features of a carcinoma of the lung with large cell undifferentiated carcinoma, adenocarcinoma, squamous cell carcinoma, and giant cell carcinoma areas in the primary site and in several metastatic foci. Two of the renal metastases showed small cell carcinoma. The combined tumors and the numerous other similar neoplasms described in the literature and reviewed here suggest an endodermal origin for digestive and respiratory tract APUD cells based on the hypothesis that cancer is a clonal proliferation, and mucous and squamous cell differentiation is an endodermal rather than neural crest characteristic. The ultrastructural features of tumors of cells of known neural crest origin, including a medullary carcinoma of the thyroid, three carotid body tumors, a pheochromocytoma, and two cutaneous melanomas were compared with those of other APUD cell tumors including small cell carcinomas of the lung, two bronchial carcinoids, a carcinoid of the appendix, and a carcinoid of the kidney. Cells of the latter group sometimes possessed cytoplasmic tonofibrils, round compact masses of cytoplasmic microfilaments, and ductal lumina. These features were lacking in the former group and may signify a different embryologic origin. The histologic, histopathologic, and embryologic evidence regarding the origin of digestive and respiratory tract APUD cells is reviewed, showing that the former are, and the latter probably are, of endodermal and not neuroectodermal origin.


Depression, facilitation, and mobilization of transmitter at the rat diaphragm neuromuscular junction. The characteristics of depression, facilitation, and mobilization of transmitter were examined at the rat diaphragm neuromuscular junction. Intracellular recording techniques were used to monitor end-plate potentials (EPPs), miniature end-plate potentials (MEPPs) and the muscle resting potentials. The cut-muscle technique was used to prevent muscle action potentials. Quantal release was determined by the direct method. The binomial statistical parameters, releasable store (n) and probability of release (p), were examined under various stimulating conditions to determine the basis for depression and facilitation. The present experiments demonstrate that p remains unchanged during repetitive nerve stimulation at low or moderately high frequencies. The experiments demonstrate that depression is due to a decrease in n and facilitation is due to an elevation in n. It is suggested that the increase in n during facilitation is due to a transient recruitment of inactive releasing sites. Substantial replenishment of n by mobilization occurs within a few ms after a stimulus but a slow residual rate of mobilization is needed to replenish n to resting levels.


Intracellular pH measurements in gastric mucosa. Intracellular pH was measured in bullfrog gastric mucosa using a pH-indicator dye, bromthymol blue (BTB), with a spectrophotometric technique. Studies showed that BTB is taken up by the gastric mucosa and bound to intracellular components. The binding of BTB was shown to cause a shift in the pKa of the dye from the solution value of 6.95 to a value of 8.0. During the nonsecreting state, intracellular pH was estimated to be 7.4 (metiamide inhibition) or 7.1 (SCN inhibition). During active secretion of acid, intracellular pH increased with increasing secretion rates, reaching values in excess of pH 8. Using preparations from which the surface epithelial cells had been removed, it was shown that at least a portion of the alkaline response to stimulation occurs in the oxyntic or tubular cells. The results are interpreted in view of existing models for the chemical reaction involved in gastric acid secretion.


Sympathetic hyperresponsiveness to hypothalamic stimulation in young hypertensive rats. The possible occurrence of central sympathetic dysfunction during development of spontaneous hypertension was studied by recording aortic pressure and sympathetic nerve activity concurrently during electrical stimulation of the posterior hypothalamus in 9-wk-old Kyoto-Wistar rats. Even at this early age, basal levels for both measurements were already elevated significantly in those with spontaneous hypertension. Increases in sympathetic neural firing induced by graded hypothalamic stimulation were always followed by corresponding increases in blood pressure; magnitude of both effects was appreciably larger in spontaneously hypertensive than in normotensive rats, as was the vasodepression caused by blocking autonomic ganglia with pentolinium. By contrast, pressor responses to injected norepinephrine were almost equal thereby suggesting that cardiovascular reactivity was unaltered and that enhanced responsiveness to hypothalamic stimulation was directly due to the concomitant increase in sympathetic nerve activity. Although the exact site from which sympathetic hyperactivity originates was unidentified, our results support the interpretation that sympathetic mechanisms involving the posterior hypothalamus participate in elevating blood pressure during development of spontaneous hypertension in rats.


Influence of volume dilution, lactate, phosphate, and calcium on mitochondrial functions. Oxidative phosphorylation of isolated canine myocardial mitochondria has been evaluated after exposure to different concentrations of phosphate (5--50 mM), lactate ion in excess (5--40 mM, pH 7.4), calcium (50--270 nmol/mg protein), to lactic acidosis (pH 6.3), and to mitochondrial protein dilution (in vitro volume expansion) for 10 min to 8 h. The influence of phosphate and lactate ion addition, lactic acidosis, and in vitro volume expansion on mitochondrial function were studied in the isolation medium (0.18 M KCl, 0.5% BSA (bovine serum albumin), with or without Tris-EDTA, pH 7.4) prior to evaluation of mitochondrial function in the assay medium (0.25 M sucrose, 10 mM Tris-HCl, and 10 mM inorganic phosphate, pH 7.4). The effect of calcium addition was assessed in the assay medium. The results of these studies demonstrate that each of these interventions detrimentally alters mitochondrial oxidative phosphorylative ability. The most severe mitochondrial functional impairment resulted from phosphate or calcium addition. The detrimental effect of phosphate and in vitro volume expansion was partially corrected by the addition of cytochrome c.


Lateralized neuropsychological dysfunction in affective disorder and schizophrenia. The authors compared the cognitive functioning of 22 schizophrenic patients, 105 patients with affective disorder, and 99 age-matched normal control subjects. Results of an aphasia screening test indicated that the schizophrenic patients made more total errors and more dominant temporal/temporoparietal errors than patients with affective disorders and that patients in both groups made more errors than controls. Patient sex, age, drug treatment received at test time, previous neuroleptic drug treatment, and severity of illness did not account for the differences. These findings support the validity of the authors' diagnostic research criteria and confirm prior reports of differences in dominant hemisphere dysfunction between schizophrenic patients and patients with affective disease.


Calcium: pacesetting the periodic psychoses. In this double-blind study dihydrotachysterol (DHT) was given orally to eight psychotic patients; in each case marked increases in psychosis and agitation accompanied increases in serum calcium and phosphorus within two weeks after active drug was substituted for placebo. In the three patients whose psychoses exhibited periodic spontaneous exacerbations, the agitated episodes grew more severe. Serum creatine phosphokinase (CPK) increased in all but one patient. By contrast, when three periodically psychotic patients received synthetic salmon calcitonin (SCT), the severity and frequency of agitated episodes decreased while CSF calcium increased in all three. These data support the hypothesis that the observed abrupt increases in serum calcium and phosphorus might cause the opposite CSF calcium shifts, the behavioral agitation and the increases in serum CPK frequently noted during acute psychosis.


Oculomotor signs in a psychiatric population: a preliminary report. Oculomotor signs were evaluated in 172 psychiatric patients. Schizophrenic patients demonstrated a significantly higher incidence of staring, pursuit breaks, and lateral glances than did controls or other psychiatric patients. Oculomotor signs may help to differentiate schizophrenia from affective and nonpsychotic disorders. Patients with tardive dyskinesia and patients treated with tricyclic antidepressants demonstrated a significant elevation in mean blink rate. Elevated blink rates may be on early indicator of tardive dyskinesia.


Management of character disorders in a hospital setting. Management of the character disorders in a hospital is synonymous with the therapeutic process itself. No single mode of therapy is the answer. The key seems to be a structured social setting, a therapeutic milieu involving an interdisciplinary team approach in which harmony, mutual trust and relative agreement about patient goals prevail.


The pharmacologic treatment of depression. This article focuses on the treatment of depression with special reference to pharmacotherapy. The treatment-resistant case and the possible means of resolving its problems are highlighted. The role of ECT will be considered. Long-term maintenance treatment with antidepressant medication for patients with cyclic occurrences is recommended.


Experimental  evaluation of myocardial preservation techniques: IV. Potassium cardioplegia. To investigate whether potassium per se plays a significant role in cold potassium cardioplegia, isolated blood-perfused rabbit papillary muscle preparations were used to determine the recovery of myocardial contractility after normothermic anoxia. Cardioplegia was induced by infusing an isotonic electrolyte solution containing either 5 or 40 mEq/liter of potassium chloride. Anoxic periods of 30 minutes (9 experiments each) 45 minutes (10 experiments each), and 60 minutes (1 experiment each) were compared. Hearts stopped contracting in 45 seconds with infusion of a 40mEq/liter of potassium chloride solution compared to 5 minutes with a 5 mEq/liter solution. After 30 minutes of anoxia, myocardial recovery was 65.39 +/- 24.48 per cent with 5 mEq/liter of potassium chloride and 90.05 +/- 6.40 per cent with 40mEq/liter of potassium chloride. The difference was highly significant (p less than 0.01). After 45 minutes of anoxia the same trend as just described was noted, but the difference was statistically insignificant. After 60 minutes of anoxia, recovery was extremely poor regardless of the potassium concentration of the cardioplegic solution. Our conclusion was that a high potassium solution will arrest the heart rapidly and provide protection against anoxic injury of the myocardium. Its protective effect becomes less significant, however, as the anoxic time is prolonged.


[Doppler ultrasonic measurement for diagnosing carotid occlusions and stenoses (author's transl)]. Doppler ultrasonic measurements were performed in 74 patients suffering from cerebrovascular disorders. Flow direction was determined in the supratrochlear artery by using a directional Doppler sonographic instrument according to the method of Keller et al. 15 patients presented, unilateral or bilateral, with a flow reversal (i.e. direction of flow into the orbita via supratrochlear artery). In 8 of these patients carotis or aoitic arch angiographies were performed and in 4 cases necropsy reports were available. In all instances where flow reversal occurred severe carotid stenoses or occlusions were demonstrable. Thus 9 internal carotid occlusions, 1 common carotid occlusion, and 3 severe internal carotid stenoses were proved. One internal carotid occlusion and 3 internal carotid stenoses were operated on. Check-up sonograms after endarterectomy of carotid occlusions or stenoses showed a normal antegrade flow thus demonstrating patency of the carotid vessels. Obviously, supratrochlear flow reversal as measured by ultrasonic technique signals ipsilateral carotid vessel occlusion or stenoses. Furthermore, the method seems to be a reliable means for controlling carotid endarterectomy.


[Incidence and peculiar changes in the electrocardiogram of patients after cerebrovascular insults.--Epidemiological study of 70--105-year-old people (author's transl)]. An epidemicological study of 70 to 105-year-old people revealed a frequency of cerebrovascular insults from 1,8% of living and of 23,9 respectively 34,4% of deceased men or women. As typical changes of the electrocardiogram in recent insults are to be found prolongations of the QT-interval, large and often terminal negative T-waves as well as large and high, but over the left precordium often negative U-waves.


[Indoor treatment of involutional depressions in cerebro-vascular insufficiency (author's transl)]. In this study we are reporting about our results concerning a combined therapy of short-time hospitalized patients, who suffered from an involutional depression and a cerebro-vascular-insufficiency. All patients had been treated outdoor without sufficient results before this. We could see, that all patients who had suffered their acute state within the last 18 months had good or very good improvements. Patients suffering already for several years showed no improvement in spite of all our efforts to promote the cerebral blood flow, the metabolic situation and the environment situation. These results proved, that one should start with a proper therapy of infusions and workshop rehabilitation immediately after the first sign of an involutional depression and cerebro-vascular-insufficiency.


Electronmicroscopical and immunoelectronmicroscopical examination of the lymphocytes of young and old people after influenza vaccination. Authors examined the lymphocytes of young and old individuals before, 6 days and 6 weeks after influenza vaccination. Vaccination was carried out with killed Influenza B/Hong-Kong virus. Electronmicroscopic structure of the lymphocytes and membrane bound surface IgG and IgM were studied. Membrane bound surface IgG and IgM were seen on the small lymphocytes and on the membrane of the medium-sized lymphocytes in young and aged individuals before and after vaccination. In both age groups intracytoplasmic tubuloreticular structures were seen in the lymphocytes. These findings were not age dependent alterations. Age dependent changes could be detected on the mitochondria of the lymphoid cells. The mitochondrial crysts in aged individuals disappeared and were replaced by myelin-like forms or by faint density substance. The mitochondrial changes were present before vaccination and after vaccination in non labelled, presumably T lymphocytes. The injury of the mitochondrium can influence the function and the proliferative capacity of the cells.


[Pathogenesis, clinical manifestations and treatment of the "postgastrectomy-syndrome" (author's transl)]. The incidence rate of complications in patients, who underwent stomach resection as surgical treatment procedure is rather high (20%). Postprandial syndromes (dumping syndrome, lactose-intolerance, afferent loop-syndrome), malabsorption syndromes (anemia, osteopathia, steatorrhea, protein deficiency) and late organic manifestations (anastomotic and suture ulcers, retrograde intussusception, gastric-stump carcinoma) were usually summarized as "postgastrectomy syndrome". A review of pathogenesis, symptoms and therapeutic approach for the various postoperative disorders is given. Selective proximal vagotomy as the surgical treatment procedure of choice is emphasized.


[Reconstructive measures to prevent lower extremity amputation for atherosclerotic occlusive disease in old age and the results obtained between 1973 to 1977 (author's transl)]. Within a 5-year-period 102 patients over the age of 70 were admitted with atherosclerotic occlusive disease. All patients had rest pain or necrosis. In 12,8% only a primary amputation could be performed. The procedures and results of reconstructive surgery on 89 patients were demonstrated: mortality rate of 11,2%, a secondary amputation rate of 13,5% and improvement of 75,3%. The problems after amputation in the senium are discussed.


[Heel necrosis: a complication of geriatric diseases (author's transl)]. 12 heel necroses were seen in a group of 596 geriatric patients. The patients average age was 73 years. 3 tentative causes for the development of heel necrosis were investigated. 1. Imobility, 2. Arterial occlusive disease, and 3. Diabetes. Immobility was demonstrable in all cases. Additionally, arterial occlusions of the leg were present in 7 and diabetes in 6 patients. The percentage of arterial occlusion and diabetes was significantly higher in the heel necrosis group than in the overall hospital cohort. The two diseases can be looked upon as risk factors for the development of heel necrosis.


A field study of depression in old age.

A field study of depression in old age. The frequency and nature of depression were studied in a random sample of septuagenarians obtained from the Birth Register of the City of Helsinki. Out of 400 newborns in 1903, 261 were pronounced dead in 1973. Of the remaining 139, 106 were examined. Four were chronic mental patients. In the clinical examination of the remaining 102 subjects, 25 were diagnosed as depressive. According to the Beck Depression Inventory 29, or 48.9 percent of the 60 subjects who consented to psychological testing, were depressive. In half of the 25 depressive subjects, chronic disabling disease was the main etiological factor. In the other cases, the main causes were loss of significant personality retirement, and other psychosocial factors involved in aging. Frequency of hypochondria was only 3.9 percent. The prognosis of active treatment was deemed good in the subjects with psychosocial disturbances. Interest in physical exercises and participation in voluntary associations correlated with absence of depression.


Treatment modalities in the affective disorders of old age. In summary, I have reviewed the application of three major treatment modalities, psychotherapy, drug therapy, and electroconvulsive therapy, to the affective disorders of old age. Older patients are remarkably responsive to each of these forms of psychotherapy. Certain modifications in therapeutic approach must be introduced to make them effective. However, once these modifications are implemented many older patients can return to normal and satisfying lives following effective treatment of their affective disorders.


[The effect of timolol and parasympathicomimetica in the treatment of the elevated intraocular pressure (author's transl)]. 45 patients with ocular hypertension or open-angle glaucoma were tested to see if, and to what extent timolol and three other different parasympathicomimetics (pilocarpine 2%, carbachol 1.5%, aceclydine 2%) produced an supplementary reduction of the intraocular pressure. An equally marked, additional drop in eye pressure was achieved when patients who had been given timolol over an extended period of time, were additionally treated with one dose of pilocarpine 2% or carbachol 1.5%. Aceclydine 2% produced no statistically significant additional effect. Patients who had only been treated with pilocarpine 2% over an extended period of time and then were given one dose of timolol 0.25% produced a drop in eye presure more than double that of those patients who had been primarily treated with timolol and then received pilocarpine or carbachol. These results will be discussed on the basis of the mode of action of the applied medications.


[Influence  of narcotic analgesics, droperidol, diazepam, and flunitrazepam on the smooth muscles of small arteries (author's transl)]. In isolated segments of the rat tail artery, the influence of narcotic analgesics, their antagonists, droperidol, diazepam, and flunitrazepam on the vascular smooth muscle was investigated. The wall of this vessel consists of about 75 per cent smooth muscle fibres. For all agents studied, pressure-diameter relations were determined before and after a virtually maximum constriction which was induced with noradrenaline. The results were compared with those obtained under control conditions, i.e. prior to the addition of the drugs to the bath solution. Tested in pure Tyrode's solution, none of the agents produced a noticeable constriction or relaxation. Among the analgesics and their antagonists, morphine was the most potent in inhibiting the noradrenaline-induced constriction of the vessel (mean increase in diameter 15%). Pentazocine and levallorphan were less effective (mean increase 8%), and the administration of pethidine and naloxone was followed by even less relaxation, resulting in mean diameter increases of 4%. Piritramide and fentanyl did not show any effect. Depending on the pressure level, droperidol caused the diameter to increase 2 to 10%. Flunitrazepam brought about a marked relaxation (mean increase in diameter 15%), diazepam, however, did not influence the vessel segments. The results obtained show that the haemodynamic effects of the drugs used in this study, in particular those on the peripheral resistance, may, at least partially, be due to their direct influences on the vascular smooth muscle. The real pharmacologic mechanisms by which these effects are initiated, in most cases still remain to be investigated.


[Influence of combined moderate arterial hypoxaemia and moderate hypovolaemic hypotension on cerebral blood flow and cerebral oxidative and energy metabolism in the dog (author's transl)]. The influence on total cerebral blood flow, cerebral metabolic rates for oxygen, carbon dioxide, glucose, lactate and pyruvate and on cerebral grey matter content of glucose, lactate and pyruvate and high energy phosphate compounds of combined moderate reduction in cerebral perfusion pressure (CPP) and moderate arterial hypoxaemia was studied. Individually arterial hypoxaemia and arterial hypotension of the same degree would neither impair autoregulation of cerebral blood flow nor cerebral oxygen availability. Four groups of 10 dogs each were studied under control conditions (group I), with reduction of CPP to 70 mm Hg (group II), with reduction of paO2 to 45 mm Hg (group III) or with a combination of these degrees of hypotension and hypoxaemia (group IV) after steady states of 30 min duration. Cbf was elevated by 40% in group III (p less than or equal to 0.01), CMRO2 was reduced significantly in group IV (p less than or equal to 0.01, CMR lactate was raised significantly in all three experimental groups (p less than or equal to 0.01). All other data were not significantly different from values in control animals. Cerebral tissue lactate content was elevated significantly in groups II to IV as compared to controls (less than or equal to 0.05); changes in cerebral tissue content of glucose and energy rich phosphate compounds were not statistically significant. From the seemingly normal cerebral blood flow in hypotensive-hypoxaemic dogs it is concluded that autoregulation of cerebral blood flow has become ineffective because of vasodilatation consequent upon arterial hypoxaemia. Reduction of CMRO2 in this group points to metabolic insufficiency and to relative cerebral hypoperfusion, but since changes in cerebral content of high energy phosphate compounds were not significant, severe tissue hypoxia may be excluded. The increase in cerebral tissue lactate content is attributable to increased glycolytic activity known from hypotensive and hypoxaemic states. The present investigation suggests that in patients with hypoxaemia and hypotension, brain function may be endangered by a similarly marked change of circulatory and metabolic parameters.


Desensitization of the beta-adrenergic receptor on leucocytes after long-term oral use of a beta-sympathicomimetic; its effect on the beta-adrenergic blockade hypothesis of Szentivanyi. Development of beta-receptor desensitization in leucocytes of asthmatics and normals during oral therapy with terbutaline was established by means of in vitro stimulation with terbutaline and isoproterenol. This desensitization disappeared about one week after oral therapy was discontinued. In addition no difference in stimulation pattern, measured as increase in intracellular c-AMP content, was determined between asthmatics and normals when both were not receiving therapy. Even when the asthmatics showed strong bronchial hyperreactivity no difference was found. These results do not support the beta-adrenergic blockade hypothesis of Szentivanyi.


Enzymes of bee venom, sac and whole body. By using the Api-Zym System 55 enzymes were determined to be present in bee venom, venom sac, sacless whole body extract and whole body commercial extracts. Acid phosphatase activity was high in bee venom and sacless whole body extracts. Arylamidase activities were elevated in sacless whole body extracts and very low or undetectable in venoms. Conversely, glycyl-prolin arylamidase activity was high in venoms and very low in the other extracts.


Intradermal responses to common bacterial antigens: influences of sex and clinical condition. Intradermal responses to antigens of 12 common bacteria were evaluated in 218 dermatologic and 155 respiratory patients. Women responded more frequently than men and respiratory patients responded significantly more frequently than dermatologic patients to certain antigens. Interpretation of interspecies associations of responses suggested that certain organisms may be key species in the development of bacterial hypersensitivity.


Andrenogonadal interactions in nicotine-induced alteration of steroidogenesis in male rat. Chronic nicotine administration in larger doses inhibits steroidogenesis in testis. This inhibition is possibly secondary to increased adrenomedullary norepinephrine activity, since the anti-steroidogenic effect of nicotine can be prevented by alpha-adrenergic blocker like phentolamine. In vitro incubation of testicular slices with nicotine failed to elicit any appreciable effect on delta 5-3 beta-hydroxysteroid dehydrogenase activity indicating lack of direct action of nicotine on testicular steroidogenesis.


Ventilatory control in patients with hypoxemia due to obstructive lung disease. In 20 patients with chronic hypoxemia due to chronic obstructive pulmonary disease, we measured responses to CO2 and hypoxia in terms of ventilation and P0.1, the pressure generated by the respiratory muscles during the first 0.1 s of inspiratory effort against a closed airway at functional residual capacity. These responses were compared to those of a control group of 17 patients with similar ventilatory abnormality but without hypoxemia. Hypoxemic patients demonstrated significantly less response to hypoxia than did control subjects in terms of both ventilation and P0.1 The decreased hypoxic response might be analogous to that reported in high altitude dwellers and patients with cyanotic congenital heart disease. Ventilatory responses to CO2 were depressed in hypoxemic patients, but P0.1 responses were not significantly decreased. While breathing at rest with arterial O2 saturation of 95 per cent, hypoxemic patients demonstrated the same minute ventilation as control subjects, but tidal volume was smaller, inspiratory duration was shorter, and breathing frequency was slightly higher. This breathing pattern appeared to be independent of whether or not these patients retained CO2.


Effect of pH on the binding of theophylline to serum proteins. The binding of theophylline to serum protein within the pH range of 7.0 to 7.8 was determined by equilibrium dialysis using serum from 8 healthy adult volunteers. The percentage of theophylline bound was independent of the total concentration of the drug, but was directly related to pH. Because changes in the free fraction of theophylline may alter the therapeutic response, toxic effects, and pharmacokinetics, any future studies of the pharmacology of theophylline should include assessment of the acid-base status of the patients and measurements of free as well as total theophylline concentrations.


Mouse kidney trehalase: purification and properties. Trehalase (E.C.3.2.1.28) was isolated from mouse kidney and purified to homogeneity. The enzyme was solubilized with n-octanol and activated by freezing and thawing before precipitation with ammonium sulfate. A 1700-fold purification was achieved by chromatography on DEAE-cellulose, SP-Sephadex, followed by gel filtration on Sephadex G-200. Only a single form of enzyme activity was shown throughout the fractionation as confirmed by gel electrophoresis of the final preparation. The enzyme was specific for trehalose and its estimated molecular weight by filtration on Sephadex G-200 was 73,000. The Km for trehalose was shown to be 2.67 x 10(-3)M and the optimum pH was in the range of 5.5-5.6. We have also shown that the optimum temperature of the enzyme is 60 degrees C, but in the absence of substrate, thermal inactivation occurred at 55 degrees C.


[Endocrine studies in cryptorchidism (author's transl)]. The endocrinological study of the cryptorchid testicle was carried out using a HCG and LH-RH tests to stimulate the hypophysis. Stimulation with LH-RH demonstrated a low hypophysis reserve in some cases which made suspect the presence of a hypo-stimulated testicle. One is led to believe in the heterogeneous nature of the endocrinological response.


Prolactin-secreting pituitary adenomas in multiple endocrine adenomatosis, type I. In three unrelated families, four patients with multiple endocrine adenomatosis, type I, had confirmed or highly probable prolactin-secreting pituitary adenomas. In one patient, selective transsphenoidal tumor resection resulted in normal prolactin levels and resumption of menses. Heretofore, the majority of pituitary tumors in such patients had been thought to be nonsecreting chromophobe adenomas, but recent studies have shown that, in sporadic cases, as many as three fourths of "nonsecreting" pituitary tumors in fact secrete prolactin. Thus, based on our experience and reports of others, we believe that prolactin-secreting tumors may be common in patients with pituitary tumors as part of the syndrome of multiple endocrine adenomatosis, type I, and we recommend that serum prolactin be measured when evaluating these patients and their families.


A rapid kinetic assay for glucose using glucose dehydrogenase. An automated kinetic assay for the determination of glucose in blood is described. The method employs the enzyme glucose dehydrogenase in the presence of mutarotase, with nicotinamide adenine dinucleotide as hydrogen acceptor. The analytical parameters of the method are determined and the flexibility of the method in relation to sample volume and sensitivity is discussed. Finally, the method is compared with automated glucose oxidase and hexokinase procedures.


Inappropriate methods for the emergency determination of plasma paracetamol. Methods for the estimation of plasma paracetamol which depend on acid hydrolysis to p-aminophenol without a prior extraction step also measure inactive metabolites which are present in high concentrations. The extent of the overestimate obtained with such methods was determined using 24 samples from patents after paracetamol overdosage. There was a positive error of between 40 and 700% compared with a high-performance liquid chromatography reference method which measured only unchanged paracetamol. These non-specific methods should not be used to determine the need for specific therapy in patients with paracetamol poisoning.


[Temperature effects at the NADP+ and NAD+ levels in the mycelium of P. nigricans Thom. strains grown on different carbon sources]. The effect of elevated temperature of the medium on the levels of NADP+ and NAD+ in the mycelium of highly productive strain 117 and low productive strain B of P. nigricans Thom was studied at various developmental periods on the mineral medium in the presence of glucose, succinate or acetate. It was found that in the presence of glucose the elevated temperature markedly stimulated the initial growth of the culture, decreased the level of NADP+ in strain 117 by the 48th hour and increased the level of NAD+ in both the strains. At later periods it decreased the rate of the dinucleotide accumulation during the culture development. With the use of succinate under these conditions the levels of NADP+ in both the strains during the growth phase (the 2nd and 5th days) and by the 9th day markedly increased, while the NAD+ concentration increased only by the 2nd day in both the strains and by the 9th day in strain B. When the strains were grown in the presence of acetate, the elevated temperature especially affected the level of NAD+.


Resistance mechanisms of multiply resistant pneumococci: antibiotic degradation studies. Strains of Streptococcus pneumoniae resistant to penicillin have been reported from several countries around the world. Many South African isolates, in addition, exhibit resistance to tetracycline, chloramphenicol, erythromycin, clindamycin, and cotrimoxazole in varying patterns. A qualitative test of the ability of antibiotic-resistant pneumococci to inactivate penicillin, oxacillin, cephalothin, cefoxitin, chloramphenicol, tetracycline, minocycline, erythromycin, clindamycin, streptomycin, gentamicin, and cotrimoxazole revealed that only chloramphenicol was degraded. This finding was confirmed in a quantitative test in which the residual antimicrobial activity of broth containing chloramphenicol in subinhibitory concentrations was determined after incubation with antibiotic-resistant bacteria. Chloramphenicol resistance was shown to be associated with the production of inducible chloramphenicol acetyltransferase. No beta-lactamase activity was demonstrated. Plasmid deoxyribonucleic acid was not demonstrable in partially purified lysates of antibiotic-resistant strains of S. pneumoniae.


The Merkel cell--a member of the APUD cell system. Fluorescence and electron microscopic contribution to the neurotransmitter function of the Merkel cell granules. Merkel cells of sinus hair follicles of nude mice were investigated by fluorescence and electron microscopy following pretreatment with amine precursors (L-Dopa, L-5-Hydroxytryptophan) and monoaminoxidase-inhibitors (Marsilid, Harmaline). Neither in control animals nor in pretreated animals any evidence for an involvement of Merkel cells in monoamine metabolism could be found. Therefore, the hypothesis that Merkel cells might share the most constant cytochemical characteristics of the cells of the APUD series, i.e., to take up amine precursors, should definitely be left. Following Harmaline treatment, however, Merkel cells were found fluorescent; cytophotometric analysis of the fluorescence emission spectra of formaldehyde-treated tissue ascertained that this fluorescence was due merely to a specific Harmaline fluorescence. The significance of Harmaline uptake in Merkel cells, most probably in the Merkel cell granules, is discussed.


Glutathione reductase in human epidermal tumors. Basal and squamous cell epithelioma, verruca seborrhoeica. Glutathione reductase activities, both with NADPH and NADH, were determined in basal and squamous cell epitheliomas, in verrucae seborrhoeicae and in human epidermis. Significantly elevated activites were measured in basal cell epitheliomas and in verrucae seborrhoeicae. Some properties of the enzyme were also investigated.


The epidermal helix: a model for the bilayer couple phenomenon. Narrow strips of isolated epidermis rapidly assume a helical conformation when placed in a dilute hypotonic aqueous solution of histamine as a free base. The same belical formations could be induced by dilute hypotonic solutions of alkalis or acids. This coiling resulted from damage to the malpighian cells, with consequent asymmetric osmotic swelling of the epidermis, thus producing torsional forces on the stratum corneum. In essence, the epidermal helix proved to be a pH dependent, osmotically induced, bilayer couple phenomenon.


Lesser curvature tubular gastroplasty with partial plication for gastroesophageal reflux: manometric and pH-metric postoperative studies. Thirty-four patients with sliding hiatal hernia, gastroesophageal reflux, or both were treated by lesser curvature gastroplasty with partial gastric plication, using a surgical stapler. Before operation, esophageal manometric studies were performed in 33 patients and during the early postoperative period (1 to 3 months), in 34. The esophageal pH test was performed before operation in 22 patients, shortly after discharge in 27, and later in 30 patients. The clinical results were considered satisfactory in 30 patients (88%) after follow-up ranging from 18 to 33 months (average, 23 months). Before the procedure, the abdominal compression test was positive in 25 of 30 patients (83%). In early postoperative studies it was positive in 1 out of 34 patients (3%), but in the second series of postoperative studies it was positive in 9 out of 32 (28%). After instillation of hydrochloric acid into the stomach, the esophageal pH test was considered positive in 17 out of 22 patients in preoperative studies (77%). In early postoperative studies the test was positive in 3 out of 27 patients (11%) and one year later, in 7 out of 30 (23%). The later postoperative studies showed a higher number of positive reflux tests than the early studies, 28 and 23% positive in manometric and pH tests, respectively.


Neurotransmitter receptors in frontal cortex of schizophrenics. Frontal cerebral cortex brain samples from schizophrenics and controls have been assayed for binding associated with muscarinic cholinergic, serotonin (5HT), gamma-aminobutyric acid (GABA), and beta-adrenergic receptors as well as for the activity of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Binding levels of tritium-LSD, presumably associated with postsynaptic 5HT receptors, were reduced 40% to 50% in samples from schizophrenics in three independent studies, whereas no other consistent alteration was observed in levels of binding associated with other receptors or in the activity of GAD. This change in receptor binding levels does not seem to be attributable to postmortem changes, to influence of drugs received by the patients, or to demographic features of the patient populations.


[Overacidified tissue and microcirculation (author's transl)]. A discussion of physiological fundamentals with respect to the inhibition of blood microcirculation in (tumor) tissue at reduced pH values around 6.0 is followed by a report on principles, design and results obtained with a light probe array which permits to determine in vivo reference values of the relative intensity of microcirulation in both normal and tumor tissues under various conditions. An analysis of the discussed records has shown that--as compared to a value of 80-66% without glucose infusion--the relative mean intensity of microcirculation in tumor tissue drops to approximately 8-4% about 300 min after the onset of glucose infusion under CMT administration at 37 degrees C. By adding the CMT step of hyperthermy, the relative mean intensity of microcirculation--compared to normal tissue at 37 degrees C--will further drop below 1%. With such a decline of microcirculation--and an adequate duration of, say, 8 hours--local hyperthermy at 41-42 degrees C is likely to cause a very pronounced damaging action on tumor tissue because the then noticeably reduced substrate offer proves to be insufficient to ensure the structure-maintaining metabolic rate of cancer cells.


Lower esophageal sphincter function after highly selective vagotomy. We evaluate whether highly selective vagotomy (HSV) might disturb functional integrity of the lower esophageal sphincter (LES). Special interest was directed to changes in position of the LES in relation to the diaphragm, LES pressure, and pH reflux pattern. The conditions of 20 patients were evaluated by manometric studies and by 12-hour overnight pH measurements before and 14 days after HSV; five of them were also studied one year after HSV. The results indicate: (1) There is a slight elongation of the LES in the early postoperative phase, which seems to disappear after one year. (2) The position of the diaphragm as measured manometrically by the pressure inversion point descends in relation to the LES 14 days after HSV, and it does not seem to return to its original position after one year. (3) There is no significant change in LES pressure after HSV. (4) There is no increase in reflux after HSV.


Separate pancreatic gastrin cell and beta-cell adenomas: report of a patient with multiple endocrine adenomatosis type 1. A patient initially showed symptoms of peptic ulcer disease in 1953 and was later found to have hypercalcemia and hyperparathyroidism. Peptic ulcer symptoms persisted after parathyroidectomy, and results of studies provided evidence of the Zollinger-Ellison syndrome. Evaluation of the patient's family showed a classic pattern of multiple endocrine adenomatosis type 1. The patient underwent total gastrectomy and excision of a gastrin cell adenoma in 1971 with relief of symptoms, but with persistent hypergastrinemia. He remained in good health until January 1976, when symptoms of hypoglycemia developed. Results of laboratory studies were compatible with the diagnosis of a pancreatic beta-cell adenoma. At the time of operation, an adenoma of the head of the pancreas was found. The tumor was excised; no other metastatic tumors were found. The tumor was compatible with a beta-cell adenoma and was found to contain high concentrations of insulin; there was no important amount of gastrin. Symptoms of hypoglycemia have entirely disappeared.


[Acid-base equilibrium changes associated with acute pulmonary edema. Intra-erythrocytic findings and comparison with plasma values]. A study was made of intra-erythrocyte acid-base balance in 7 subjects with metabolic and 3 with mixed acidosis in the course of acute haemodynamic pulmonary oedema. Comparison with plasma values showed that, in metabolic acidosis, the buffers (bicarbonate) are evenly involved in the maintenance of hydrogen ion balance, whereas in mixed forms a greater demand is made on non-bicarbonate bases. Examination of this phenomenon and its quantitative evaluation are geared to intra-erythrocyte determinations of the acid-base balance, particularly to the very important B.E. index.


Ocular findings in metachromatic leukodystrophy. An electron microscopic and enzyme study in different clinical and genetic variants. Histopathological studies of the eyes from three patients affected with the infantile form of metachromatic leukodystrophy (MLD) showed the storage of metachromatic complex lipids in the retinal ganglion cells, in the optic nerve and the ciliary nerves, as well as the storage of a mucopolysaccharide-like material in the nonpigmented epithelium of the ciliary body. The lesions were limited to the optic, ciliary, and sensory nerves in a fourth patient with the juvenile form of the disorder. These morphological aspects, which are probably related to differences in sulfatase A activities, may explain the variability of the ocular manifestations in metachromatic leukodystrophy. Seven children affected with infantile MLD or with mucosulfatidosis were examined by conjunctival biopsy. Typical lesions of the sensory nerves were obvious and allowed the diagnosis of the disease. However, it seemed impossible to separate the different forms by histopathological studies only. The tear enzymes were assayed in most of the cases and demonstrated a profound deficiency of arylsulfatase A, or of arylsulfatase A and B, in the classical MLD and in mucosulfatidosis, respectively.


Pneumococcal disease and its prevention with polyvalent pneumococcal polysaccharide vaccines--a review. Polyvalent pneumococcal polysaccharide vaccines have been shown to be safe, immunogenic and efficacious and are becoming available for use in patients at high risk of developing pneumococcal infections. Precise estimates of the role of the pneumococcus in human respiratory disease are difficult to obtain, as this organism is also a frequent commensal of the upper respiratory tract; and as the optimal techniques for the identification and proof of its role are not widely used. Nevertheless, the pneumococcus remains the principal cause of adult pneumonia and paediatric otitis media, and is also an important cause of death from bacteremia and meningitis. At present it seems likely that in Australia these vaccines will be most useful amongst people over the age of 50 years, those with chronic systemic disease, alcoholics, splenectomized individuals and disadvantaged groups such as Australian aborigines, all of whom are particularly susceptible to pneumo-coccal bacteremia which has a considerable mortality rate. The possibility of preventing pneumococcal otitis media in childhood is still being evaluated. Studies of the role played by the various pneumococcal serotypes in Australian populations are urgently needed.


Behaviour therapy as precipitant and treatment in a case of dual personality. The patient described is a 33-year -old woman, L.,who developed a transient dual personality while undergoing desensitization for contact phobia, the alternate personality, Toni, manifesting overtly aggressive behaviour. L. was taught how to behave angrily using role-playing techniques within 48 hours of Toni's first appearance and the alternate personality did not reappear after this treatment was commenced. It is suggested that behavioural psychotherapy may, in some instances of multiple personality, have advantages over psychodynamically oriented psychotherapy, which has frequently been advocated as the treatment of choice for this condition.


Polyarteritis nodosa in childhood a clinical pathologic study. The clinical and pathologic findings of 2 infants and 7 older children with polyarteritis nodosa who were autopsied are reported. The most frequent clinical features included prolonged high fever, skin rash, abdominal symptoms, leukocytosis, proteinuria, and signs of either cardiac or renal failure. The 2 infants died of cardiac arrest, whereas renal or neurologic involvement was the most common cause of death in the older children. A consistent finding at autopsy was arteritis of the epicardial coronary arteries.


A syndrome resembling progressive systemic sclerosis after bone marrow transplantation. A model for scleroderma? Six long term survivors of bone marrow transplants developed a syndrome similar to progressive systemic sclerosis (PSS). Cutaneous involvement (6/6), pulmonary disease (6/6), musculoskeletal involvement (4/6), keratoconjunctivitis/positive Schirmer's test (4/6), Raynaud's phenomenon (2/6), and renal and cardiac disease (1/6) were similar to findings in PSS patients. T and B lymphocyte counts and functions were also similar. This PSS-like syndrome, including visceral involvement, after bone marrow transplantation lends support to an immunologic hypothesis of the pathogenesis of progressive systemic sclerosis.


[Endorphines--the endogenous ligands of opiate receptors (author's transl)]. The demonstration of opiate receptors in the nervous tissue of vertebrates in 1973 was the starting point of an intensive search for the endogenous ligands of these receptors. During the following years, several of such "edogenous opiates", called "endorphines", were isolated from various tissues of the mammalian organism. These are peptides which are able to elicit the same effects as do opiates. Possibly, they play a role in the reaction of the organism to stress.


[Clinical side and adverse effects of antidepressant drugs (author's transl)]. Cases of extrapyramidal-motoric and psychologic side effects are reported when treatment with antidepressant drugs was performed. They have not been mentioned in the literature before. Hypokinetic disorders of speech and motion, tonic-atonic disturbances, dyskinesia and myoclonic muscle contractions are listed. Besides the latter movement disorders, "dreamy state", episodic amnesia ("ictal" amnesia) and amnestic "black out" as transient memory disorders have been observed.


[The influence of MIF (melanocyte-stimulating hormone-release inhibiting factor) on psychomotor function and mood in parkinsonian patients. Preliminary report (author's transl)]. In 12 parkinsonian patients aged from 40--76 years the L-dopa-potentiating effect of MIF was investigated using a doubleblind crossover design. MIF was given i.v. in a dose of 200 mg. The following psychological tests were carried out 4 times after the injection of MIF at hourly intervals: Purdue pegboard, Minnesota-Rate of manipulation test, 2-key-tapping, simple and complex reaction time and a state of well-being scale. The results revealed a marked effect on finger dexterity, drive and complex reaction time. That means MIF does not only lead to an improvement of psychomotor performance but also of cognitive functions. In contrast thereto the influence on the state of well-being was less impressive.


[Experimental and clinical findings indicating anxiolytic properties of gestagens (author's transl)]. Employing the technique of quantitative pharmaco-EEG investigations on the psychotropic effects of progestogens indicated that progestogens produce a profile similar to that of minor tranquilizers. A short review of the clinical literautre adds support to the suggestion that progestogens may have sedative/tranqulizing properties.


[Relationship between perazine serum concentration and clinical results in long-term treated schizophrenic outpatients (author's transl)]. The perazine serum concentration was determined with a new gaschromatographic method in 33 schizophrenic outpatients of our psychiatric catamnestic unit who had received perazine for a period of 18 years. A very high constancy of the perazine serum level could be demonstrated by repeated measurements. A close connection existed between perazine dosage and perazine serum level. Both findings suggest a very good complicance of these patients. Serum levels were correlated positively with the intensity of the psychopathologic symptoms as well as with the frequency of side-effects, particularly with slight changes of liver enzymes.


[Radioenzymatic simultaneous determination of epinephrine and norepinephrine in plasma (author's transl)]. The high-pressure liquid chromatography (= HPLC) was used in simultaneous determinations of a few pg epinephrine and norepinephrine. This separation procedure improves the efficiency when compared with the conventional thin-layer chromatographic methods (TLC) and allows routine assays in plasma.


[Studies on the effect of oxprenolol on experimentally induced anxiety (author's transl)]. This experiment studied the question of whether the receptor blocking agent oxprenolol (20 mg) influences somatic and subjective responses to experimentally induced anxiety. 72 male students were Ss in a two-factorial design with type of drug (oxprenolol, placebo) and type of situation as the two factors. Anxiety was induced by the signaled application of shocks to one arm, under condition A with and under condition B without time control (clock available or not). Condition C was a control condition with neither shock nor time control. Heart rate, blood pressure and verbal reports of emotional experience were measured. An analysis of variance revealed the following: Oxprenolol showed physiological effects typical of a receptor blocking agent. The drug positively affected emotional experience not related to the experimentally induced anxiety but did not affect the emotional responses induced by the anxiety-provoking conditions. For explaining the results the possible meaning of the variable "internal vs external control of emotional responses" was considered.


[Experimental psychophysiological studies on the effects of fenetylline and mefenorex]. 16 male subjects were tested 1--7 h after the application of either 40 mg of the anorectic mefenorex, 50 mg of the stimulant fenetylline or a placebo by a battery of psychophysiological and psychological methods. Two problems of basic psychological interest were investigated: 1. covariation of appetite and central stimulation; 2. indicators of activation assessed by different parameters. The results concerning the first problem were inconclusive. The results with respect to the second show that pharmacological substances may cause dissociation of different indicators of activation.


Pharmacological studies on 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino ]1,2-a] quinoline hydrochloride (compound 69/183). Part III: Assessment of tranquillising activity. The tranquillising activity of 3-[gamma-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,6-hexahydro-1-(H)-pyrazino [1, 2-a]quinoline hydrochloride (centpyraquin), a new adrenergic neurone blocking antihypertensive agent, has been evaluated in various laboratory animals. The compound has a calming effect in mice, rats, cats and monkeys. In low doses it reduces the spontaneous motor activity followed in progressively higher doses by hypothermia, ptosis and catalepsy and a taming effect in monkeys and cats. It potentiates pentobarbitone-, hexobarbitone- and ethanol-induced sleep and antagonises amphetamine induced toxicity in mice. It, however, fails to antagonise morphine induced mania and hyperactivity in cats. It blocks conditioned avoidance response in rats at a much lower dose (ED50 = 2.73 mg/kg) than the unconditioned response (ED50 = 10,9 mg/kg). In cats centpyraquin increases the voltage and slows the frequency of cortical EEG discharges. Centpyraquin has the profile of activity of a neuroleptic on the central nervous system.


Comparative studies on starvation - and indomethacin - induced ulcerations in albino rats. Experimental models of chronic and acute peptic ulcerations were produced in the albino rats by means of prolonged starvation and indomethacin administration. In the case of acute indomethacin-induced peptic ulceration, the effects of anticholinergic drugs on the ulcers produced were also studied. Starving the rats for a period of seven days produced gastric ulceration in all the rats used while indomethacin produced gastric ulceration within five hours in all the rats used. Severe ulceration of the degree found in human peptic ulcer disease was produced only by chronic starvation. Anticholinergic drugs ameliorated indomethacin-induced gastric ulceration, partly at least, by reducing intra-gastric acidity.


Comparison of flunitrazepam and diazepam for oral premedication in older children. A double-blind trial was conducted of two benzodiazepines, flunitrazepam and diazepam, given orally to 142 children (30 kg in weight or heavier) undergoing routine surgery. Flunitrazepam was associated with greater sedation before operation and less vomiting after operation than diazepam. Flunitrazepam caused a greater frequency of amnesia for the periods of induction and immediately after operation. Plasma concentrations were measured in 65 children and were found to be significantly greater in those children having amnesia for the induction period in both flunitrazepam and diazepam groups. In the diazepam group, plasma concentrations were significantly smaller in those who vomited than in those who did not vomit.


Comparison of I.M. pethidine, diazepam and flunitrazepam as premedicants in children undergoing otolaryngological surgery. Pethidine 1 mg kg-1, diazepam 0.25 mg kg-1 and flunitrazepam 0.02 mg kg-1 i.m. wer compared as premedicants in a double-blind study in 145 children undergoing otolaryngological surgery. Both flunitrazepam and pethidine had an anxiolytic effect in the children of less than 5 yr whereas diazepam had little effect. All of the drugs were anxiolytic in the children aged 5 yr and older. Sleep following thiopentone was restless more often in the younger than in the older children. Cardiovascular responses to thiopentone and to tracheal intubation were most obvious following benzodiazepines in children of less than 5 yr. After anaesthesia 10--33% of the older children could not recall pictures shown to them before anaesthesia. Forty-five (+/-SD 13) min after injection, the concentration of diazepam in serum was similar in both age groups; after 90 min it decreased in the younger and increased in the older children. All concentrations of flunitrazepam were significantly greater in the older compared with the younger children.


Comparison of diazepam and flunitrazepam as adjuncts to general anaesthesia in preventing arousal following surgical stimuli. A comparison has been made between the effects of the administration of flunitrazepam 1 mg i.v. and diazepam 10 mg i.v. in 90 female patients undergoing abdominal surgery. The drugs were given immediately before the skin incision as a booster to the induction agent thiopentone. The response to the incision, the quality of anaesthesia and the need for supplementary medication during maintenance were monitored. A standard post-anaesthesia interview was performed to evaluate the amnesic action and patient acceptability. The skin incision caused only slight increase in arterial pressure and heart rate in both groups. Only six patients of the diazepam group reacted to the incision with defensive movements. The overall quality of anaesthesia was better (P less than 0.05) and the need for supplementary doses of pethidine lower (P less than 0.01) in the flunitrazepam group. Recovery was equally good and the duration of sleep after operation was the same in both groups. The frequency of nausea after operation was low. The post-anaesthesia interview revealed that flunitrazepam possesses a more specific anterograde amnesic action than diazepam. Acceptability of the anaesthesia to the patient was equally good in both groups.


Plasma concentrations of medazepam and its metabolites after oral administration. The plasma concentrations of medazepam and its metabolites, diazepam and desmethyldiazepam, were determined in volunteer subjects following the oral administration of medazepam 10 mg. The results indicated that medazepam was absorbed rapidly, that low concentrations of metabolites were present during the 1st h, and that the build-up in the circulation of the major metabolite, desmethyldiazepam, was prolonged and variable. As many of the clinical effects and possible adverse reactions of medazepam appear to be associated with the presence of this major metabolite, the metabolic and pharmacokinetic characteristics of the drug should be considered when using medazepam as an anxiolytic before dentistry or surgery.


Response of mean and phasic coronary arterial blood flow to graded hypercapnia in dogs. An electromagnetic flow meter was used to assess the changes in coronary blood flow in response to four levels of increased PaCO2 in six dogs. Mean, diastolic and systolic flow all increased during hypercapnia, the increase being maximal at mean PaCO2 11.3 KPa. Mean and diastolic coronary vascular resistances decreased progressively as PaCO2 increased, but systolic resistance, although decreasing with the lower levels of hypercapnia, returned to control at the greatest PaCO2. Although the oxygen available to the myocardium was increased markedly during hypercapnia, coronary sinus PO2 increased also, reflecting a reduction in myocardial oxygen extraction; thus myocardial oxygen consumption was unchanged. Cardiac output was increased significantly only at the greatest PaCO2. Total body oxygen handling was not altered significantly.


Quantitative assessment of bronchial beta-adrenoceptor blockade in man. 1. We describe a method for assessing bronchial beta-adrenoceptor blockade quantitatively in man. Specific airway conductance is measured after increasing doses of inhaled salbutamol and the extent to which the dose-response curve is displaced to the right after beta-adrenoceptor blocking drugs is used to assess bronchial beta-adrenoceptor blockade. 2. Salbutamol dose-response curves were plotted for six normal subjects by measuring sGaw 15 min after increasing doses of inhaled salbutamol. Salbutamol produced a 30-70% increase in sGaw. 3. Salbutamol dose response curves were obtained 2 h after oral practolol (100 mg and 200 mg) and oral propranolol (40 mg and 80 mg) on separate days and were displaced to the right. 4. The mean dose ratios for practolol 100 mg and 200 mg were 1.2 and 2.1 and for propranolol 40 mg and 80 mg they were 21 and 61 respectively.


Onset and duration of beta-adrenergic receptor blockade following single oral dose acebutolol hydrochloride (Sectral). 1. The onset and duration of action of once daily acebutolol (400 mg) on resting and exercise heart rate and blood pressure were studied in normal subjects in a double-blind, cross-over trial against placebo. Subjects were studied 1.5, 3, 8 and 24 h after the first dose and 24 h after the fifth dose. 2. Resting and exercise heart rate and blood pressure were significantly reduced within 90 min of the first dose. 3. A significant reduction in these variables persisted throughout 24 h after the fifth daily dose. However, at 24 h the effects were considerably attenuated, the falls in resting and exercise systolic blood pressure being only 5%. 4. A linear relationship was noted between log serum drug level and percentage reduction of exercise heart rate.


Improved physical performance as a therapeutic objective in patients with angina. 1 Improvement in physical performance, based on exercise tolerance, self-assessed work and physician-rated functional capacities, is proposed as a measure of efficacy of anti-anginal therapy in the rehabilitation of the cardiac patient. 2 Improved physical performance parallels changes in frequency of anginal attacks and a nitroglycerin requirements following beta-blocker therapy. 3 Nadolol (a beta-blocker), given once daily is as effective as propranolol, given four times daily as an anti-anginal agent.


Effect of beta-blockers on exercise double product (systolic blood pressure x heart rate). 1 The effect of single oral doses of six beta-receptor antagonists on exercise-induced changes in double product (systolic blood pressure x heart rate) were studied in 25 human volunteers. 2 Three doses of propranolol, nadolol, oxprenolol, pindolol, timolol and atenolol were selected for study on the basis of in vivo beta-blocking potency. 3 Although all beta-blockers studied reduced the double product response to exercise, the pharmacodynamics of this effect differed markedly. 4 Pharmacodynamic half-lives, estimated for the drug tested, were 39 h for nadolol, atenolol 21 h, timolol 15 h, oxprenolol 13 h, propranolol 11 and pindolol 8 h. 5 These results suggest that the clinical choice of a beta-blocker with the least problems of compliance can be made on the basis of pharmacodynamics as well as pharmacological profile.


Possible significance of the pharmacological differentiation of beta-blockers for therapy of hypertension. 1 Cardioselective and non-selective beta-blockers affect to a different degree several aspects of the circulatory homeostasis. The evidence available in this regard has been evaluated and the possible clinical importance of these differences has been discussed. 2 Venous return in partly regulated by beta-receptors (possibly of the beta 2 type) in the venous resistance vessels. Differences in blockade of venous return by the two classes of beta-blockers may, therefore, influence the degree of increase in left ventricular size, left ventricular end diastolic BPs and stroke volume during beta-blockade. 3 At the first part of the dose-reponse curve, non-selective beta-blockers seem to block more effectively renin release than cardioselective beta-blockers. 4 The direction and the extent to which beta-blockers 'directly' affect total peripheral resistance (TPR), is determined by the resultant of the degree of decrease in TPR by blockade of renin release and the extent of the increase in TPR by blockade of the beta 2-receptors in the arteriolar wall. 5 The clinical relevance of these differences could be that--especially in the low doses range--non-selective beta-blockers may be more 'safe' in patients with compromised cardiac function and may be more appropriate for the therapy of high renin hypertension than cardioselective blockers, whereas the latter may be more appropriate for the majority of hypertensive patients who have low to normal renin hypertension.


Diuretics as initial treatment for essential hypertension. 1 In the United States, the thiazide diuretics are considered the cornerstone of all antihypertensive regimens for four reasons: by themselves, they are capable of controlling the blood pressure in 60-70% of the hypertensive population; they prevent the sodium retention produced by all other antihypertensive agents; they can be given once a day; and they are inexpensive. 2 Despite these advantages, the thiazide do cause hypokalaemia hyperuricaemia and hyperglycaemia. The incidence of hypokalaemia (K less than 3.0 mEq/l) is only 2-4%; the incidence of hyperuricaemia (uric acid greater than 10 mg per cent is 3-4%; and the incidence of hyperglycaemia is 1-2%. 3 The possibility that a beta-blocking agent combined with a thiazide diuretic might produce better BP control, prevent thiazide-induced abnormalities and exert a coronary prevention action with once daily administration would suggest that such a combination should be the ideal initial therapy for most patients with hypertension.


Diuretics, beta-blockers or both as treatment for essential hypertension. 1 Patients with borderline (group I) and sustained hypertension (group II) were treated with beta-blocking drugs, diuretics and the combination of both. In the two groups of patients the antihypertensive effectiveness of both short-term intravenous or chronically oral propranolol was directly related to the extent to which the drug produced an absolute reduction in plasma renin activity (PRA). No such a correlation could be obtained with pindolol. In group I following beta-blockade, day-night profiles of PRA were similar to those observed in group II before treatment. Thus, in this latter subgroup, low renin profiles might reflect reduced beta-adrenergic activity. 2 When the chronically beta-blockaded patients were changed to chronic diuretic therapy it became evident that young hypertensive patients of group II showed a more pronounced BP response than the patients of group I. In those patients of group II in whom pressure was not controlled by the diuretic alone, combination with a beta-blocker led to pressure normalization. 3 The beta-blocking drug induced reduction in pressure was greater in the 25-35 yr olds, than in those older than 55. In contrast, the antihypertensive effect of the diuretic was more pronounced in the 55-70 yr olds than in those younger than 40. 4 It is concluded that sympathetic nervous system activity mainly determined PRA as well as antihypertensive effectiveness of both the beta-blockers and the diuretics. As to outpatient management it is proposed that with exception of young borderline hypertensives who seem to respond best to beta-blockers, initial antihypertensive drug therapy may consist of a diuretic agent. If the antihypertensive effect of the diuretic is insufficient, combination with a beta-blocking drug could be used to achieve the best effect.


Long-term treatment of essential hypertension using nadolol and hydrochlorothiazide combined. 1 The stepped care approach for the treatment of hypertension was adopted in a study at Ain Shams Hospital using hydrochlorothiazide (HCT) and a new beta-blocker, nadolol. Sixty mild to moderately hypertensive patients were studied for 20 weeks (2 weeks no antihypertendive the therapy, 3 weeks placebo, 3 weeks HCT, 4 weeks nadolol + HCT dose titration and 8 weeks nadolol + HCT maintenance). The dose of HCT was 50 mg once daily throughout the study except for six patients who had their HCT dose increased to 100 mg daily during maintenance. The dose of nadolol ranged from 40-240 mg daily. 2 No patient on HCT monotherapy achieved full control of his supine diastolic blood pressure (SDBP less than 90 mm Hg). On combined therapy, 55 patients (91.7%) showed a full response, whereas the remaining five patients a good or adequate response. 3 Thirty-two of these patients agreed to continue in the study for a further 21 months (totalling 2 yr of therapy). To date, 15 of them have completed a total of 10 months, 7 have completed 11 months and 10 have completed 12 months. The delta percentage decrease in supine BP continued to be 28.0 and 19.5 for systolic and diastolic BPs respectively. 4 No significant changes in funduscopies, chest X-rays, ECGs, or full laboratory investigations were noted. A few side-effects of mild nature occurred. None necessitated discontinuation of therapy. 5 Combined therapy with nadolol and HCT is a safe and effective method of controlling hypertension over extended periods.


Antihypertensive action of beta-adrenoceptor blockade and the renin-angiotensin system. 1 The regulation of renin secretion is mediated by way of adrenoceptors. The role of alpha-adrenoceptors remains controversial, whereas it is generally accepted that activation of beta-adrenoceptors stimulates renin and their blockade suppresses renin. 2 Although experimental renin regulation appears to be a beta 2-receptor function, clinical studies suggest that in man it is a beta 1 effect. 3 beta-Adrenoceptor-blocking agents are effective antihypertensive agents, but have variable effects on renin secretion; this variability may be attributable to different degrees of instrinsic partial beta-agonistic activity and/or different receptor or organ selectivity of various compounds. 4 Antihypertensive effectiveness seems unrelated in magnitude or timing to the baseline levels or the changes of plasma renin activity for the majority of beta-adrenoceptor-blocking drugs.


beta-Adrenoceptor-blocking agents and the kidney: effect of nadolol and propranolol on the renal circulation. 1 Nadolol was administered intravenously to five hypertensive patients and three healthy volunteers in balance on a 10 mEq sodium intake. 2 Nadolol (0.3-10.0 micrograms/kg) induced a significant, dose-related increase in renal blood flow, measured with radioxenon, with a maximum increase of 72 +/- 4 ml/100g/min (26%) at 3.0 micrograms/kg. 3 Heart rate and plasma renin activity decreased significantly over the same dose range. 4 The renal vascular response to nadolol contrasts sharply with those found with other beta-adrenoceptor-blocking agents. 5 The magnitude of the increase in renal blood flow, its time-course and the parallel fall in plasma renin activity raise the possibility that the renal vasodilation reflects the reversal of angiotensin's influence on the renal arterial bed.


Elimination of nadolol by patients with renal impairment. 1 Nadolol excretion was studied in 24 patients with chronic renal failure. 2 The amount of nadolol excreted during the 120-h period after receiving the drug ranged from less than 1% in functionally anephric, patients up to 11.5% in patients with average creatinine clearance of 57.9 +/- 3.6 ml/min/1.73 m2. 3 Renal clearance of nadolol was found to correlate with creatinine clearance; nadolol elimination is retarded in patients with renal failure. 4 Nadolol serum half-life is prolonged in proportion to the remaining renal function. Therefore, dosage intervals in renal patients receiving nadolol should be adjusted to creatinine clearance. 5 Haemodialysis effectively reduced serum concentration of the drug; it may therefore be a useful therapy for drug intoxication.


Regression of left ventricular hypertrophy during treatment with antihypertensive agents. 1 Echocardiography showed 14 of 24 patients with essential hypertension to have hypertrophy of their left ventricular walls. In eight of these 14 patients the left ventricular configuration initially fulfilled the criteria for asymmetric septal hypertrophy (ASH) and six were symmetrically hypertrophied, the remaining ten being normal. 2 Following 12 weeks' treatment of hypertension with the object of reducing the supine BP to 150/90 mmHg or below, there was a reduction of wall thickness so that only two of the eight continued to show ASH. 3 The six patients with symmetrical left ventricular hypertrophy also showed a significant reduction in the thickness of the septum and the posterior wall. Those with normal echocardiograms did not change. 4 This reduction of wall thickness produced by antihypertensive therapy may represent regression of left ventricular hypertrophy.


Effect of treatment of hypertension in the primary preventive trial, Göteborg, Sweden. 1 A treatment group comprising 635 hypertensive men (casual SBP greater than 175 or DBP greater than 115 twice) was compared with a reference group (n = 391 men; casual SBP greater than 175 or DBP greater than 115 only at screening). All men belonged to the same population sample of 7,455 men aged 47-54 yr. 2 The two groups did not differ with respect to age, smoking habits or cholesterol values, but screening BPs were higher in the treatment group. 3 During 4.3 years' follow-up there was a significantly lower total death rate in the treatment group compared with reference group. 4 There was also a strong tendency towards lower incidence of non-fatal myocardial infarction (P = 0.06). The pooled incidence of non-fatal myocardial infarction and fatal CHD was lower in the treatment group than in the reference group (P less than 0.03).


Hydroxylation of dehydroepiandrosterone in human scalp hair follicles. The dehydroepiandrosterone hydroxylating enzyme system in the hair follicle has been characterized. It is found in the particulate fraction of the follicle, and is inhibited by carbon monoxide and the cytochrome P450 inhibitor metyrapone, and appears to be dependent upon NADPH. In these major characteristics the hair follicle enzyme is very similar to the liver monooxygenase system.


Relevance of colony forming assays to bone marrow transplanation with particular reference to grafting for aplastic anaemia. The value of bone marrow colony-forming assays in monitoring transplanted patients has been assessed by comparing results from two pairs of bone marrow recipients. One pair received marrow from their identical twins for acute lymphoblastic leukaemia; the other pair were grafted with allogeneic marrow from their siblings for aplastic anaemia. One of each pair showed successful engraftment while in the others the grafts failed. The colony-forming assay was then used to investigate marrow function in five grafted aplastic patients. Of these, four rejected their first grafts and required further immunosuppression before engraftment could be accomplished. The remaining patient was immunosuppressed at the outset with antithymocyte globulin (ATG) and her first graft was successful. Sera from all five patients inhibited colony formation by normal human marrow and it is suggested that this activity was related to graft rejection as well as to the pathogenesis of the condition.


Oscillation-frequency and baseline fetal heart rate in the last 30 minutes of labour. The last 120 minutes of 394 intrapartum fetal heart rate (FHR) records of high technical quality were evaluated. Baseline FHR was estimated and oscillation frequency (OF) counted for each minute. There was a highly significant association between the baseline FHR and the number of oscillations/minute; an increase in baseline FHR of 10 beats/minute was associated with a fall of about one oscillation/minute. The highest mean OF (9.6 +/- 4.8 events/minute) was found in fetuses with an umbilical artery pH of between 7.20 and 7.25. The baseline FHR should be taken into account when assessing fetal condition.


The digestion of pectin in the human gut and its effect on calcium absorption and large bowel function. 1. The effect of dietary fibre digestion in the human gut on its ability to alter bowel habit and impair mineral absorption has been investigated using the technique of metablic balance. 2. Five healthy male students were studied for 9 weeks under controlled dietary conditions and during the last 6 weeks they took 36 g pectin/d. Bowel habit, transit through the gut, faecal fibre excretion, calcium balance and faecal composition were measured. 3. During the control period only 15% of the dietary fibre ingested was excreted in the stools and when pectin was added to the diet there was no increase in fibre excretion. Stool frequency and mean transit time were unchanged by pectin but stool wet weight increased by 33% and faecal excretion increased (%) for fatty acids 80, nitrogen 47, total dry matter 28 and bile acids 35. Ca balance remained unchanged. 4. It may be concluded from these results that dietary fibre is largely metabolized in the human gut and dietary pectin completely so. This could explain its lack of effect on bowel habit and Ca balance. Other changes in the faeces may be related to an increase in bacterial mass.


Escherichia coli phosphoenolpyruvate dependent phosphotransferase system. NMR studies of the conformation of HPr and P-HPr and the mechanism of energy coupling. 1H and 31P nuclear magnetic resonance investigations of the phosphoprotein intermediate P-HPr and the parent molecule HPr of the E. coli phosphoenolpyruvate dependent phosphotransferase system (PTS) show that HPr can exist in two conformations. These conformations influence the protonation state of the reactive histidine residue, thereby determining the reaction pathway in the phosphoryl group transfer step. A general mechanism is proposed for the energy-coupling process in the PTS.


Aminoacyl-tRNA synthetase stimulatory factors and inorganic pyrophosphatase. A protein was purified from rat liver which stimulated a number of liver aminoacyl-tRNA synthetases. This stimulatory factor was identical with the "tRNA activator" of Dickman & Boll [(1976) Biochemistry 15, 3925] in its mechanism of action and chemical properties, although it was considerably more purified. The two preparations stimulated synthetases by virtue of their pyrophosphatase activity which destroyed the potent inhibitor, PPi, that was present in the reaction mixtures. This PPi was either generated during the reaction or was introduced by contamination of the tRNA or ATP preparations. The degree of inhibition of PPi was strongly influenced by assay conditions, being most effective at low amino acid concentrations, at low pH, and in the presence of heterologous tRNAs. By use of certain assay conditions, PPi concentrations as low as 2 microM could inhibit some synthetases close to 50%. The pitfalls associated with some assay conditions commonly used for aminoacyl-tRNA synthetases are discussed. These studies raise questions about the physiological significance of many previously described aminoacyl-tRNA synthetase stimulatory factors.