Contribution to the understanding of the mechanism of cytokinesis in plant cells: the action of deoxyguanosine on the kinetics of a root meristem cell population.

The kinetics of binucleate cells, formed by the action of deoxyguanosine, are studied using three methods: in a population synchronized with hydroxyurea, by autoradiography after pulse-labelling, and in a sample of a cell population morphologically located at the M--G1 limit. Deoxyguanosine induces a slowing down in S and G2, independent of the inhibition of cytokinesis. It is only when it takes effect during the G2 stage that deoxyguanosine brings about the formation of binucleate cells.


The measurement of cell turnover rates using stable isotope-labelled thymidine: experiments on the small intestine and on a transplantable lymphatic tumour of the mouse.

Multilabelled, non-radioactive thymidine and tritiated thymidine were incorporated simultaneously into the DNA of a rapidly-growing, transplantable mouse lymphoma and the DNA of mouse small intestine by a single intraperitoneal injection of both labelled nucleosides. Mice were killed at selected times during the next 7 days, and the specific activities of the tissues and extracted DNA and the 132/126 mass ratio of thymine isolated from the DNA were determined by scintillation counting and by field ionization mass spectrometry respectively. The rates of decrease of the concentrations of tritiated and stable isotope-labelled thymine in the DNA of the tumour or of the intestine were essentially identical. These results indicate the feasibility of using thymidine multilabelled with stable isotopes for measurement of cell turnover rates in conjunction with cancer therapy.


beta-Adrenergic insulin release and adrenergic innervation of mouse pancreatic islets.

An investigation of the stereospecificity of beta-adrenergic insulin release, its relation to alpha-adrenergic blockade and the adrenergic innervation of the pancreatic islets was performed in the mouse. It was observed that in vivo beta-adrenergic stimulation of insulin release by isopropylnoradrenaline was stereospecific for the L-stereoisomer and selectively blocked by the L-isomer of the beta-adrenergic antagonist L-propranolol. D-propranolol had no effect. Pretreatment of mice with a dose of D-isopropylnoradrenaline devoid of insulin releasing activity, slightly increased the subsequent insulin response to a half-maximal dose of L-isopropylnoradrenaline. Basal insulin secretion was blocked by L-propranolol (beta-adrenergic blockade) and increased by phentolamine (alpha-adrenergic blockade). A beta-blocked insulin response to L-isopropyl-noradrenaline could be overcome by alpha-adrenergic blockade depending on the dose of the beta-agonist, suggesting a close association between the adrenergic receptors. The adrenergic innervation of the islet cells was studied by electron microscopic autoradiography after injection of 3H-L-noradrenaline. It was observed that labelled adrenergic nerve terminals were associated with both A1- (D-), A2- and B-cells. The nerves were mainly distributed in the periphery of the islets either as single axons or as bundles. The majority of the terminals were associated with A2-cells, the most frequent cell type in the islet periphery. However, in all islets examined terminals were found close to B-cells. Adrenergic terminals often caused indentations in the contour of an islet cell and were separated from the islet cell membrane only by a narrow intercellular space, about 20 nm in width. It is concluded that the islet cells of the mouse are equipped with the morphological substrate for direct adrenergic regulation. Further it is suggested that the B-cell is supplied with L-stereospecific beta-adrenergic receptors and that the alpha- and beta-adrenergic receptors are at least partially interrelated.


Changes at the ecto-mesodermal interface during development of the duck preen gland.

An ultrastructural investigation of the organogenesis of the duck preen gland showed variations at the ecto-mesodermal interface in the course of development. During the period of invagination, ectoderm and mesoderm were separated by a continuous basal lamina. Morphogenesis of the tubules is characterized by a preferential deposition of non-oriented collagen fibres localized at the branching sites. Direct contacts between ectodermal extensions and mesodermal cells, through gaps in the basal lamina, appeared at the end-buds after the morphogenetic pattern was established and before the onset of the glandular secretory activity. The correlation between the modification of the ecto-mesodermal interface and the differentiation of uropygial ectoderm is discussed.


Ultrastructural and cytochemical studies on the cytodifferentiation of duodenal endocrine cells.

The development of cytodifferentiation of endocrine cells that produce the gastrointestinal hormones gastrin, cholecystokinin and secretin have been studied by a combined fluorescence-cytochemical, immunocytochemical and ultrastructural approach. The results show that, during development, several ultrastructurally distinct cell types exhibit COOH-terminal gastrin and cholecystokinin immunoreactivity. Furthermore, some cells simultaneously contain both gastrin- and cholecystokinin-specific antigenic determinants. Studies on the time course of development of gastrin and cholecystokinin cells, together with the above-mentioned data, suggest that gastrin cells may be converted into cholecystokinin cells in development. During this period, gastrin, cholecystokinin and secretin cells store the biogenic monoamine, 5-hydroxytryptamine a feature not displayed by the adult counter-parts of these cells. In the adult duodenum, characteristic enterochromaffin (EC) cells store 5-hydroxytryptamin for which, evidence for a possible hormonal role has been presented. Taken together, our data indicate that the differentiation of duodenal endocrine cells occurs in distinct steps, each involving a restriction in the biosynthetic repertoire of the cell.


Processing of rRNA by RNAase P: spacer tRNAs are linked to 16S rRNA in an RNAase P RNAase III mutant strain of E. coli.

To determine which enzymes are responsible for the processing cleavages of ribosomal RNA transcripts in Escherichia coli, we constructed a mutant strain lacking RNAase III and containing a thermolabile RNAase P. At the nonpermissive temperature, this strain accumulates a novel "19S" RNA species which contains 17S precursor rRNA sequences covalently linked to tRNA sequences transcribed from the ribosomal RNA spacer region between the 16S and the 23S rRNA cistrons. In vitro treatment of 19S RNA with cell extracts releases tRNA2Glu and other tRNA species. These "spacer" tRNA sequences are apparently not contained with the 18S RNA species found in an RNAase III- RNAase P+ cell. RNAase P-deficient extracts are incapable of cleaving space tRNA from 19S RNA, indicating that RNAase P is required for the release of spacer tRNAs from rRNA transcripts of E. coli cells.


Translation of tobacco mosaic virus RNA In Acetabularia cell cytoplasm.

Isolated Acetabularia nuclei were microinjected with Tobacco Mosaic Virus RNA and then implanted into an anucleate posterior fragment of an Acetabularia cell. Injected RNA was translated in the Acetabularia cytoplasm from the first to twelfth day after implantation of the nuclei. The production of specific virus proteins was detected and localized in the Acetabularia cytoplasm by an immunofluorescence precipitation technique.


Compartmentalizing the S period.

In order to increase the resolution of interphase analysis we have developed a method which is an alternative to cytofluometric techniques for tissues where cell flow is not applicable. The method combines the estimation of cell frequency in G1, S, G2 and mitosis after a 3H-thymidine pulse with the grouping of interphase cells according to their DNA content, as estimated by cytophotometry in Feulgen stained nuclei. By superimposing both sets of data we get three different artificial compartments within the S period. As a biological test of the resolution reached, the method readily confirmed that hydroxyurea, after one cycle time, accumulates cycling cells of Allium cepa L. root meristems in early S.


The [18F]fluorodeoxyglucose method for the measurement of local cerebral glucose utilization in man.

A method has been developed to measure local glucose consumption in the various structures of the brain in man with three-dimensional resolution. [18F]-2-deoxy-2-fluoro-D-glucose is used as a tracer for the exchange of glucose between plasma and brain and its phosphorylation by hexokinase in the tissue. A mathematical model and derived operational equation are used which enable local cerebral glucose consumption to be calculated in terms of the following measurable variables. An intravenous bolus of [18F]-2-deoxy-2-fluoro-D-glucose is given and the arterial specific activity monitored for a predetermined period of from 30 to 120 minutes. Starting at 30 minutes, the activity in a series of sections through the brain is determined with three-dimensional resolution by an emission tomographic scanner. The method was used to measure local cerebral glucose consumption in two normal volunteers. The values in gray matter structures range from 5.79 mg/100 g per minute in the cerebellar cortex to 10.27 in the visual cortex, whereas, in white matter structures, the values range from 3.64 mg/100 g per minute in the corpus callosum to 4.22 in the occipital lobe. Average values for gray matter, white matter, and whole brain metabolic rates, calculated as a weighted average based on the approximate volume of each structure, are 8.05, 3.80, and 5.90 mg/100 g per minute, respectively. The value of 5.9 mg/100 g per minute compares favorably with values previously reported.


Contribution of prostaglandins to muscle blood flow in anesthetized dogs at rest, during exercise, and following inflow occlusion.

The role of locally formed cyclo-oxygenase products (endoperoxide intermediates, prostaglandins, or prostacyclins) in resistance to blood flow was studied in the hindlimbs of anesthetized dogs during rest, during exercise, and following release of inflow occlusion. Meclofenamic acid, indomethacin, or sodium meclofenamate reduced mean resting blood flows of 86, 113, and 118 ml/min to 54, 82, and 67 ml/min, respectively. Inhibitors of prostaglandin synthesis reduced the vasodilator response to arachidonic acid by 81%. In addition, prostaglandin synthesis inhibitors attenuated the hyperemic responses following inflow occlusions in the resting hindlimb. The attenuation was most marked following a 1-second occlusion (74%) and progressively less following a 10-second (44%) and a 300-second (24%) occlusion. However, the portion of the total postocclusive hyperemic response attributable to prostaglandins was constant and independent of occlusion duration. Inhibition of prostaglandin synthesis did not affect the hyperemia of exercise, but reduced significantly the postocclusion hyperemia that followed the release of a 1-second (63%) and a 2-second (43%) period of inflow occlusion in the exercising hindlimb; attenuation was minor following a 10-second occlusion (10%). In three of four exercising hindlimbs, the portion of the postocclusion hyperemia attributable to prostaglandins was inversely related to the duration of the occlusion. These data indicate that locally synthesized cyclo-oxygenase products, possibly prostaglandins, are important in the maintenance of blood flow in resting but not exercising muscle, contribute significantly to postocclusive hyperemia in resting and exercising hindlimbs, and mediate the hyperemia that follows occlusions of 5 seconds or less in resting and 2 seconds or less in exercising hindlimbs.


An improved enzyme immunoassay for progesterone in human plasma.

We describe an enzyme immunoassay for progesterone in which we use a progesterone-11alpha-hemisuccinyl-horseradish peroxidase conjugate as the "label" and an antiserum raised in rabbits to a progesterone-11alpha-hemisuccinyl-bovine serum albumin conjugate. In this assay, antibody-bound and free steroid are separated by using a second antibody precipitation procedure. The assay has a lower limit of sensitivity of 10 pg/assay tube and satisfies the usual criteria of specificity, precision, and accuracy. Results obtained with a comparison radioimmunoassay and our procedure agreed well (r = 0.98). Eighty samples can be assayed per day. It is not only well suited for surveys where accurate determination of progesterone concentrations in small plasma aliquots is required, but also for monitoring ovulation induction in patients attending infertility clinics.


Differences in reading achievement between spina bifida children attending normal schools and those attending special schools.

This paper reports the reading scores measured on Neale's Analysis of Reading Ability of a series of 55 spina bifida children, some of whom attended normal schools and the remainder attended special schools and matched controls. A multiple regression equation was used to compare observed scores with the expected scores. The children receiving a normal school education were reading up to the level expected from their intelligence test scores, but the children in special schools had significant differences between observed and expected scores. The discrepancies may be accounted for by more profound physical handicap among the special school children but teachers' expectations may also be important in influencing reading achievement.


The vomero-premaxillary suture--a neglected growth site in mid-facial development of unilateral cleft lip and palate patients.

The growth capacity of the vomero-premaxillary suture (VPS) was analysed as this growth site, sometimes exposed during cleft surgery, is usually unrecognized in the patient's mid-facial development. Metallic implants were inserted on both sides of the suture in eight infants with unilateral cleft lip and palate at the time of the first surgery. The patients were followed roentgencephalometrically to the age of three years. Growth between the vomer and premaxilla was recorded in every case, with growth being especially marked during the first year of life. The horizontal increment of growth between the pins was greater than the vertical increment. On the basis of these findings, it was proposed that surgery which seriously impedes or stops growth in the VPS is likely to be an important factor in the etiology of the mid-facial retrusion that is sometimes seen in patients with unilateral cleft lip and palate.


Measurement of gonadotrophins, testosterone, delta4 androstenedione and dihydrotesterone in idiopathic oligospermia.

Basal concentrations of FSH, LH, testosterone, delta4 androstenedione and dihydrotestosterone, together with FSH and LH responses to single injections of LHRH were determined in eighty-four patients with oligospermia and in twenty-seven normal men. LHRH responses were heterogeneous and indicate that various disorders might cause this syndrome. In six cases there appeared to be an isolated deficiency in spermatogenesis, as indicated by an increased FSH response, whilst the LH response was normal as were the concentrations of the testicular hormones. In twenty cases a concomitant disorder of Leydig cell function and spermatogenesis is suggested as indicated by increased FSH and LH responses and decreased concentrations of testosterone and delta4 androstenedione (six) or concentrations at the lower limit of normal (fourteen). Furthermore, in five cases a hypothalamic and/or pituitary disturbance may be accepted on the basis of normal or decreased basal concentrations decreased and responses to LHRH with decreased concentrations of testosterone and delta4 androstenedione. Finally, in thirty-seven cases, oligospermia was not associated with any modification basal gonadotrophin concentrations or response to LHRH when compared with normal subjects.


Oestrogen amplification of LH-RH response in the polycystic ovary syndrome and response to clomiphene.

An LH-RH test was performed before and 44 and 92 h after treatment with 2.5 mg oestradiol benzoate in 17 patients with a diagnosis of polycystic ovarian (PCO) disease. The responses were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Patients were divided into two groups on the basis of their LH responses to LH-RH. In Group A (seven patients) the response at 92 h was greater than at 44 h as in the normal subjects, but in Group B (ten patients) the response at 44 h was greater than at 92 h. Basal serum hormone values were similar in the two groups except for androgens and oestrone, which were significantly (P less than 0.01) higher in Group B patients. There was a negative correlation between the basal androgen and oestrone concentrations and the LH and FSH amplifications at 92 h in all PCO patients. The ratios of the basal concentrations of LH to FSH and the ratios of the highest levels of each achieved during the basal LH-RH test, were significantly higher in the two groups of patients when compared to controls (P less than 0.01). The test is of value in predicting the subsequent responsiveness to clomiphene. All patients in Group A showed evidence of ovulation following treatment with 100 mg clomiphene for 5 days, but only one of Group B responded in this way.


The immunosuppressive and mitogenic effects of Trypanosoma musculi.

In CD-1 mice infected with Trypanosoma musculi, the production of IgM and IgG antibodies in response to sheep erythrocytes (SRBC) was significantly suppressed when mice were immunized with SRBC once high parasitaemias had developed. In infected mice which were not immunized with SRBC, background plaque-forming responses of spleen cells to SRBC were significantly higher than in uninfected, unimmunized mice. Factors derived from T. musculi were found to be mitogenic in vitro for spleen cells taken from CD-1 mice. The mitogenic response to these factors by spleen cells from athymic mice was highly significant, whereas the response of spleen cells taken from CD-1 mice which had been pre-treated with cyclophosphamide was much less, suggesting that the B cell was the major target of the trypanosome-derived mitogen. In this paper we discuss the possible relationship of T. musculi-induced mitogenesis to the immunosuppression and non-specific antibody formation associated with T. musculi infections.


Identification of I/i, Pr1-3 and Gd antigens in the human kidney: possible relevance to hyperacute graft rejection induced by cold agglutinins.

Human cold agglutinins (CA) with I/i, Pr1--3 and Gd specificities were tested for reactivity against kidney tissue by immunofluorescent techniques. I/i antigens were found on the epithelia of the Henle's loops and distal tubules. Pr1--3 antigens were demonstrated on the glomerular capillaries. Gd antigens were localized on the endothelia of the glomerular and peritubular capillaries as well as in the kidney interstitium. From these results, it is suggested that hyperacute rejection of renal transplants in recipients with high-titre CA may not only be caused by intravascular erythrocyte agglutination but also by direct cytotoxic damage of the transplant. Since CA occur frequently in potential kidney recipients, pre-operative determinations of CA in these patients should be recommended.


Distribution of IgA 1 and IgA 2 plasma cells in various normal human tissues and in the jejunum of plasma IgA-deficient patients.

The distribution of IgA 1 and IgA 2 plasma cells was studied in normal human tissues. IgA 2 is a minor constituent in peripheral lymph nodes as well as in serum and in bone marrow plasma cells. An increased proportion of IgA 2 plasma cells was observed in gastric and intestinal mucosa, as well as in bronchial mucosa and salivary and mammary glands. Tonsils and mesenteric lymph nodes exhibit values intermediate between those of central and peripheral lymphoid systems. In patients with plasma IgA-deficiency, IgA 2 is the predominant intestinal IgA plasma cells. This may explain the frequent association of an asymptomatic condition and plasma IgA deficiency.


Human peripheral lymphocytes bearing surface immunoglobulin do not have readily detectable Fc receptors.

The question of whether human peripheral B lymphocytes have Fc receptors was examined directly by double-label immunofluorescent techniques utilizing assays for detection of Fc receptors, surface immunoglobulin, and complement receptors. Fc receptors were detected by indirect immunofluorescence after incubation with soluble antigen-antibody complexes. Complement receptors were detected by the binding of fluoresceinated bacteria coated with complement. It was demonstrated that most surface immunoglobulin-bearing, complement-receptor positive lymphocytes did not bind soluble antigen-antibody complexes. Conversely, most cells which readily bound soluble complexes did not have surface immunoglobulin or complement receptors. Therefore, most peripheral B lymphocytes do not have easily detectable Fc receptors and most Fc receptor-bearing lymphocytes do not have B cell markers.


A comparison of hemodialysis and transplantation in reversing the uremic disturbance of male reproductive function.

A comparative study of the capacity of maintenance hemodialysis and renal transplantation to reverse the uremic damage to testicular function in 27 men with chronic renal failure was performed over a two year period. Despite two years of stable hemodialysis there was only minor improvement in sexual activity. Testosterone levels failed to improve and luteinising hormone (LH) levels remained high. Elevation of serum follicle stimulating hormone (FSH) together with severe spermatogenic damage persisted. Transplant patients showed a significant improvement in sexual activity, a return of testosterone to normal, and a significant fall in LH levels. Fertility, as assessed by sperm count, was improved in 50% of transplant patients. Thus while renal transplantation may restore reproductive function in men with chronic renal failure maintenance hemodialysis has no effect.


Membranous glomerulonephritis associated with anti-tubular and anti-alveolar basement membrane antibodies.

The renal biopsy of a 3-year old boy with complete Fanconi syndrome showed the association of a membranous glomerulonephritis with severe tubulointerstial changes. Immunofluorescence microscopy disclosed linear and granular deposits of Ig along tubular basement membranes. The presence of anti-tubular basement membrane antibodies in the patient's serum was demonstrated by indirect immunofluorescence and radioimmunoassay. The child also developed pulmonary involvement associated with episodes of acute anemia. Anti-alveolar basement membrane antibodies were detected by indirect immunofluorescence. The present case is the first reported example of auto-immune disease characterized by the presence of anti-tubular and alveolar basement membrane antibodies associated with an immune complex glomerulonephritis.


Histocompatibility antigens in urinary tract infection and vesicoureteral reflux: a preliminary communication.

Various factors may predispose urinary tract infection (UTI) due to E. coliin pediatric patients. Our observations on HLA typing of three families and 36 unrelated patients with recurrent UTI suggest that reflux is inherited through factors(s) loacated on the sixth pair of human chromosome in a close linkage with the Major Histocompatibility Complex. Thus, HLA haplotyping may be used as a marker for vesicoureteral reflux within a family. HLA specificity AW32 may be in linkage disequilibrium with factor(s) responsible for reflux. Furthermore, HLA typing of UTI patients revealed that certain HLA specificities (A2, A10 and BW16) may be assoicated with the susceptibility to UTI due to E. coli regardless of the presence of a reflux. The incidence of blood group A was found to be elevated in patients with recurrent TUI but only in the group which had no detectable reflux.


In vitro marrow culture techniques in aplastic anaemia and related disorders.

In vitro studies of marrow growth from patients with AA have generally confirmed the hypothesis that the disease is due to stem cell injury. By studies of marrow growth from AA patients (when possible) and their relatives to detect altered sensitivity of marrow stem cells to drugs or toxins, it may be possible better to identify suspected aetiological agents, and study genetic susceptibility to toxic AA. Lack of adequate stimulation has not been shown to be aetiological in AA as both ESF and CSF levels are generally higher than normal. Serum from AA patients has not been shown to be toxic to marrow and recent data suggesting that lymphocytes mediate some cases of AA have been questioned. Further studies of committed stem cell growth and the interaction between lymphocytes and stem cells are indicated in attempting to understand the complex of diseases that result in marrow aplasia.


Paroxysmal nocturnal haemoglobinuria in aplastic anaemia.

The syndrome of paroxysmal nocturnal haemoglobinuria is a stem cell disorder characterized by the production of abnormal cells in all three lines of the peripheral blood. These cells react abnormally with the activated components of complement, resulting in the clinical symptoms. The clone of stem cells characteristic of paroxysmal nocturnal haemoglobinuria may arise spontaneously without demonstrable abnormalities of the other stem cells of the bone marrow. On the other hand, the abnormal stem cells of paroxysmal nocturnal haemoglobinuria may arise as part of a prior stem cell disorder. This is especially true for aplastic anaemia. The paroxysmal nocturnal haemoglobinuria stem cell may arise at any time during the evolution from aplasia through recovery and may disappear during full recovery of the bone marrow. The paroxysmal nocturnal haemoglobinuria stem cell may arise less commonly in other disorders of the stem cell, such as refractory anaemia with excess blasts, erythroleukaemia and myelofibrosis. As with all disorders of the stem cells, paroxysmal nocturnal haemoglobinuria and aplastic anaemia may eventuate into acute leukaemia.


Pharmacological stimulation of marrow function.

Studies of the pharmacological stimulation of marrow function have provided insight into mechanisms which might possibly affect cell proliferation in vivo. However, the most dramatic and clear-cut effects have come with studies employing normal marrow or populations of cells recovering in a predictable manner from suppression. Even with this, a wide number of agents appear to be active and capable of influencing the growth or cycle activity of more than one class of progenitor, including both committed and pluripotent stem cells. Perhaps the most useful clinical insight from these studies is that they provide a rationale for 'rescuing' deliberately damaged marrow (as with high dose chemotherapy) and suggest that it may be possible to reduce the period of severe hypoplasia under controlled circumstances. In cases of idiopathic marrow failure, the situation is less hopeful. The studies do not indicate that we are at a stage where we may hope to enhance marrow function significantly in the severely aplastic patient. Initial suggestions that in vitro culturing of marrow cells with various agents might lead to a programme of specifically designed therapy have resulted in limited, but negative, experiments. It is not likely that this is going to be fruitful. It seems clear, however, that the phenotypic expression of marrow failure in man masks a number of pathogenetic mechanisms, and that further attempts to characterize marrow growth in such patients are warranted. Perhaps by identifying patients with normal growth patterns it will be possible to select individuals for rational pharmacological therapy with some expectation of success.


Androgen therapy of aplastic anaemia.

The current published reports have indicated that the young patient with aplastic anaemia who has a compatible marrow donor can obtain a successful marrow graft, especially if sex matched and with a past record of little or no transfusion therapy. Despite these encouraging results, only a small number of patients will have such donors available. Immunosuppressive therapy has been considered as an alternative, but this treatment has high risk in older patients. Past studies with androgen therapy have reported a response rate at one year similar to the current recovery rates with bone marrow transplantation. However, contemporary reports have indicated a marked decrease in the recovery rate following androgens, and some of these comparisons may be related to differences in supportive transfusion therapy. In part, the decreased rates may be related to an inadequate evaluation of residual marrow function in the aplastic patient. Patients to be treated with androgens always should have a physiological evaluation of residual erythropoietic committed bone marrow cells. In the absence of such an erythropoietic nidus, one may anticipate a poor response to any steroid therapy. Supportive blood component transfusions should be provided, especially in the initial three months of androgen treatment. In past studies the majority of patients have received only oral androgens, predominantly oxymetholone. Other androgens may be more effective in a particular patient, and there is an urgent need to develop procedures that define stem cell receptors for specific testosterone preparations. Current investigations have indicated that the 5 beta steroid metabolites of testosterone are haematopoietic without the complication of virilization. It is anticipated that a variety of these metabolites can be prepared for evaluation in the patient with aplasia. While there is continuing evaluation of the immune responses and suppressive therapies the clinician should continue to treat the aplastic patient with vigorous supportive transfusion therapy and different androgens for comparative evaluation.


Severe aplastic anaemia: a prospective study of the effect of androgens or transplantation on haematological recovery and survival.

A prospective study was performed (1) to evaluate the role of androgens in treatment of severe aplastic anaemia, and (2) to compare the efficacy of early bone marrow transplantation with more conventional therapy for severe marrow aplasia. Results fail to support a beneficial effect of androgens on the course of patients with severe aplastic anaemia. In contrast, histocompatible bone marrow transplantation significantly improves survival and haematological recovery. Alternative therapies should be carefully evaluated for non-transplantable patients with severe marrow aplasia.


Metoprolol with and without chlorthalidone in hypertension.

After a control period on a placebo, 45 patients with mild to moderate hypertension were treated with metoprolol, 100 mg twice daily alone and in free combination with chlorthalidone 50 mg daily using a double-blind crossover technique. The beta-blocker alone induced a significant fall in blood pressure; the diastolic pressure was reduced to 100 mg Hg or less in 37 of the 45 patients and to 95 mm Hg or less in 19 patients. The addition of chlorthalidone enhanced the antihypertensive effect so that in 33 patients diastolic pressure fell to 95 mm Hg or less. The drugs were well tolerated even by a small number of patients with chronic bronchitis and diabetes mellitus. None of the patients developed cardiac failure. Adding a diuretic caused a small reduction in serum potassium concentrations, and the relevance of this observation is discussed.


Hydrochlorothiazide and spironolactone in hypertension.

A double-blind study of hydrochlorothiazide and spironolactone, alone and in combination, was conducted in 49 patients with mild-to-moderate essential hypertension after a 4-wk placebo washout period. In the whole group mean arterial blood pressure fell to levels of less than or equal to 107 mm Hg or declined by more than 15 mm Hg in 78% of the patients after twelve weeks of treatment. Sixty-nine percent of patients receiving hydrochlorothiazide alone developed serum potassium levels lower than 3.5 mEq/L; serum potassium levels were above 5.5 mEq/L in 2 patients (5.5%) receiving spironolactone 400 mg/day. Uric acid levels rose in all patients, more in those on hydrochlorothiazide, but clinical gout did not develop in any subject. Hydrochlorothiazide, spironolactone, and the combination of the two are effective antihypertensives. Spironolactone in doses of 200 and 400 mg/day was associated with side effects but did not induce a greater antihypertensive effect than doses of 100 mg/day. Our data suggest that when hydrochlorothiazide is associated with potassium loss, when gout or elevated uric acid levels are of concern, or when carbohydrate tolerance is abnormal, supplementation or replacement with spironolactone (up to 100 mg/day) may be useful in controlling blood pressure while reducing side effects.


Proposals for standardization of terms in clinical trials of caries preventive agents and procedures.

The purpose of this paper was to comment on FDI's terminology for clinical trials of caries preventive agents and procedures. It is recommended that terms used to describe the score transitions observed in clinical trials, or checks of caries diagnostic reproducibility of examiners, should not contain words which imply qualitative judgments on the observed changes. It is suggested that caries increment should be used instead of "positive reversal", caries decrement instead of "negative reversal"; and scoring inconsistencies for score changes occurring in the results of checks on the diagnostic reproducibility of examiners. These recommendations would avoid the contradictions in terms which complicate the understanding of FDI's terminology.


Variability of gingival bleeding in experimental gingivitis trials.

Gingival bleeding is a difficult parameter to assess in experimental trials. The Confirmed Bleeding Day was recently developed as a measurement for this purpose. It was observed that considerable variations existed between the measurements made in a pilot study and an experimental trial, and these variations were subjected to a statistical analysis. The reasons for the variations are discussed, and recommendations made for the design of experimental trials involving gingival bleeding.


Inhibition of ovulation in women by chronic treatment with a stimulatory LRH analogue - a new approach to birth control?

A stimulatory luteinizing hormone-releasing hormone (LRH) analogue D-Ser (TBU)6-EA10-LRH was administered subcutaneously once daily in a dose of 5/microgram to four regularly menstruating women. Treatment was instituted within the first three days of the menstrual bleeding and continued for 22--30 days. Ovulation was inhibited in all the women during the treatment cycle. The treatment resulted in disturbances in the pituitary gonadotropin secretion which presumably led to disordered follicular maturation and anovulation. The maximum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) responses to the LRH analogue were obtained during the first few days of treatment. The gonadotropin responses then rapidly decreased during the prolonged treatment. This change in the pituitary responsiveness probably prevented the release of a normal preovulatory LH surge. After the treatment, all the women resumed normal ovulatory menstrual cycles. The results suggest that it might be possible to use stimulatory LRH analogues for birth control.


Contraception with long acting subdermal implants: I. An effective and acceptable modality in international clinical trials.

This paper presents results of a double blind, multi-centered and multi-national study of two progestin only subdermal implants used for contraception. A regimen of six capsules of levonorgestrel (Ng) used by 492 women had a net cumulative 12-month pregnancy rate of 0.6 percent and a continuation rate of 74.6 percent. 498 women used six capsules of norgestrienone (R2010) and experienced a net cumulative 12-month pregnancy rate of 3.5 percent and a continuation rate of 79.4 percent. The difference in the pregnancy rate was significant at P less than 0.01, while there was no significant difference in the continuation rates. Menstrual problems were the principal reason for termination of the levonorgestrel regimen, accounting for approximately half of all terminations. There were significantly fewer menstrual problems among users of the norgestrienone (R2010) capsules; the net cumulative 12-month termination rate for this reason was 4.3 percent. Results are compared with continuation and termination rates for acceptors of the Copper T 200 at the same clinics. The low pregnancy rate and reasonably high continuation rate of the norgestrel implants coupled with the fact that the expected effective lifetime of a set of capsules is of the order of 3-5 years appears to warrant further development of this contraceptive regimen.


Long acting contraceptive implants. An analysis of menstrual bleeding patterns.

The menstrual patterns of women using subdermal implants of levonorgestrel and norgestrienone included in a double-blind clinical trial was evaluated by the method developed by the International Committee on Contraception Research. Women using Copper T200 randomly selected in the same clinics were used as controls. Both implant regimens were associated with a high frequency of reduced bleeding and norgestrel patients had also a high proportion of increased and irregular bleeding. Termination of use was associated to increased bleeding but not so much to reduced bleeding.


Amatoxins, phallotoxins, phallolysin, and antamanide: the biologically active components of poisonous Amanita mushrooms.

This review gives a comprehensive account of the molecular toxicology of the bicyclic peptides obtained from the poisonous mushrooms of the genus Amanita. The discussion of the biochemical events will be preceded by a consideration of the chemistry of the toxic peptides. The structural features essential for biological activities of both the amatoxins and the phallotoxins will be discussed, also including the most important analytical data. Similar consideration will be given to antamanide, a cyclic peptide, which counteracts phalloidin. In addition, the phallolysins, three cytolytic proteins from Amanita phalloides will be discussed. The report on the biological activity of the amatoxins will deal with the sensitivity of the different RNA-polymerases towards the toxins and with their action on various cell types. Consideration will also be given to systems in which alpha-amanitin was used and can be used as a molecular tool; in the past, many investigators used the inhibitor in molecular biology, genetics, and even in physiological research. As for the phallotoxins, discussion of the affinity of these toxins for actin is provied. Further discussion attempts to understand the course of intoxication by filling in the gap between the first molecular event, formation of microfilaments, and the various lesions in hepatocytes during the intoxication.


Long-term infusion of sodium thiopental: hemodynamic and respiratory effects.

To establish the possible advantages of ultrashort acting barbiturates administered in continuous infusion as the only sedative agent for mechanically ventilated patients, sodium thiopental was given to 30 subjects for periods ranging from 2--14 days. Plasma levels were maintained at approximately 15 microgram/ml, using both laboratory determinations and clinical judgment. This technique proved effective for patients requiring either controlled ventilation or intermittent mandatory ventilation. None of the hemodynamic and respiratory variables studied was significantly altered during the infusion, with the exception of decreased heart rates. In view of these results, the technique is considered both expedient and safe for prolonged sedation of patients requiring ventilatory support.


Optimal flow pattern for mechanical ventilation of the lungs. 2. The effect of a sine versus square wave flow pattern with and without an end-inspiratory pause on patients.

In four series of patients, the efficiency of ventilation of a sine wave without an end-inspiratory pause was compared to a square wave without a pause, a sine wave with a pause to a square wave with a pause, a sine wave to a sine wave with a pause, and a sine wave with a long pause to one with a short pause.  The primary mode of evaluation was through simultaneous airway and arterial argon washout curves. Additional cardiopulmonary measurements were made. Results indicate: (1) a statistically significant improvement in ventilation with a sine wave with a pause; (2) a statistically significant improvement with the longer pause as compared to the short pause.


Historical overview of the cinnamon industry.

Cinnamon (Cinnamomum zeylanicum, Nees in Wall) is one of the world's oldest spices. Sri Lanka is the main provider of cinnamon, mainly exported as "cinnamon quills." From a phytochemical viewpoint, cinnamon is q uniquely interesting plant. The volatile oils obtained from the bark, leaf, and root bark vary significantly in chemical composition. Each oil has a different primary constituent: cinnamaldehyde (in the bark oil), eugenol (in the leaf oil), and camphor (in the root-bark oil). Recent studies based on techniques such as gas-liquid chromatography and infrared spectrometry have revealed that the three oils possess the same array of monoterpene hydrocarbons in different proportions. Both gas-liquid chromatography and quantitative infrared spectrometry have recently been used to study changes in the chemical composition in the volatiles of cultivated and wild-growing cinnamons. As a result, some interesting biosynthetic speculations have evolved, and reliable methods of analytical assessment of quality have been developed. The technology of production of cinnamon oils has varied little from the methods introduced by the early Dutch settlers. They are based on variations on the general theme of steam distillation. Recently, new still designs have greatly enhanced the technological capability in Sri Lanka. Cinnamon bark and leaf oils form the basis of a variety of synthetically derived chemicals used in the food and cosmetic industries.


The effects of expiratory positive airway pressure on functional residual capacity in normal subjects.

Functional residual capacity (FRC) was determined by constant volume, whole body plethysmography in seven normal subjects under resting conditions and following the addition of increasing levels of expiratory positive airway pressure (EPAP). There was a significant increase in FRC in six of the seven subjects studied. Grouped data showed a progressive increase in FRC with increasing EPAP (p less than 0.01). The highest level of EPAP (15 cm H2O) was associated with a 20% increase in FRC. We have been able to confirm that EPAP provides a simple and effective method of increasing FRC which could be applied to the treatment of conditions characterized by temporary and reversible reduction in lung volume.


Terminology update: optimal PEEP.

The term, optimal PEEP, requires redefinition in the light of new clinical data. With the onset of acute respiratory failure heralded by blood gas evidence of decreased oxygenation, PEEP is supplied in quantities sufficient to restore intrapulmonary shunt (Qsp/Qt) to a preselected goal of 15%. This is compatible with published criteria defining adequate blood gas exchange. Now rather than permitting reduction of cardiac output to be the end point of PEEP application, selective cardiovascular interventions to support preload, contractility, or afterload are made as appropriate so that cardiac function may be maintained until the preselected endpoint of shunt reduction of 15% can be made.


Recent progress in dietary fiber (plantix) in human nutrition.

Dietary fiber was extensively discussed in an article by G.A. Spiller and R.J. Amen in this journal in 1975 (Volume 7 Issue 1). The progress in this field has been tremendous in the past 2 years. What was an uncertain field in 1975 and what at that time to some investigators still appeared as a hypothesis or fad without much proof has turned into a much more respected part of nutritional sciences. The scientific quality of recent studies on dietary fiber in human nutrition shows a great deal of sophistication and care. Improved analytical methodologies are being used more extensively. Many nutritionists and clinicians have accepted the fact that a reasonable increase in the dietary fiber intake in the U.S. and U.K would be advisable. In this article, the possible beneficial effects of dietary fiber on health, the possible harmful side effects, and the food science aspects are carefully discussed after an update on chemistry, analytical procedures, and nomenclature. Undoubtedly, dietary fiber has found a new niche in the sciences of nutrition, medicine, epidemiology, and foods.


Lysosomal enzyme release from guinea pig alveolar cells: biochemical and morphologic observations.

Cells lavaged from guinea pig lungs selectively release the lysosomal enzymes beta-glucuronidase and lysozyme during the process of phagocytosis. The total enzymatic activity of beta-glucuronidase was elevated in zymosan-exposed compared with non-exposed cells. The divalent cation carrying ionophore A23187 did not stimulate lysosomal enzyme release. Transmission and scanning electron micrographs demonstrate particle uptake and are consistent with enzyme release.


Floorplans and cartoon strips--diagnostic techniques in working with children.

Two useful techniques in assessing and treating children ages 7-15 are described. Children are asked to draw a floorplan of their home. Drawing the floorplan reveals the child's ability to approach a task; some of the preferred activities in the home; the sleeping arrangements; and, most importantly, other significant people. With some children, constructing a comic strip can reveal their core conflicts and establish rapport. The comic strip is particularly useful with children who are very inhibited in their verbal utterances.


[The topographic-anatomical starting point in reconstructive surgery on the choledochus].

Operative tactics in reconstructive surgery of the common bile duct depend on localization of the lesions or strictures and special topography of this region. At first, it must be decided whether a direct suture seems to be practicable or a biliodigestive anastomosis has to be constructed. There is a better chance to succeed in performing an end-to-end anastomosis the farther away the occlusion is situated from the liver hilus. The main advantage of this procedure can be seen in the restoration of physiological bile discharge. Frequently, however, it shows a tendency to shrink even years later. Often--for establishing a choledochocholedochostomy without tension--it is an important fact that the terminal common bile duct can be partially removed from the pancreas and thereby lengthened for 1--2 cm at the most. From this point of view, the topographic details particularly concerning reconstructive surgery of the common bile duct are described, based on post mortem studies of 48 human cadavers.


Metronidazole in anaerobic infections: a review of its activity, pharmacokinetics and therapeutic use.

Metronidazole which has been widely used for many years in the treatment of trichomoniasis, amoebiasis and giardiasis, has recently been shown to be active against anaerobic bacteria. Serum, cerebrospinal fluid and tissue concentrations bactericidal for Bacteroides species are attained after usual dosages given orally or intravenously or higher dosages given rectally (suppository). Prospective studies have demonstrated that the addition of metronidazole to regimens for pre-operative bowel preparation, decreases the frequency of postoperative infection and eliminates anaerobic infection. Similarly, anaerobic infection after acute appendicectomy or hysterectomy has been virtually eliminated by metronidazole given before and up to 1 week after surgery. Metronidazole has been successfully used in the treatment of anaerobic infections of the chest, head, gastrointestinal and female genitourinary tract, and of anaerobic septicaemia and bacteraemia. Metronidazole is the most active agent available against obligate anaerobes and is likely to be of major value in the treatment of serious infections due to these organisms. Although the absence of formal comparative trials in many areas of use makes it difficult to clearly state the relative therapeutic efficacy of metronidazole, compared with other drugs such as clindamycin, chloramphenicol or penicillin, it is nevertheless a very effective agent in the treatment and prevention of anaerobic infections.


Drip breast milk: it's composition, collection and pasteurization.

"Drip breast milk" is that milk which spontaneously drips from the contralateral breask during the suckling of an infant. Biochemically and immunologically, pooled drip milk resembled pooled mature expressed breast milk, although it has a lower fat concentration. About 15% of lactating women are capable of producing drip milk; volumes produced are up to 188 ml/donor/day. A milk bank is described which processes 1400 liters of drip milk/yr. Heat treatment of this milk with a semi-automated holder pasteurizer caused a 21% reduction in IgA concentration and a 36% reduction in lysozyme activity, as well as a decrease in the ability of the milk to inhibit the growth of E. coli. In comparison with boiling, pasteurization was as effective in reducing total bacterial content provided the milk initially contained fewer than 10(6) bacteria/ml.


Drug treatment of breast cancer.

Breast cancer is the most common malignancy of women in the United States, affecting one out of every 13 women at some time in their lives. Although only 10% of patients have demonstrable distant metastases at the time of diagnosis, a majority will eventually die of disseminated disease. Chemotherapy was formerly considered to be the treatment of last resort in patients with breast cancer, reserved for those who had failed surgery, radiotherapy and hormonal manipulation. However, combination chemotherapy has now been shown to be highly effective. The most active drug combinations produce objective tumour regression in about 60% of patients with advanced disease. Parallel to the development of effective chemotherapy, there has been a renewal of interest in hormonal therapy. The ability to predict whether or not a patient will respond to hormonal therapy has been improved significantly by the clinical application of the oestrogen receptor assay. The selection of a specific treatment for the patients with advanced breast cancer must be individualised. It should take into account a number of prognostic variables, including: sites of metastatic involvement; total extent of disease; disease free interval; menopausal status; and the presence or absence of oestrogen receptor in tumour tissue. The final decision regarding treatment should then be based not only on the probability of response, but also on the anticipated degree of toxicity. Current efforts to improve the management of advanced breast cancer include the development of more effective drug regimens and the combination of chemotherapy with hormonal manipulation. For instance, it would appear that in premenopausal patients, the combination of chemotherapy with oophorectomy may yield results that are superior to those achieved with either treatment alone. The most promising development in the management of early breast cancer has been the use of chemotherapy as an adjuvant treatment in patients with operable disease.


Catecholamines: role in health and disease.

The naturally occurring catecholamines, noradrenaline, adrenaline and dopamine, have been found in a wide range of animal and vegetable tissues, but are particularly associated with nervous tissue in animals. Of the many processes affecting the response to stimulation of catecholamine containing nerves, the synthesis of catecholamines, particularly the first enzymatic stage involving tyrosine hydroxylase, and the re-uptake process, whereby the nerve recovers much of the released catecholamine, appear to be the most significant. In peripheral tissues noradrenaline appears to be involved predominantly in the sympathetic control of blood pressure and flow while adrenaline is more important to metabolic processes especially fat and glucose turnover. Both may be released in increased amounts by various stimuli that cause stress or arousal in the body. Dopamine has not yet been shown to have any significant physiological function in peripheral tissues. In the central nervous system, noradrenaline and dopamine are the two main catecholamines. The working of the brain is complex and involves balanced interactions between a variety of neurotransmitters, known or as yet unrecognised. However, noradrenaline appears to play a role in the central control of blood pressure, and in determining mood and activity probably by affecting the emotional drives. Dopamine is certainly important in the control of motor pathways, as shown by the dopamine deficiency syndrome in Parkinson's disease, and is possibly of significance in the abnormal behaviour of psychotics. The role of the small concentration of adrenaline in the brain has yet to be fully established.


Triiodothyronine (T3) modulation of gonadotropin secretion in the female rat.

The effect of T3 upon gonadotropin secretion was examined in ovariectomized (Ovarx), Ovarx thyro-parathyroidectomized (Ovarx-TxPx), or proestrus rats. T3 (50 microgram/-100 gBW), administered late diestrus-2, abolished the LH surge during the critical period of proestrus in 7 out of 9 rats; the rise in sera FSH was not inhibited, although a distinct peak was absent. Administration of 5 or 50 microgram T3/100gBW 2.5h before the critical period resulted in either a suppression or an alteration of the timing of LH release. In the 5 microgram T3/100gBW treated animals the sera FSH peak was delayed in timing, whereas in the 50 microgram T3/100gBW treated rats sera FSH demonstrated two separate peaks during the critical period. Treatment with various dosages of T3 of Ovarx-TxPx rats resulted in significant suppressions (p less than 0.05) of sera LH and FSH. Despite depressed concentrations of sera LH and FSH in T3-treated rats pituitary sensitivity to a challenge of 3LHRH was enhanced. Hence, the pituitary was not the site of T3 inhibition of gonadotropin secretion. Additionally, T3 did not modify pituitary LH content or hypothalamic LH3 releasing activity (LHRH). Since T3 did not inhibit gonadotropin secretion at the pituitary level, a neural site of T3 action is suggested.


Theoretical and practical considerations on the problem of metal--metal interaction.

The interaction between two metals, which can be either synergistic or antagonistic, implies that the behavior of one is changed by the presence of the other. Possible mechanisms of these interactions, which include chemical association, competition for carriers, metabolic changes, induction of binding proteins, membrane alterations are discussed.


Carcinogenicity of saccharin.

Saccharin is carcinogenic for the urinary bladder in rats and mice, and most likely is carcinogenic in human beings. The neoplasms of the urinary bladder are malignant and invade and metastasize. Male rats are more susceptible to urinary bladder carcinogenesis than female rats. Rats exposed as fetuses develop neoplasms more readily than rats exposed as weanlings. The lesions in the urinary bladder go through the stages of hyperplasia, hyperplastic nodules, and later carcinomas. The male of the human species ingesting saccharin, as for rats, is more susceptible to carcinogenesis of the urinary bladder than the female. Neoplasms of the urinary bladder in rats were not caused by stones, parasites, sodium, or impurities. There is a cocarcinogenic effect between saccharin and methylnitrosurea for the urinary bladder. Even through carcinomas of the urinary bladder are present in rats given the higher doses of saccharin, one was observed in a female rat given 0.5%. Chronic renal disease develops in rats ingesting saccharin. The disease is more advanced at the lower doses than at the higher doses, suggesting that saccharin at the lower doses does not reach the urinary bladder. Early neoplasms are seen in the renal pelvis of rats given the higher doses of saccharin. The risk ratios for urinary bladder carcinomas in human beings increase with both frequency andduration of saccharin usage. Benign and malignant neoplasms at all sites are significantly increased in mice and rats ingesting the higher doses of saccharin. These neoplasms are present in the reproductive and hematopoietic systems, and to a lesser extent in the lungs, vascular system and squamous epithelium. Neoplasms in some organs develop with the lower doses of saccharin. Lymphosarcomas of the lung are significantly increased in rats given 0.01% saccharin. Chronic renal disease in rats given saccharin interferes with the health and life span and consequently with development of neoplasms. Saccharin initiates neoplasms of the skin when its application is followed by croton oil. Epidemiological studies have not been done for neoplasms other than the urinary bladder in human beings.


In vitro assay of cytotoxicity with cultured liver: accomplishments and possibilities.

Tissue cultures offer potential advantages for assaying the toxicity of chemicals and for evaluating tissue susceptibility to toxic agents. Several properties of cultured cells hinder the immediate, widespread use of tissue cultures to assay toxicity routinely. These points are illustrated by briefly reviewing attempts to utilize different types of hepatic cultures to evaluate the actions of carcinogenic chemicals in vitro. Hepatocytes in vivo apparently can metabolize all known procarcinogenic chemicals, but the process of tissue isolation and the environmental conditions in vitro may modify drastically the responses of hepatocytes and other cultured hepatic cells to toxic chemicals. Before cell cultures can be used routinely as the basis of screening systems to detect chemical toxins, specificity and sensitivity of response to chemicals representing all chemical classes must be validated by laboratory studies.


Vascular permeability and neurotoxicity.

Neurotoxic substances affect the nervous system in a selective manner. One possible basis for this selectivity is blood vessel permeability. In general, the central nervous system and the peripheral nerve trunks have impermeable blood vessels, but in certain parts the capillaries are "leaky," allowing the passage of a plasma filtrate. Intravenously injected protein tracers rapidly reach nerve cells in these regions, with the implication that these nerve cells are also readily accessible to circulating neurotoxic substances. Some examples of neurotoxicity in the central nervous system show a selectivity that could be due to capillary permeability. In experimental methylmercury poisoning, cranial nerve V and sensory dorsal root ganglia, which lie in regions of vascular permeability, are particularly susceptible. A number of drug and chemically induced neuropathies are predominantly sensory, and may be due, directly or indirectly, to the accessibility of neurotoxic substances to sensory neurons. Examination of areas of potential vulnerability to circulating toxic substances may be of value in the experimental testing of substances for neurotoxicity, where pharmacological tests may be negative and clinical symptoms difficult to assess.


Interaction between selenium and methylmercury.

The available data on the influence of selenium on the toxicity of methylmercury and of methylmercury on selenium as a nutrient and toxic agent are reviewed. Selenium as selenite has a relative protective effect on acute and subacute toxicity of methylmercury in the rat and the quail. The protective mechanism is far from clear. Of special interest is the fact that selenium-treated animals may remain unaffected, even when they have attained tissue mercury levels otherwise associated with toxic effects. Selenite causes some increase of tissue mercury levels in methylmercury-exposed animals. On the other hand, methylmercury induces a remarkable enhancement of organ concentrations of selenium in animals given selenite. The interaction between selenium and methylmercury is in many ways different from that between selenium and inorganic mercury, and also from that between selenium and other metals. Due to the considerable interspecies differences in the toxicity of methylmercury, the available data do not allow conclusions on interactions in man. Practical implications of a possible protective effect of selenium on methylmercury toxicity in humans are discussed.


Neuropathology of heavy metal intoxication.

The basis for utilizing altered morphology, i.e., pathology, in defining diseases of the nervous system is presented. The importance of recognizing the dynamics of pathologic processes is emphasized, particularly in understanding the pathogenesis of neural diseases. Demonstrative examples of the neuropathology of human heavy metal toxicity are presented. The limitations of descriptive pathology are considered, and the potentials of quantitative (morphometric) analysis for studying pathologic processes are introduced.


Autonomic innervation of the heart.

This brief review describes recent advances in the areas of myocardial receptors that discharge into nonmyelinated, afferent, vagal C-fibers and the regional distribution of sympathetic postganglionic neurons to the myocardium. Complex, nonencapsulated nerve endings discharging into myelinated afferents have been known to exist for many years. More recently, however, indirect evidence for the existence of cardiac receptors that are either silent or exhibit low resting rates of activity, and discharge into slowly conducting C-type fibers, has been demonstrated. The receptors themselves have not yet been identified histologically. Cardiac receptors include subpopulations that are preferentially activated by chemical stimuli, including a variety of exogenous chemicals as well as prostaglandins. Another subpopulation is preferentially activated by mechanical stresses in the physiological range. Further investigation may reveal their participation in overall cardiovascular regulation, and mediation of responses to exogenous chemical stimuli. Four principal cardiac sympathetic nerves have been identified in the right thoracic region and three on the left. Most carry sympathetic and parasympathetic fibers. Stimulation of individual nerves, before and after parasympathetic blockade, results in regionally, well-defined myocardial responses.


Ultrastructure of heart muscle.

The ultrastructure of cardiac muscle is described. In the course of the descriptions advantage has been taken of comparative anatomy, in order to elucidate the relationships between structure and function. Physiologic parameters are discussed in a comparative manner including information from skeletal muscles fibers that often provide a well-studied point of departure. The descriptions of the ultrastructure of cardiac muscle are illustrated by a few electron photomicrographs to give a general overview.


Interspecies variation in myocardial physiology: the anomalous rat.

THE HEART OF THE ADULT RAT HAS LONG BEEN RECOGNIZED TO BE ANOMALOUS IN AT LEAST TWO RESPECTS: an absent or negative inotropic response to an increase in rate of electrical stimulation (negative staircase); resistance to digitalis glycosides. The heart of the neonatal rat (less than 2 weeks old), on the other hand, demonstrates a markedly positive staircase and a large increase in force upon application of glycoside. It is significant that the action potential of the neonate ventricle demonstrates a prolonged plateau component which progressively decreases with age. The shortening of the plateau correlates with the disappearance of the positive staircase and glycoside responses. Previous studies indicated that a major factor contributing to the prolonged plateau of the neonate was a high level of sodium (Na) conductance. Thus transmembranous Na movement associated with excitation is considerably greater in the neonatal heart as compared to the heart of the adult rat. The higher level of intracellular Na would produce increased activity of a proposed sodium-calcium (Na-Ca) carrier. This is believed to mediate the augmented influx of Ca which is responsible for positive staircase and glycoside responses. Ventricular muscle from the hearts of most mammalian species demonstrates a prolonged plateau with maintenance of a "slow" channel for Na. It appears that in the rat this channel closes with age. It follows that there would be a reduced tendency for the adult rat heart to accumulate intracellular Na, [Na](i), when excitation frequency is increased or the Na pump is inhibited by digitalis. Since elevation of [Na](i) is the stimulus for the proposed Na-Ca carrier, this system would not be activated, Ca influx would not increase and contractility would not be augmented.


Effects of anesthesia on cardiovascular control mechanisms.

The manner in which general anesthesia affects circulatory control was studied by examining the effects of commonly employed anesthetics on left ventricular function and distribution of cardiac output, and the extent to which responses to physiological and pharmacological stimuli are modified by general anesthesia. While commonly employed anesthetics affect almost every aspect of the circulatory system, the importance of general anesthesia on the circulation tends to be underestimated by considering only its direct effects. More important is the modification of the organism's integrative response to any perturbation. Major differences often directionally opposite, in responses of conscious and anesthetized animals were found for reflex control of the circulation, effects of hemorrhage and alterations in preload and after load. In addition, commonly employed pharmacologic agents, e.g., cardiac glycosdies, catecholamines, and morphine sulfate exerted differing actions in the conscious and anesthetized states. Thus, while it is generally held that the overall responses to complex physiological functions such as exercise or eating can be best described in the intact, conscious organism, the importance of conducting any experiment involving integrative control of the circulation in the conscious organism should also be recognized.


Is behavior or morphology a more sensitive indicator of central nervous system toxicity?

Both behavior and morphology can be altered by exposure of the CNS to toxic substances. The brain is an organ with considerable structural redundancy and this presumably accounts for some of the ability of the CNS to maintain normal function in the presence of some structural damage. Compensation for damage may also occur through a form of "learning" due to the biochemical and morphological plasticity of the CNS. Examples of these kinds of compensation are enzyme induction and axonal sprouting. Compensatory changes such as these are likely to require days or weeks to develop. On the other hand, short-term, reversible effects of substances such as drugs are not likely to cause morphological changes at doses which affect behavior. The importance of appropriate quantitative data on both morphology and behavior in evaluation of the CNS toxicity of substances is evident.


How operant conditioning can contribute to behavioral toxicology.

Operant conditioning can contribute to the development of behavioral toxicology in many ways. Its techniques are useful in training animals in the various behaviors the toxicologist may wish to study. They make possible the sophisticated assessment of sensory functioning. Operant conditioners excel at using schedules of intermittent reinforcement to create the type of stable animal performance needed in studying substances that produce effects only after prolonged exposure. Schedule-controlled behavior also helps elucidate the precise behavioral mechanisms involved in toxicity. In the early assessment of toxic substances a judiciously chosen sample of schelule-controlled performances may provide the best estimate whether the integrity of complex operant behavior remains unchanged. The development of improved behavioral techniques and  computer technology promises to bring down the cost of such assessment.


The National Institute of Environmental Health Sciences: a perspective.

This paper attempts to place the programs of the National Institute of Environmental Health Sciences into correct perspective in relation to the other Federal environmental programs. Its goal is to illuminate the field of environmental health as a new field in science that confronts a wide variety of complex and diverse issues. It is unrealistic to believe these issues can somehow be rendered less complex and diverse. What is hoped is that the Institute will contribute to providing the tools which will make is possible for us to develop principles leading to an understanding of the underlying problems. Then we should be able to build a base for effective public health programs for the years ahead, years that should prove to be as eventful and challenging as those just past.


Behavioral assessment of visual toxicity.

A wide variety of behavioral methods has been employed with animals to assess visual changes induced by drugs or toxicants. The methods range from simple to complex, from broad screening devices to narrowly focused techniques. Their relative advantages for the environmental toxicologist are discussed. Manipulation of stimulus values is an essential ingredient in the identification of specific sensory functions. The percentage of correct choices from a discrete-trial, multiple-choice discrimination procedure is to be preferred to measures of response rate, speed or reaction time when experiments require answers about specific visual functions.


Stimulus properties of inhaled substances.

Inhaled substances can modify behavior by their toxic action, or because they are discriminable events, or because they can support or suppress behavior. They can be used as discriminative stimuli at concentrations above the olfactory threshold. Inhalants can elicit unconditioned reflexes. As aversive stimuli, they can be studied in respondent conditioning experiments (e.g. conditioned suppression), in punishment paradigms, or as negative reinforcers in escape paradigms. Inhalants can also be positive reinforcers; their intoxicating properties have engendered patterns of chronic self-administration (solvent abuse). Such stimulus properties should be considered in industrial hygiene and environmental quality decisions. Laboratory techniques to study such properties abound.


Clinical expression of neurotoxic injury and diagnostic use of electromyography.

The clinical features of neurological damage produced by acrylamide, lead, organophosphates, hexacarbon solvents, and methylmercury are described, and the differences in effects of these compounds are stressed. The characteristic pattern of electrophysiological changes for each group of substances are described and correlated with pathological findings.


Use of activity measures in behavioral toxicology.

Locomotor activity measurements have been used extensively to evaluate chemically-induced changes in CNS function. This paper focuses on several factors including apparatus, age, biological rhythm, and social setting, which influence both locomotor activity levels per se and chemically induced changes in these activity levels. These data illustrate that failure to recognize, specify, and consider these factors is likely to result in equivocal studies subject to possible misinterpretation.


Binding of substrates and other anions to yeast phosphoglycerate kinase.

1. The binding of all four substrates to yeast phosphoglycerate kinase has been studied using a gel filtration technique. The binding of phosphate and sulphate anions has also been investigated. 2. Two sites for each adenine nucleotide were found, one site being weaker than the other by between 30 and 50-fold. Only one binding site for the phosphoglycerate substrates was found. 3. 1,3-Bisphosphoglycerate (1,3-P2-glycerate) bound to the enzyme approximately 1000 times tighter than the other three substrates, its dissociation constant being 0.06 micrometer at ionic strength 0.15 M. 4. Sulphate and phosphate were mutually competitive and sulphate competed with the binding of all substrates except MgADP. MgADP bound to the enzyme more weakly in the presence of sulphate. The dissociation constant for sulphate binding was 1.6 mM at ionic strength of 0.15 M, and 0.05 mM at ionic strength 0.015 M. 5. These results are consistent with sulphate acting as a competitive inhibitor, as found by kinetic studies at high sulphate concentrations. The activatory effect of sulphate at lower concentrations and the substrate activation phenomea displayed by this enzyme, are interpreted in terms of a two-step dissociation of 1, 3-P2-glycerate. The presence of moderate concentrations of MgATP, 3-phosphoglycerate or sulphate causes acceleration of the rate of dissociation of the product, 1, 3-P2-glycerate, this being the rate-limiting step in the overall enzyme reaction.


Structural studies of Shigella flexneri O-antigens.

The structures of the O-antigens of all known serotypes and subserotypes of Shigella flexneri have been reinvestigated. The results support the assumption that these antigens are composed of a basic tetrasaccharide repeating unit (1), to which alpha-D-glucopyranosyl and/or O-acetyl groups are attached at different positions. Leads to 3)-beta-D-GlcNAcp-(1 leads to 2)-alpha-L-Rhap-(1 leads to 2)-alpha-L-Rhap-(1 leads to 3)-alpha-L-Rhap-(1 leads to The immunological determinants responsible for O-factors I, II, IV, V and 7, 8 contain alpha-D-gluco-pyranosyl groups, the locations of which have been determined. O-Factor 6 is due to O-acetyl groups, linked to O-2 of the 3-substituted alpha-L-rhamnopyranosyl residue in unit 1 and O-factor III seems to be due to the same groups. The chemical natures of the determinants responsible for O-factors 4 and 3, 4 are still obscure. The structural studies indicate that the immunological classification of Sh. flexneri serotypes and subserotypes, as regards these O-factors, may need revision.


Rapid purification of plasmid DNAs by hydroxyapatite chromatography.

A method is described for the rapid preparation of plasmid DNAs of molecular weight up to 14 X 10(6). This method involves the chromatography, at room temperature, of bacterial cleared lysates on hydroxyapatite in the presence of high concentrations of phosphate and urea. All detectable protein and RNA contamination of plasmid DNA is removed by this procedure and the conformation of the plasmid DNA is unaffected. Less than 0.5% chromosomal DNA is present in the purified preparation and even this can be removed if necessary by a simple extention of the procedure to include a heat-denaturation step. The method is extremely rapid and amenable to large-scale plasmid preparation; 5 mg ColE1 DNA have been purified within 40 min. The yield of plasmid DNA is similar to that obtained with the conventional dye-centrifugation technique, however the purity is greater.


The genetic control of the molybdoflavoproteins in Aspergillus nidulans. IV. A comparison between purine hydroxylase I and II.

The purine hydroxylases I and II of Aspergillus nidulans [previously called xanthine dehydrogenases I and II: Scazzocchio, Holl and Foguelman, Eur. J. Biochem. 36, 428--445 (1973)] have been studied in crude extracts. The two enzymes differ in their substrate specificities, purine hydroxylase II being able to accept nicotinate as a substrate and unable to hydroxylate xanthine. The kinetics of inhibition with allopurinol and oxypurinol are also different, the two analogues being pseudo-irreversible inhibitors of purine hydroxylase I, while allopurinol is a competitive inhibitor of purine hydroxylase II and oxypurinol shows anti-competitive inhibition. Differences in electro-phoretic mobility and molecular size are also shown. We have failed to show the formation of hybrid purine hydroxylase I/II molecules. While a common evolutionary origin of the purine hydroxylases could be postulated, the data reveal a considerable divergence.


The modification of the peptidyl transferase activity of 50-S ribosomal subunits, LiC1-split proteins and L16 ribosomal protein by ethoxyformic anhydride.

Ethoxyformic anhydride abolishes the peptidyl transferase activity of 50-S ribosomal subunits, LiC1 split proteins and L16. Hydroxylamine treatment results in reactivation. Erythromycin exhibits significant protection with 50-S ribosomal subunits. With LiC1 split proteins and L16 significant protection was exhibited only after reconstitution. The results indicate that the ethoxyformic anhydride is reacting with approximately six histidines in LiC1 split proteins and one in L16. Since L16 has been reported to contain a single histidine, the results presented indicate the involvement of this histidine in peptidyl transferase activity.


A mutation in the xanthine dehydrogenase (purine hydroxylase I) of Aspergillus nidulans resulting in altered specificity. Implications for the geometry of the active site.

A point mutation in the structural gene for purine hydroxylase I (xanthine dehydrogenase) of Aspergillus nidulans results in several dramatic pleiotropic effects. The mutant enzyme oxidises 2-hydroxypurine at position 6 rather than 8, shows a 70-fold reduction in the V for hypoxanthine, and loses the ability to accept xanthine as a substrate. Allopurinol, a powerful pseudoirreversible inhibitor of the wild type enzyme, behaves as a good substrate of the mutant enzyme. We propose that the substrate and inhibitor specificities of the enzymes depend on the relative position of an orientating site ann a catalytic site. All the properties of the mutant enzyme can be explained by assuming that the mutation results in a change of the relative positions of the catalytic and orientating sites. We have assumed that the catalytic site comprises a Mo(VI) atom and an--S-group as proposed by Coughlan [FEBS Lett. 81, 1--9 (1977)] and the orientating site is a lysyl residue. While these assumptions are not strictly necessary for the construction of an abstract geometric model, they are consistent with other data bearing on the structure of the active site of the molybdenum-containing hydroxylases.


Initial clinical experience of lorcainide (Ro 13-1042), a new antiarrhythmic agent.

Lorcainide is a promising antiarrhythmic agent that belongs to the class of local anesthetics. It was tested in 7 patients with malignant ventricular arrhythmias that were resistant to other antiarrhythmic agents. Lorcainide was effective in all cases (complete disappearance of arrhythmias in 6 cases and more than 50% disappearance in the 7th case), and the tolerance was within acceptable limits. The drug was effective at rest, as assessed by 24-h dynamic electrocardiographic monitoring, and during physical exercise. Longer studies with more patients are warranted, since the drug appears to be a promising antiarrhythmic agent.


Absorption, effectiveness and side effects of highly purified porcine NPH-insulin preparations (Leo).

The clinical characteristics of highly purified porcine NPH-insulin (Insulin Retard RI) were investigated, including absorption from the subcutaneous tissue, blood glucose-lowering effect, stability of mixtures of NPH and regular insulin and measurement of circulating porcine proinsulin and insulin antibodies in diabetes. The absorption of NPH-insulin followed first order kinetics. The half time was 6.9 +/- 2.6h, with an intraindividual coefficient of variation of 26% and an interindividual coefficient of variation of 55%. After 24 h 90% of the injected insulin had disappeared from the subcutaneous tissue. The plasma insulin concentration was maximal 4-5 h after the injection and 24 h after the injection it was not significantly higher than before the injection. The blood glucose-lowering effect was significant 2.5 h after subcutaneous injection of NPH-insulin and was maximal after 5.5 h. The blood glucose-lowering effect of a pre-prepared mixture of 70% NPH and 30% regular insulin was not significantly different from the effect of 70% NPH and 30% regular insulin injected separately, which indicates the stability of mixtures of NPH and Regular insulin. Porcine proinsulin disappeared from the serum of patients switched to treatment with highly purified porcine NPH insulin and the insulin antibody titer fell. It was concluded that insulin Retard RI has a well-defined, reproducible effect with a clinically useful time course.


Intramuscular or intravenous glucagon for sulphonylurea hypoglycaemia?

Because of the differing opinions on the value of glucagon and the best way of administering it in severe hypoglycaemia induced by sulphonylurea drugs, experiments were conducted on normal subjects, and in diabetic patients before and during treatment with chlorpropamide. In all subjects glucagon raised blood sugar concentrations, and produced a greater and more prolonged increase in blood glucose concentrations when given intramuscularly than when given intravenously. Hypoglycaemia did not occur in any subject.


A comparison of slow release oxprenolol with conventional oxprenolol in the treatment of hypertension.

Sixteen patients with uncomplicated hypertension were studied in a double-blind within-patient trial comparing slow release oxprenolol (SRO) with conventional oxprenolol (CO). The anti-hypertensive effect of SRO once daily was greater than that of CO once daily, although this did not reach statistical significance. CO once daily was less effective than CObd and this difference was statistically significant for lying diastolic blood pressure. After exercise testing 26 hours post-dose, blood pressure and pulse rate were marginally lower on SRO than on CO, but this difference was not significant. Blood pressure readings 24 h post-dose were lower following morning dosing than following evening dosing, although pulse rates showed the opposite trend.


Image processing in pathology.

The present study is an effort to ally biopsies to well defined groups of diseases by means of automatic analysis of liver cell nuclei. The results obtained should support the morphologic differential diagnosis of liver diseases. A total of 78 liver biopsies from patients with obstructive jaundice, chronic hepatitis, acute viral hepatitis or with alcoholic liver injury were investigated. Performing automatic analysis of the microscopic pictures 95% of the equatorial sectioned liver cell nuclei are correctly recognized.


Prostacyclin-like activity of endothelium and subendothelium - important for atherosclerosis?

Morphological control of Moncada's bioassay for prostacyclin (PG I2) activity measurement shows that the activity depends not only on endothelium, but in important amounts on subendothelial tissue too. Therefore, it can be concluded that platelet thrombus formation after endothelial cell injury does not depend only on the PG I2-producing ability of the tissue.


Endotoxemia and adrenaline-hyperreactive death in mice.

Mice given i.v. a sublethal dose of endotoxin in advance died with shock-like symptoms on administration of sublethal adrenaline dose. The lethal adrenaline-hyperreaction induced by endotoxin appeared gradually within a few h, showed maximum response after several h and almost disappeared 24 h after endotoxin administration.


Chromosomal and morphological diversity in 2 populations of Asian mountain vole, Alticola lemminus Miller (Rodentia, Cricetidae).

Voles from Yakutia and Chukotka were found to differ in the morphology of 3 pairs of autosomes and sex chromosomes, as well as in M3-structure and skull dimensions. This makes their conspecificity doubtful. A variation in short arm lengths of the X- and Y-chromosomes has been discovered.


Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.


Dithiols simulate endotoxin in the Limulus reaction.

Dithiothreitol, dithioerythritol and bacterial lipopolysaccharides increase optical absorbance and clot Limulus lysate. Purification of dithiothreitol from possible endotoxin contamination by vacuum sublimation or chromatography does not abolish the reaction with lysate. The dithiols reported active here represent the smallest molecules capable of simulating endotoxin in the Limulus test.


Superiority of human complement for assaying bacterial lipopolysaccharides by their anticomplementary activity.

In assaying bacterial lipopolysaccharides (LPS) for anticomplementary activity, human complement (C) allowed detection of approximately 200 times smaller amounts of LPS than guinea-pigs C. Pig C was slightly inferior to human.


Effect of injectable contraceptives Depo-Provera and norethisterone oenanthate on pituitary gonadotropin response to luteinizing hormone-releasing hormone.

The pituitary response to luteinizing hormone-releasing hormone (LHRH) was tested in women before and approximately 2, 8, and 12 weeks after the injection of either Depo-Provera or norethisterone oenanthate. The secretion of both luteinizing hormone and follicle-stimulating hormone in response to LHRH was similar in the two groups of women, and the pituitary was capable of responding to LHRH at all times studied after injection of the gestagens. There was no statistically significant difference between the response obtained prior to injection and that at any of the other time periods studied after injection.


Effect of postovulatory treatment with a luteinizing hormone-releasing hormone analog on the plasma level of progesterone in women.

(des-Gly-NH2(10),Pro-ethylamide9) luteinizing hormone-releasing hormone (LH-RH) (100 microgram) was administered subcutaneously once daily for 5 days during the postovulatory period in six women with regular menstrual cycles. Plasma levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone were measured daily by radioimmunoassay from the ovulatory stage to menses. Suppression of plasma progesterone occurred during the treated luteal phase as compared with that of the control luteal phase. This finding suggests that repetitive, massive, endogenous luteinizing hormone or massive, exogenous, LH-RH itself during the early luteal phase of the cycle may induce functional luteolysis.


Unusual anti-reproductive properties of the analog [d-Leu6,des-Gly-NH2(10)]-luteinizing hormone-releasing hormone ethylamide in male rats.

Nanogram quantities of a luteinizing hormone-releasing hormone (LHRH) agonist, [D-Leu6,des-Gly-NH2(10)]-LHRH ethylamide, were injected into immature male rats twice daily for 40 days. Treatment with the analog significantly increased serum luteinizing hormone and follicle-stimulating hormone levels, but suppressed accessory sex organ weights. Plasma and testicular concentrations of testosterone were also significantly decreased. The agonist did not alter body, pituitary, or testis weights. Spermatogenesis and the morphology or density of the Leydig cells also appeared not to be affected. A possible direct effect of the analog on the testes is discussed.


[Immunological characterization of malignant epidermotropic lymphoma cells in cutaneous infiltrates (author's transl)].

Immunological characterization of cells in the malignant epidermotropic lymphomas requires techniques which define the lymphocytic nature of the cells, and for the lymphocytes techniques which demonstrate subpopulations of T or B cells. The results obtained using such methods in patients with cutaneous lymphomas are reported. The predominantly thymodependent nature of the cells of epidermotropic lymphomas is confirmed and the existence of a thymodependent non-epidermotropic cutaneous lymphoma is demonstrated.


[Systemic chemotherapy in mycosis fungoides (author's transl)].

The clinical experience with chemotherapy in mycosis fungoides is practically limited to the action of different types of chemotherapeutic agents on the lesions in far-advanced cases. A large number of agents from almost all classes--alkylating agents, antimetabolites, antibiotics, alkaloids, hormones--have some efficacy in clearing skin lesions. Despite this fact, combination chemotherapy has been the subject of a very small number of publications with conflicting results. The influence on survival, the comparative effects of combination versus single-agent chemotherapy, the value of chemotherapy combined to other treatment modalities have not been submitted to scientific evaluation. Considering the low frequency of the disease and the great variability of the clinical picture, it seems mandatory to implement large cooperative trials, possibly on an international scale.


A comparison of the effects of single doses of mianserin and amitriptyline on psychomotor tests in normal volunteers.

Eight healthy volunteers received single doses of either mianserin 10 mg, mianserin 20 mg, amitriptyline 25 mg or placebo. Critical flicker frequency, reaction time, digit substitution and addition times were tested up to six hours afterwards. Mianserin 20 mg and amitriptyline 25 mg significantly prolonged reaction time and mianserin 10 mg and 20 mg significantly reduced critical flicker frequency. No other significant effects were found. Patients should be warned of possible sedation when first starting treatment with mianserin.


Pindolol: a potent beta-adrenergic blocking agent in the treatment of hypertension.

Two groups of twenty-five hypertensive patients each were treated with a beta-adrenergic blocking agent (pindolol), either alone or in combination with classical anthihypertensives. In the group under monotherapy a significant lowering of the blood pressure was observed. The effect was, however, not so consistent as in the group under combined therapy. The trial shows the efficacy and safety of pindolol in the treatment of hypertension mainly if applied in combination with a diuretic.


An overview of results of world-wide clinical trials with cefadroxil.

Céfadroxil, a new semisynthetic oral cephalosporin, is absorbed similarly by fasted and non-fasted subjects, produces sustained serum levels and is eliminated at a relatively slow rate. These pharmacokinetic properties permit less frequent and more convenient dosage scheduling than cephalexin and cephradine and consequently greater patient compliance. Cefadroxil was evaluated for safety in 1051 patients and for efficacy in 1030 patients. Overall it achieved a 91.8% rate of clinical success resulting from 881 complete cures and sixty-five clinical cures. Among 363 patients with respiratory tract infections and 471 patients with genito-urinary tract infections, cefadroxil treatment produced 97.5% and 84.5% clinical success, respectively. In the remaining infectious diseases treated, cefadroxil therapy resulted in 99.0% clinical success. Cefadroxil eradicated 87% of 1110 pathogens isolated, among which the most predominant pathogens were Staphylococcus aureus, beta-haemolytic streptococci, Streptococcus pneumoniae, Escherichia coli and Proteus mirabilis. Drug-related side-effects were reported in 7.2% of the patients.


Butorphanol and promethazine as pre-anaesthetic medication.

An open evaluation of a combination of butorphanol (1 or 2 mg), promethazine (25 or 50 mg) and atropine (0.5 mg) in 109 adult consenting patients was carried out to determine their safety and efficacy for preanaesthetic medication. All patients were kept under direct surveillance from before intramuscular medication until they were in satisfactory condition post-operatively for discharge from the recovery room. The medications employed did not disturb the blood pressure, pulse rate or respiration rate in any of the patients. None complained of nausea or dizziness while only one was slightly excited. Sedation was rated as satisfactory in 97 per cent, and 90 per cent were free of apprehension. In addition, global evaluation of the premedication by the investigator was rated good to excellent in 99 per cent of the patients. On the basis of these observations, the combination of butorphanol with promethazine and atropine appears safe and useful for pre-anaesthetic medication.


Gentamicin in the treatment of Salmonella infections.

Changes in the ecology of Salmonella organisms impose the use of highly specific chemotherapeutic agents both in animals and in attempts ot combat salmonella typhi in man. An examination of inhibition achieved by the use of a number of antibiotics against strains isolated from 52 hospitalized patients in our clinic, over the past three years, has shown the majority of strains to be sensitive to gentamicin (78%), followed by nalidixic acid, nitrofurantoin, chloramphenicol (44%) and other chemotherapeutic agents, including the combination of sulphamethoxazole and trimethoprim (28%) and ampicillin (11%).


Double acting betamethasone (Celestone Chronodose) in the treatment of supraspinatus tendinitis: a comparison of subacromial and gluteal single injections with placebo.

The author reports the results of a placebo controlled trial of Celestone Chronodose in the treatment of supraspinatus tendinitis involving a total of 180 patients. The results after local injection and deep gluteal injection are also compared.


Preventive treatment of migraine headache with a new isoergolenyl derivative.

In the present double-blind clinical trial an isoergolenyl derivative with periphal antiserotonin, central dopaminergic activity and alpha-increasing effect on the human EEG, lisuride hydrogen maleate, was tested against placebo in a six-month trial involving 240 patients. Lisuride in long-term administration significantly reduces the frequency of migraine attacks in comparison to placebo. Its advantages are good tolerance and minimal side-effects. It is therefore concluded that lisuride is a suitable and effective drug for the prevention of migraine.


Biosynthesis of gonadotropins by rat pituitary cells in culture and in pituitary homogenates: effect of gonadotropin-releasing hormone.

The incorporation of labeled amino acids and glucosamine into LH and FSH by cultured rat anterior pituitary cells and anterior pituitary homogenates is reported. There was a significant augmentation in this incorporation by cells after 6 days of culture in the presence of GnRH. Tritiated LH and FSH were found in the cell extracts as well as in the media by the method of immunoprecipitation. An increase of approximately 7--13-fold in the release of LH and FSH into the cell incubation medium was observed in the presence of GnRH (3 ng/ml). The rate of incorporation of [3H]proline was higher than that of [3H]glucosamine into LH and FSH. At the same time a higher incorporation of labeled amino acids was observed in the case of FSH than with LH. Cycloheximide inhibited completely the incorporation of labeled proline but the inhibition was partial for the incorporation of labeled glucosamine. Freshly dispersed cells, short-time cultures maintained for 20 h and pituitary homogenates also incorporated labeled amino acids into LH and FSH, but GnRH had no effect on this incorporation. Pituitary homogenates also incorporated [3H]glucosamine into LH and FSH with an optimal incorporation after 30 min of incubation. Three different concentrations of GnRH had no effect on the incorporation of [3H]proline by homogenates. Cycloheximide and puromycin inhibited this incorporation completely.


Failre of suppress plasma glucagon concentrations by orally administered glucose in diabetic patients after treatment.

Plasma glucagon response to glucose in diabetic subjects was observed before and after treatment. In normal subjects, plasma glucagon concentrations decreased substantially after an oral glucose load. In all diabetic patients before treatment, plasma glucagon was not suppressed and rather tended to rise paradoxically despite pronounced hyperglycemia. In diabetics treated with sulfonylurea or insulin, basal plasma glucagon concentrations were significantly lower than those in patients who were not treated. However, plasma glucagon response to an oral glucose load was not normalized by successful treatment with sulfonylurea or insulin, in spite of improvement of glucose tolerance. These results suggest that the insensitivity of the A-cell to hyperglycemia exists after treatment, and this abnormal plasma glucagon response to glucose after treatment may be caused either by impaired response of endogenous insulin to glucose, which is sustained even after treatment, or by an intrinsic defect of the A-cell.