Insignificant Rise Research Articles

Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension

Background Circulating mediators, including thromboxane A2, the vasoconstrictor, platelet aggregant, and smooth muscle mitogen, may contribute to the progression of vascular narrowing in primary pulmonary hypertension (PPH). Methods To further understand the contribution of thromboxane and to provide novel therapy for PPH, we administered the potent orally active thromboxane synthetase inhibitor and thromboxane receptor antagonist terbogrel for 12 weeks to patients with New York Heart Association functional classification II and III PPH. The study had a multicenter randomized placebo-controlled design. The primary endpoint was a change in the distance walked during 6 minutes. The pharmacologic effects of terbogrel on thromboxane and prostacyclin metabolism also were studied. Results Although the planned enrollment was 135 patients, the study was halted after only 71 patients had been randomized because of the unforeseen side effect of leg pain, which occurred almost exclusively in patients with terbogrel treatment. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. The leg pain confounded the primary endpoint of walking distance. On an intention-to-treat analysis, no improvements in 6-minute walk distance or in hemodynamics in patients with terbogrel treatment were seen. However, terbogrel was effective from a pharmacologic standpoint, reducing thromboxane metabolites by as much as 98% (P <.0001), with a modest but statistically insignificant (39%) rise in prostacyclin metabolites. Conclusion Inhibition of thromboxane with an orally active agent is feasible in PPH, but the incidence of severe leg pain with terbogrel precludes its use in this disorder. Similar therapeutic efforts, with other thromboxane inhibitors, should be considered. (Am Heart J 2002;143:e4)

Systemic Bioavailability and Potency of High-Dose Inhaled Corticosteroids: A Comparison of Four Inhaler Devices and Three Drugs in Healthy Adult Volunteers

To compare the systemic bioavailability (assessed by cortisol suppression) of high-dose budesonide when given by four inhaler devices and orally. Also studied are the relative systemic potencies of three inhaled steroids (budesonide, fluticasone propionate, and beclomethasone dipropionate) when given by metered-dose inhaler (MDI) with a large volume spacer. Double-blind, crossover, placebo-controlled trial. Sixteen healthy, steroid-naive adult volunteers. On separate occasions, each subjects took 4 mg of budesonide through the following devices: MDI alone, MDI with 750-mL. spacer, dry-powder inhaler and nebulizer; 4 mg of budesonide was also taken orally to assess the effects of GI absorption. For the drug comparison, each subject took 4 mg of budesonide, fluticasone, and beclomethasone, and 2 mg of budesonide and fluticasone by MDI and spacer. Greatest percent suppression (95% confidence interval) of 9:00 AM cortisol with budesonide was observed with MDI alone (73% [57 to 90]) and turbohaler (72% [58 to 86]) compared with MDI spacer (42% [22 to 64]) and oral administration (14% [+6- to -34]). Nebulized budesonide produced an insignificant rise in 9:00 AM cortisol level. The most suppressive drug (given by MDI spacer) was fluticasone at 4 mg (86% [82 to 91]) and at 2 mg (72% [59 to 85]). The least suppressive drug was budesonide at 4 mg (43% [22 to 64]) and at 2 mg (25% [3 to 47]). The effects of 4 mg of beclomethasone were intermediate (66% [49 to 82%]). The choice of delivery device for administration of budesonide can lead to important differences in systemic bioavailability. Fluticasone has greater systemic potency than budesonide or beclomethasone when given at microgram equivalent dosage. The systemic potency ratio of fluticasone propionate to budesonide in normal human volunteers in the present study is similar to the therapeutic potency ratio of the drug in asthmatic patients (approximately 2:1).

Formation of pyrite thin films by sulfidation annealing of iron films

Iron films deposited by magnetron sputtering on glass substrates were converted into FeS 2 films by sulfidation during isothermal annealing at 400°C. The formation of FeS 2 microcrystalline has been investigated under different annealing times. The conversion of Fe→FeS 2 may occur during annealing for 1 h. The grain size and the amount of FeS 2 phase significantly increase with the annealing time. However, the crystallization rate indicates an insignificant rise when the annealing time is longer than 10 h. The iron films can be substantially converted into FeS 2 thin films which have an approximate stoichiometric composition under the condition of sulfidation annealing from 20 h to 30 h.

Role of nNOS in blood pressure regulation in eNOS null mutant mice.

The role of neural nitric oxide synthase (nNOS) in regulating blood pressure (BP) remains uncertain. Recently it was reported that in mice lacking functional endothelial NOS (eNOS) genes (-/-), acute administration of a nonselective NOS inhibitor, Nw-nitro-L-arginine, decreased mean BP, suggesting that NO released by non-eNOS isoforms increases BP. Because the inducible NOS isoform is not constitutively expressed and when induced causes hypotension, we hypothesize that it is NO produced by nNOS that increases BP in the absence of eNOS activity. To test this hypothesis, we studied the acute effect of selective and nonselective nNOS inhibitors on BP and cerebellar NOS activity in eNOS (-/-), wild-type (+/+), and heterozygous (+/-) mice as well as in +/+ mice with renovascular hypertension. Because it is not known whether the decrease in BP caused by acute NOS inhibition in -/- mice can occur chronically, we also studied the effect of chronic NOS inhibition on both BP and cerebellar NOS activity. eNOS (-/-) mice had higher BP than +/+ or +/-mice, and acute administration of the selective nNOS inhibitor 7-nitroindazole (7-NI) decreased their mean BP from 137+/-13 to 124+/-12 mm Hg (P<0.01). In +/+, +/-, or renovascular hypertensive +/+ mice, 7-NI caused a small but insignificant rise from 105+/-5 to 110+/-6 mm Hg, from 115+/-9 to 119+/-13 mm Hg, and from 146+/-6 to 150+/-6 mm Hg, respectively. Fifteen minutes after administration of 7-NI, cerebellar NOS activity decreased by 70%; however, this inhibitory effect was brief, since 2 hours after 7-NI administration NOS returned toward control values. Chronic oral or intraperitoneal administration of 7-NI did not inhibit cerebellar NOS activity, whereas the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) decreased this activity by 50%. Therefore, we studied the effect of chronic L-NAME administration (4 weeks) on BP. In -/- mice, chronic L-NAME administration decreased BP from 135+/-4 to 120+/-3 mm Hg (P<0.05), whereas in +/+ and +/-mice, as expected, it increased BP from 109+/-2 to 125+/-3 mm Hg (P<0.001) and from 107+/-6 to 119+/-5 mm Hg (P<0.02), respectively. After L-NAME administration was stopped, BP returned to baseline. These results suggest that in eNOS -/- mice, NO derived from nNOS increases BP both acutely and chronically.

T-cells and HLA-class II expression in the large intestine of infants in the early postnatal period.

There is only limited knowledge of the development of the immune responses of the gut in very young infants after exposure to bacterial and food antigens at birth. In this study, 49 large intestinal biopsy specimens, which were judged to have normal morphology, were taken from 49 young infants. Eleven patients had Hirschsprung's disease (group 1) and 38 had miscellaneous conditions (group 2). The densities of T cells, their subsets expressing surface antigens CD8 and CD4, and T-cell receptors alpha/beta or gamma/beta were measured, as well as densities of mononuclear and epithelial cells expressing HLA-class II antigens. T-cell densities in groups 1 and 2 were similar. Patients with Hirschsprung's disease had significantly more HLA-DR (p = 0.006) and HLA-DP-expressing cells (p = 0.003) in the lamina propria than did the patients in group 2. In group 1, HLA-DR- (r = 0.58; p = 0.46) and HLA-DP-expressing cells (r = 0.66; p = 0.03) showed a significant positive regression with age in the lamina propria, whereas in group 2, HLA-DR+ cells in the lamina propria showed marked (r = -0.9; p = 0.006) negative regression during the first 1.5 months of life. In contrast to results in previous reports, in the current results, HLA-D region antigens were present in the epithelium in a considerable proportion (up to one fourth) of specimens from the large intestine in both groups. CD3+ (r = -0.59; p = 0.006) and CD4+ (r = -0.64; p = 0.002) cells showed a strong negative regression with age in the lamina propria during the first 2.5 months; and thereafter, there was a weak, insignificant rise in the numbers of these cells. The distribution of CD4+, CD8+, and TCR alpha/beta or gamma/beta T cells of the epithelium of the young infants did not differ significantly from that in the epithelium of adults. These results show that several significant changes occur in the mucosal immune system during the first few weeks of life.

Bleeding Complications and INR Control of Combined Warfarin and Low-Dose Aspirin Therapy in Patients with Unstable Angina and Non-Q-Wave Myocardial Infarction.

The purpose of this study was to compare bleeding complications in patients with non-Q-wave myocardial infarction and unstable angina receiving combination therapy with aspirin plus warfarin versus aspirin alone. A post-hoc analysis was performed on patients enrolled in the Antithrombotic Therapy in Acute Coronary Syndrome (ACTACS) study, which was a prospective, randomized, multicenter trial of antithrombotic therapy in unstable angina or non-Q-wave myocardial infarction. A total of 358 patients admitted within 48 hours of chest pain were randomized to antithrombotic therapy with either (1) aspirin alone or (2) aspirin (162.5 mg) plus heparin followed by aspirin plus warfarin, and were prospectively followed up for 12 weeks. Major and minor bleeding episodes, hemoglobin levels, and prothrombin times or INR levels were prospectively recorded. Major bleeding episodes were subclassified as relating to CABG/PTCA or not. The rate of major bleeding complications not associated with CABG or PTCA was 2.0%, and did not differ between therapy assignments. Among 55 patients undergoing CABG, 29 (53%) required transfusion of two or more units of blood. Minor bleeding was also infrequent (2.8%). All patients with minor bleeding had a full clinical recovery, and only one patient with a major bleed resulted in minor disability. Warfarin was well managed, with 50% of INRs falling between 1.9 and 2.7. Combination therapy with low-dose aspirin and warfarin (INR mean 2.5) produces an insignificant rise in the incidence of major and minor bleeding. These events are infrequent and do not usually result in major disability. The effect of longer duration combination therapy remains to be determined.

Gonadal development and sex steroids in a female Arctic charr broodstock

Gonadal development and plasma levels of sex steroids were investigated in female Arctic charr at 3‐week intervals over a 12‐month period. Circulating levels of oestradiol‐17β (E2), testosterone (T) and 17,20β‐dihydroxy‐4‐pregnen‐3‐one (17,20β‐P) were measured by radioimmunoassay, and gonadal status assessed through histological examination and measurement of gonadosomatic index (GSI) and frequency distribution of oocyte size‐classes. Gonadal recrudescence during March‐July was characterized by modest but insignificant increases in plasma levels of E2 (2–4 ng ml−1) and T (2–5 ng ml−1) and recruitment of oocytes into yolk accumulation. Only a small and insignificant rise in GSI and no apparent increase in oocyte diameter occurred during this period, indicating that the rate of yolk formation and oocyte growth was low. Following transformation from stage V (peripheral yolk granule stage) to stage VI (yolk granule migration stage) in late July, the vitellogenic oocytes entered a phase of rapid growth which resulted in a marked rise in GSI until ovulation commenced in late September. Gonadal growth during this period was accompanied by increases in plasma levels of E2 and T which peaked at 11 ± 1 (mid‐August) and 71 ± 5ng ml−1 (late September), respectively. The levels of both steroids dropped rapidly during final maturation and ovulation, followed by a surge in plasma levels of 17,20β‐P which peaked at an average of 74 ± 17 ng ml−1 in early October. All three steroids returned to basal levels within a month after ovulation, and all steroids, except E2, remained low until March of the following year. A slight increase in E2 detected in February and March during the second season may have been associated with recruitment into vitellogenesis of a new generation of oocytes. It is suggested that the abrupt increase in vitellogenesis in late July may reflect a condition‐dependent decision to proceed with maturation, once the energy reserves have been repleted during spring‐early summer.

A Scenario of Storm Surge Statistics for the German Bight at the Expected Time of Doubled Atmospheric Carbon Dioxide Concentration

Past variations of water levels at Cuxhaven, Germany (German bight), are examined, and a scenario for future changes due to expected global warming is derived. The observational record of Cuxhaven water levels features a linear upward trend in the annual mean water level of about 30 cm 100 yr−1 overlaid by irregular variations due to synoptic disturbances. These irregular storm-related variations are shown to have remained mostly stationary since the beginning of observations until today. A scenario for future conditions is derived by means of a two-step downscaling approach. First, a “time slice experiment” is used to obtain a regionally disaggregated scenario for the time mean circulation for the time of expected doubling of atmospheric CO2 concentrations. Then, an empirical downscaling model is derived, which relates intramonthly percentiles of storm-related water-level variations at Cuxhaven to variations in the monthly mean air pressure field over Europe and the northern North Atlantic. Past variations of storm-related intramonthly percentiles are well reproduced by the downscaling model so that the statistical model may be credited with skill. The combined time slice–statistical model “predicts,” for the expect time of doubled atmospheric CO2 concentrations in the decade around 2035, an insignificant rise of the 50%, 80%, and 90% percentiles of storm-related water-level variations in Cuxhaven of less than 10 cm, which is well within the range of natural interdecadal variability. These numbers have to be added to the rise in mean sea level due to thermal expansion and other slow processes.

Down-regulation of hepatic LDL receptor expression in experimental nephrosis

Nephrotic syndrome (NS) is invariably associated with elevation of plasma total and LDL cholesterol concentrations. The present study was carried out to test the hypothesis that nephrotic LDL hypercholesterolemia is, in part, due to acquired LDL receptor (LDLR) deficiency. To this end, hepatic LDLR mRNA (Northern blot analysis) and protein mass (Western blot analysis) were measured longitudinally before and during the course of puromycin-induced NS. In addition, the rate of LDLR gene transcription by isolated hepatic nuclei was determined using nuclear run-on assay. Hepatic LDLR mRNA remained virtually unchanged during the 30-day course of the study period. However, after an insignificant rise on day 5, LDLR protein mass gradually declined to a level which was significantly below the baseline values (P < 0.05 ANOVA). This was accompanied by a normal rate of LDLR mRNA synthesis excluding impaired gene transcription as a cause. The fall in hepatic LDLR protein was associated with a marked rise in plasma total and LDL cholesterol concentrations but no rise in hepatic tissue cholesterol concentration. The latter observation is indicative of impaired hepatic cholesterol uptake and provides functional evidence for the demonstrated acquired LDLR deficiency in the NS animals. Likewise, our findings elucidate the molecular basis of the previously reported impaired LDL clearance in NS. In conclusion, severe hypercholesterolemia in rats with experimental NS is associated with and perhaps, in part, is due to down-regulation of LDL receptor expression.

Phorbol Ester Activation of the Rat Vascular Myocyte Na + -H + Exchanger Isoform 1

Vascular myocytes from the spontaneously hypertensive rat (SHR) demonstrate elevated Na(+)-H(+) exchanger activity associated with increased cell proliferation and hyperresponsiveness to agonists such as phorbol esters. Since the Na(+)-H(+) exchanger isoform 1 (NHE-1) is stimulated by protein kinase C, we have investigated the effects of phorbol esters on NHE-1 activity and its phosphorylation in vascular myocytes of these rats. SHR cells demonstrated a larger alkalinization response to 12-O-tetradecanoylphorbol 13-acetate than Wistar-Kyoto rat (WKY) cells. Kinetic analyses indicated that whereas 12-O-tetradecanoylphorbol 13-acetate increased the maximal transport capacity of NHE-1 in both cell types, affinity for H+ was increased in WKY cells and cooperativity for H+ at the internal modifier site was reduced in SHR cells. In neither cell type was the subcellular distribution of NHE-1 altered by phorbol ester stimulation. NHE-1 phosphorylation was markedly reduced in WKY cells stimulated by the phorbol ester, an effect abolished by inhibition of protein kinase C. In contrast, NHE-1 phosphorylation in quiescent SHR cells was approximately double that of WKY cells and was reduced after phorbol ester treatment. Inhibition of protein kinase C in SHR cells led to a marked elevation of NHE-1 phosphorylation that was not associated with a change in the exchanger activity, but WKY cells exhibited a small, insignificant rise in NHE-1 phosphorylation. Thus, the kinetic responses of NHE-1 to phorbol esters in vascular myocytes of these rat strains are different, the changes in exchanger kinetics of SHR resembling those described in human hypertension. NHE-1 phosphorylation has an inverse relationship with protein kinase C activity. However, modulation of NHE-1 phosphorylation may not be associated with concurrent alterations in activity, indicating a role for non-phosphorylation-dependent mechanisms.

Serum troponin T values in 7‐day‐old hypoxia‐and hyperoxia‐treated, and 10‐day‐old ascitic and debilitated, commercial broiler chicks

Troponin T is a cardiac-specific protein forming part of the contractile apparatus of striated muscle, and in humans it is a new, sensitive and highly specific indicator of early myocardial damage in 'at risk' patients. Serum troponin T values were investigated in 7-day-old hypoxia- and hyperoxia-treated and 10-day-old ascitic and debilitated commercial broiler chicks. The results showed that there was a significant increase in troponin T values in the hypoxic chicks (P< 0.05) compared with their normoxic flockmates. There was also a small, but insignificant rise in the troponin T values of the hyperoxia-treated chicks. The results confirm previous studies that myocardial damage in these young chicks is associated with hypoxia and that the injury caused permits the measurement of troponin T released from the cardiomyocytes. Significant increases in troponin T were also measured in 10-day-old ascitic (P < 0.05) and debilitated (P < 0.02) broiler chicks compared with age-matched control broilers. In both age-groups of birds, the arterial pressure index, a measurement of right ventricular hypertrophy caused by chronic pulmonary hypertension, was similar with the respective control values and yet the troponin T concentrations were significantly different. These results demonstrate the importance of this assay in young broiler chickens as a marker of early myocardial damage in these birds. It is proposed that this assay for troponin T could be a valuable prognostic tool in future genetic selection programmes to reduce the degree of susceptibility to hypoxia and with it the incidence of ascites in young broilers.

The interaction of (1-4)-fragment of thymosin beta 4 with calmodulin-sensitive cAMP phosphodiesterase from hypothalamus.

Evidence was accumulated indicating that cyclic nucleotides are involved in regulation of growth, differentiation and function of lymphoid cells. It was previously shown that the N-fragment (1-4) of thymosin beta 4 (Ac-Ser-Asp-Lys-Pro-OH) inhibits in vivo the entry of cell populations into S-phase. In the course of the study of the interrelationship between the immune and neuroendocrine systems we have found that the tetrapeptide caused incomplete competitive inhibition of hypothalamic calmodulin (CaM)-dependent phosphodiesterase (PDE) stimulated by CaM. In the presence of the peptide, the 20-fold increase of the constant for PDE activation by CaM was accompanied by an insignificant rise in the maximum rate of cAMP hydrolysis. The value of the inhibition constant (Ki) amounted to 600 nM. In the absence of CaM, the peptide at saturating concentrations reduced the basal activity of PDE nearly 2- to 3-fold. The effect of the peptide on PDE was noncompetitive with respect to cAMP. The results support our suggestion that the tetrapeptide realizes its effects in the immuno-neuroendocrine system by the mechanism of cyclic nucleotide metabolism.

The safety of oxygen‐driven nebulisers in patients with chronic hypoxaemia and hypercapnia

ABSTRACTThere is potential to cause deterioration due to hypoxia in patients with acute exacerbation of obstructive airways disease with the indiscriminate use of aerosol bronchodilators delivered by air‐driven nebulisers without supplemental oxygen. Traditionally, air‐driven nebulisers have been reserved for the treatment of chronically hypoxic and hypercapnic patients with an exacerbation of chronic obstructive pulmonary disease (COPD). The purpose of this pilot study was to assess the safety of oxygen‐driven nebulisers (6 L/min) in the treatment of COPD patients.Sixteen patients received bronchodilator via an oxygen‐driven nebuliser for 30 minutes. No patient deteriorated clinically and in all the PaO2 rose significantly (mean baseline 43.7 ± 6.3 mmHg (± SD) post nebuliser 108.8 ± 30.4 mmHg). There was an insignificant rise in PaC02 from 59.7 ± 9.1 mmHg to 66.4 ± 15.3 mmHg and this was not important clinically.On the basis of this pilot study, we suggest that aerosol bronchodilators may be safely delivered by oxygen‐driven nebulisers in chronically hypoxic and hypercapnic COPD patients. A larger scale formal trial is indicated to compare oxygen‐driven versus air‐driven nebulisers in COPD.

Ventilatory effects of acetazolamide in cats during hypoxemia.

In normoxemic cats, acetazolamide (ACTZ) has been shown to cause a large rise in ventilation (VE) but a decrease in peripheral chemoreceptor activity. The relative contribution of the peripheral chemoreceptors to ventilation is higher during hypoxemia than during normoxemia. Therefore, what are the effects of ACTZ during steady-state hypoxemia? The aims of this study in anesthetized cats were 1) to study the effect of ACTZ (50 mg/kg iv) on mean hypoxemic [arterial PO2 (PaO2) approximately 6 kPa] ventilation and 2) to study the effect of ACTZ on the isocapnic hypoxic ventilatory response. In the first study, in six cats with an inspiratory CO2 fraction of 0, ACTZ led to an insignificant rise in mean VE of 119 ml.min-1.kg-1 after 1 h. In five other cats maintained at an inspiratory CO2 fraction of 0.015, ACTZ resulted in a significantly larger response in VE (268 and 373 ml.min-1.kg-1 after 1 and 2 h, respectively). In the second study, before infusion in five cats, an isocapnic fall in mean PaO2 from 13 to 4.7 kPa led to a significant rise in mean VE of 385 ml.min-1.kg-1; 1 h later, the response (at the same mean alveolar PCO2) was reduced to an insignificant rise of 38 ml.min-1.kg-1. Before infusion four other cats showed a significant rise in mean VE of 390 ml.min-1.kg-1 when mean PaO2 was lowered isocapnically from 12.4 to 6.8 kPa; 2 h after infusion, an isocapnic fall in mean PaO2 from 13.9 to 7.2 kPa led to an insignificant rise of 112 ml.min-1.kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of infusion of branched chain amino-acids enriched TPN solutions on plasma amino-acid profiles in sepsis and trauma patients

Total parenteral nutrition with branched chain amino-acids enriched solutions has been advocated in patients with sepsis and stress because of favourable effects on nitrogen balance, protein synthesis and immune competence. The rationale for the use of BCAA-enriched solutions is based on their potential to correct the plasma amino-acid imbalances seen in these patients. In a 7-day prospective randomised study we investigated the effects on plasma amino-acid concentrations of a standard amino-acid solution (15.6% BCAA) and a branched chain amino-acid enriched solution (50.2% BCAA) in 101 parenterally fed patients with carefully assessed sepsis and/or stress scores. The infusion of the BCAA-enriched solution led to an imbalance of the essential plasma amino-acids. The branched chain amino-acids valine, leucine and isoleucine increased significantly while the non-BCAA essential amino-acids decreased significantly. In the standard solution the non-BCAA-essential amino-acids increased significantly with a slow and insignificant rise in the levels of the branched chain amino-acids. We conclude that infusion of a BCAA enriched TPN formulation induced amino-acid profile derangements that can be considered ill-suited to the achievement of anti-catabolic effects.

Effects of acetazolamide on medullary extracellular pH and $${\text{P}}_{{\text{CO}}_{\text{2}} } $$ and on ventilation in peripherally chemodenervated catsand on ventilation in peripherally chemodenervated cats

The responses of ventilation and of medullary extracellular fluid (ECF) pH and PCO2, to an intravenous (i.v.) infusion of 50 mg/kg acetazolamide (an inhibitor of carbonic anhydrase), were measured in cats anaesthetized with chloralose and urethane, in which both bilateral vagotomy and carotid nerve section had been performed. After 2 h, it was observed that: acetazolamide caused an acidosis in medullary ECF which was still developing after 2 h, reflected by a progressive fall in pH (mean = 0.215 pH units in 2 h), while ECF PCO2 showed an insignificant rise of about 1 kPa; acetazolamide caused a considerable rise in ventilation, which largely developed in the first 15 min after drug infusion; the direction of the ECF acid-base responses in the first 15 min varied, whereas that of the ventilatory response did not. Furthermore, the time course of the former developed quite differently from the latter. It was therefore concluded that the observed changes in medullary ECF pH and PCO2 can not explain the large and fast ventilatory response of acetazolamide.

Serological response of experimental ponies orally infected with Ehrlichia risticii.

Ten healthy, mature ponies were orally infected with Ehrlichia risticii using Ehrlichia-infected P388D1 mouse monocyte tissue culture cells. Seven developed signs of equine ehrlichial colitis including fever, depression, anorexia, reduced borborygmi, increased abdominal hyperresonance, and diarrhoea. Three remained clinically normal apart from early fever in one. Indirect fluorescent antibody titres were detected in the clinically affected ponies by Days 12 to 17 post infection and increased rapidly to high levels (1:640 to 1:5120) which were maintained until the end of the observation period (Day 28 post infection). Mean antibody titres significantly increased from Days 12 to 14 and from Days 14 to 17 post infection. The rapid increase in antibody titre which occurs close to first appearance of clinical signs may explain the insignificant rise in antibody titres in many naturally occurring cases.

Effects of ovulen-50, diethylnitrosamine and phenobarbital on liver regeneration in female rats

Short term effects of ovulen-50, a combination type oral contraceptive agent and phenobarbital—an established hepatic tumour promoter, were examined in the livers of diethylnitrosamine-initiated and uninitiated female rats. Liver mitotic activity as judged by liver weight, ( 3 H) thymidine incorporation into DNA and levels of DNA, RNA and protein were measured in non-regenerating and regenerating liver. Hepatic γ-glutamyl transpeptidase activity and hepatocyte agglutination with concanavalin A were examined in diethylnitrosamine- and/or phenobarbital-treated rats. The results indicate that diethylnitrosamine or ovulen-50 individually are mitoinhibitory in regenerating liver. Phenobarbital alone has a slight mitostimulatory effects in non- regenerating liver, but no effect on liver regeneration. Administration of ovulen-50 and phenobarbital to diethylnitrosamine initiated rats mitigated the mitoinhibition during regeneration. Contrary to the earlier observation with ovulen-50, neither phenobarbital nor diethylnitrosamine induced hepatocyte agglutination in the presence of concanavalin A. Like ovulen-50, diethylnitrosamine also increased the level of hepatic γ-glutamyl transpeptidase. Phenobarbital produced only insignificant rise and did not substantially exacerbate the effect diethylnitrosamine. The data show that though some of the effects of ovulen-50 resemble those of diethylnitrosamine or phenobarbital, the changes observed may not be related to the neoplastic phenomenon since they were not seen in an initiator-promoter combination regimen.

Effect of etidronate disodium on bone turnover following surgical menopause

A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover. Twenty healthy, premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively. Sequential measurements of serum calcium (Ca), alkaline phosphatase (AP), bone Gla protein (BGP), and urinary calcium and hydroxyproline excretion, expressed as a ratio of urinary creatinine (UCa/Cr and UOHp/Cr, respectively) were obtained. Twenty-four-hour whole body retention of diphosphonate (WBR) and radial bone density were also measured. When a postoperative increase in bone turnover was observed, patients were randomized to receive either 400 mg etidronate disodium daily or placebo for 3 months. Oophorectomy was associated with a significant increase in WBR, Ca, AP, and BGP and an insignificant rise in UCa/Cr. A variable pattern of UOHp/Cr was seen. Patients on placebo maintained these elevated levels of Ca, BGP, and UCa/Cr. WBR and AP continued to rise. Etidronate disodium therapy resulted in a fall towards premenopausal levels in WBR, Ca, and UCa/Cr. AP and BGP were unchanged. Three months after stopping etidronate, BGP fell significantly and the decrease in Ca was maintained; however, WBR and UCa/Cr had returned towards pretreatment values. Bone density measurements did not change significantly. An increase in several of the indices of bone turnover was seen following oophorectomy. Etidronate disodium suppressed this increase, affecting indices of both resorption and formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in the incidence of acute appendicitis in Glasgow Asian and white children between 1971 and 1985.

Between 1971 and 1985 there was a significant rise in the annual hospital discharge rate for acute appendicitis in Glasgow Asian boys aged 10-19.9 years. A smaller and statistically insignificant rise occurred in Asian girls of 10-19.9 years; discharge rates for younger Asian boys and girls did not change significantly. In keeping with national trends, discharge rates for acute appendicitis in all Glasgow children fell significantly between 1971-85. The divergent trend in older Asian children may reflect dietary adaptation which is most marked in older Asian boys.