Cardiovascular effects of eating,atenolol and their interaction: beta1-adrenergic modulation does not play a predominant role in the genesis of postprandial effects

1. Eight healthy subjects were investigated on four occasions at least 1 week apart when they either ate a standard 3100 kJ cold meal or fasted. One hour earlier, either 50 mg atenolol or placebo was administered. 2. Eating was followed by prominent changes of systolic cardiovascular function: a rise of heart rate (+7, 95% CI: 4 to 9 beats min(-1)), systolic BP (+5, CI: 1 to 8 mmHg), a drop of diastolic BP (-6, CI:-9 to -3 mmHg), shortening of the pre-ejection period PEP (-11, CI: -13 to -9 ms) and electromechanical systole QS2c (-13, CI: -17 to -8 ms), a rise of the estimated cardiac output CO (+1.3, CI: 1.0 to 1.6 1 min(-1)) and a reduction of the calculated total peripheral resistance TPR (-306, CI: -389 to -222 dyn s cm(-5)). 3. Eating was also followed by an increase of the non-renal clearance of sorbitol (as a measure of hepatic blood flow) and this change was larger than proportional to the increase of CO. The plasma renin activity rose after the meal but the venous plasma noradrenaline and adrenaline concentrations were not affected. 4. The postprandial effects peaked over the first 1-2 h after the meal but remained well detectable up to 4 h after eating. 5. The administration of 50 mg atenolol before the meal reduced the postprandial effects to the same extent as the atenolol effects in the fasting state. This lack of interaction (or mere arithmetic additivity) indicates that the efferent beta1-adrenergic tone does not play a predominant role in the modulation of postprandial cardiovascular changes.     

The use of natural interferon alpha conjugated to a monoclonal antibody anti mammary epithelial mucin (Mc5) for the treatment of human breast cancer xenografts

Summary An immunoconjugate composed of natural interferon (nIFN) bound in a noncleavable fashion to a monoclonal antibody (MoAb) recognizing a breast epithelial membrane mucin (Mc5) was used to treat xenografts of a human mammary carcinoma cell line (MCF-7) growing in nude mice. The immunoconjugate (nIFN/Mc5) was administered as 20 intralesional (i.l.) injections to 1 of 2 xenografts in each animal. It was found that nIFN/Mc5 produced a significant enhancement of the growth inhibitory actions of nIFN on the injected tumors. Further enhancement was obtained when nIFN or nIFN together with Mc5 (at a dose 10 times larger than that present in nIFN/Mc5) were added to the immunoconjugate. Biodistribution experiments showed that the uptake of¹²⁵I-nIFN/Mc5 by the tumors was greater and its elimination slower than for¹²⁵I-nIFN alone or conjugated to irrelevant mouse IgG₁. In addition, the immunoconjugate up-regulated the antigenic expression of a breast epithelial membrane mucin by the carcinoma cells, an up-regulation which was not significantly different from that produced by nIFN alone. The contralateral noninjected tumors exposed to systemic levels of the immunoconjugate showed an enhancement of antitumor effects, but to a lesser extent than the injected tumors. These findings suggest that the enhancement of the growth inhibitory action of the immunoconjugate was related to the specific binding of Mc5 which targeted the IFN to the carcinoma cells and impeded its elimination. It is likely that the targeting was favored by the IFN-mediated up-regulation of antigenic expression by the carcinoma cells, thereby producing a cascade of interrelated effects. The results of this study point out the feasibility and potential usefulness of IFN treatment by means of immunoconjugates as well as the worth of pursuing and improving this form of therapy.     

Substance P effects on intraspecific aggressive behaviour of isolated male mice: an ethopharmacological analysis

Adult male mice of the Swiss CD1 strain were used to evaluate the effects on isolation-induced aggressive behaviour of a single intravenous administration of substance P (SP; 0.25, 1.0 or 2.5mg/kg dose). All mice were injected 15min before testing (10min videotaped dyadic encounters with an isolated male untreated opponent). Control mice were injected with vehicle. All animals were tested again 24h later in a drug-free state. SP treatment produced a decrease in offensive scores (Attacks and Rattling behaviour), a longer latency to the first Attack episode, and enhanced defensive displays. These effects were reversed 24h later. In no case did SP treatment affect locomotor activity levels or freezing behaviour. A role of SP in the regulation of murine aggressive response is strongly suggested through a direct action of the drug on the central nervous system and specifically on the hypothalamus.     

Difenoxin and loperamide: studies on possible mechanisms of intestinal antisecretory action

Summary Experiments have been performed to determine whether the antisecretory (antidiarrhoeal) actions of difenoxin and loperamide are mediated by enteric neurones. An iso-osmotic perfusion solution was circulated around the lumen of the jejunum of anaesthetised rats. Vasoactive intestinal peptide was infused intra-arterially to induce net fluid secretion which was inhibited by difenoxin (ED₅₀, 0.23 mg/kg) and loperamide (ED₅₀, 0.5 mg/kg). However, neither were able to restore the fluid transport rate to the control level of absorption.The antisecretory effects of difenoxin (0.77 mg/kg) and loperamide (0.6 mg/kg) were blocked by the opiate receptor antagonist naloxone (2 mg/kg). Their effects were also abolished by pretreatment with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA; 200 mg/kg; with desmethylimipramine given beforehand to protect noradrenergic nerves and enhance 5-HT depletion). The effect of difenoxin was blocked with methiothepin (1 mg/kg) and methysergide (30 g/kg) but not ketanserin (30 g/kg), ritanserin (30 mg/kg), ondansetron (10 g/kg) or ICS 205-930 (3 mg/kg). None of the above 5-HT receptor antagonists modified the antisecretory effect of loperamide. The antisecretory effect of difenoxin but not loperamide was prevented by phentolamine (2 mg/kg) and by pretreatment with 6-hydroxydopamine (150 mg/kg) total.It is concluded that both difenoxin and loperamide inhibit net fluid secretion by indirect mechanisms. It is proposed that the initial action is on enteric -opiate receptors and that this results in the release of 5-HT. In the case of difenoxin, the 5-HT may act on 5-HT₁-like receptors to release noradrenaline. However, the major difference in the mechanism of action of loperamide compared to difenoxin is that it does not utilize noradrenaline as the final mediator of its antisecretory action.Correspondence to A. De Luca at the above address     

Blood styrene concentrations in a “normal” population and in exposed workers 16 hours after the end of the workshift

Summary Blood styrene was measured by a gas chromatography-mass spectrometry method in 81 normal people and in 76 workers exposed to styrene. In the normal subjects, styrene was also tested in alveolar and environmental air. Styrene was found in nearly all (95%) blood samples. Average styrene levels in the normal subjects were 221 ng/1 in blood (Cb), 3 ng/1 in alveolar air (Ca) and 6 ng/1 in environmental air (Ci). Styrene levels did not differ significantly between smokers and non-smokers, 95% of values being below 512 ng/1 in Cb, 7 ng/1 in Ca and 15 ng/l in Ci. In workers with an average exposure to styrene of 204 g/l, at the end of the workshift, mean blood styrene concentration was 1211 g/l. In blood samples collected at the end of the Thursday shift, styrene levels were significantly higher (1590 g/1) than those found at the end of the Monday shift (1068 g/l. A similar difference was found in samples taken the morning after exposure (60 and 119 g/l, respectively). Significant correlations between blood and environmental styrene were found both at the end of the shift and the morning after exposure (r=0.61 and 0.41, respectively). In workers occupationally exposed to styrene, 16 h after the end of the workshift, blood styrene (94 g/l) was significantly higher than that found in the normal subjects (0.22 g/l). The half-life of blood styrene was 3.9 h.     

PCR (polymerase chain reaction) and the future of molecular testing

Molecular testing is no longer exotic, distant, or complex. It's moving into your lab and revolutionizing the rapid diagnosis of pathogenic organisms as well as your role as a laboratorian.     

Evaluation of health interventions. 2. To evaluate a maternal-child protection program

The process of evaluating maternal-child health services in Tokombere, North Cameroon, is described to illustrate the use of different indicators to evaluate different aspects of a health program. The maternal-child health program in Tokombere calls for children 5 and under and their parents to meet once each month for health education and weighing of children to screen for nutritional problems. Vaccinations are provided elsewhere during regular campaigns. The 1st step in evaluating the program is to determine whether a maternal-child health program actually exists in the village and whether it meets regularly. Attendance at the maternal-child health services can be evaluated by calculating the proportion of children 1-5 years old who attended at least 3 meetings during the year. To ascertain the proportion, attendance can be taken at each meeting, or the proportion can be estimated by checking at a single well-attended meeting to see how many children have attended 2 other meetings in the past year. The total number of children can be estimated through a survey, by asking the village head, or by consulting the census or vital register, if they exist. Indicators of the effectiveness of the maternal-child health program in screening for and treating malnutrition include the proportion of children for whom a growth curve is completed and correctly interpreted, the proportion of children identified as malnourished, and the proportion of children among those identified at the maternal-child health meeting who are followed up until their weight returns to a satisfactory level. The most difficult aspect of the valuation is determining its impact on the health status of children. Often quantitative measures are impossible, and even with qualitative measures it may be impossible to distinguish between the effects of the program and effects of other actions or of general social development. THe infant mortality rate, if available, may be a useful indicator, as may the existence of other development projects prompted by the maternal-child health program. The Tokombere project demonstrates the importance of having a series of indicators to measure different aspects of project functioning. The evaluation should be repeated periodically to assess trends and longterm impact. Each result or trend should be examined and explained in order that program weaknesses can be identified and corrected.     

“In vitro” and “ex vivo” effects of picotamide,a combined thromboxane A2-synthase inhibitor and -receptor antagonist,on human platelets

Summary Picotamide (G 137), a new non prostanoid inhibitor of in vitro arachidonic acid induced platelet aggregation, has been further characterized in in vitro and ex vivo studies.When whole blood was activated with collagen in the presence of picotamide 5×10^–4 M, thromboxane B₂ production was decreased, and 6-keto-PGF₁ generation was significantly increased, suggesting a reorientation of platelet endoperoxide metabolism following blockade of thromboxane synthetase. Picotamide also inhibited platelet aggregation and clot retraction induced by the endoperoxide analogue U46619 in human platelets, indicating thromboxane A₂-receptor antagonism, possibly of competitive nature.A single oral dose of picotamide 1 g in 24 healthy volunteers produced a significant inhibition of collagen, arachidonic acid and U46619-induced platelet aggregation. Serum levels of thromboxane B₂ were also reduced.Chronic administration of picotamide 1.2 g/d to patients with vascular disease resulted in a prompt and persistent fall in their increased plasma levels of -thromboglobulin.The results indicate that picotamide is a combined thromboxane B₂-synthetase inhibitor and thromboxane A₂-receptor antagonist in human platelets, and that it may prove useful as an antithrombotic agent.     

Identification of T-cell antigens expressed by metastatic T-cell hybridomas and lymphomas

Using the murine BW5147 tumor model system, we have identified 3 MAbs that discriminate between metastatic and non-metastatic BW5147-derived T-cell hybridomas and BW5147-unrelated T-lymphomas. The 3 rat MAbs appear to recognize an identical membrane-associated sialoglycoprotein with an approximate molecular weight of 95-100 kDa. We thus defined "metastatic T-cell hybridoma" antigens (MTH-Ags) that are also expressed on normal T-lymphocytes. No correlation was found between the expression of the MTH Ags and in vitro invasive behavior of normal and malignant cells. Neither did we find any relationship between organ specificity of i.v. inoculated tumor cells and their MTH-Ags expression. It thus remains unclear whether our MTH-Ags are functionally involved in the metastatic process, or whether their expression is only incidentally related to the metastatic potential.     

粉防己碱对兔瘢痕组织作用的实验研究

目的 :研究粉防己碱对兔病理性瘢痕的组织学作用 ,为瘢痕治疗提供一种新方法。方法 :采用兔耳腹侧瘢痕模型 ,用粉防己碱 5 0mg /ml、粉防己碱 10mg /ml、去炎松 40mg /ml及生理盐水分别注入瘢痕组织 ,图像分析瘢痕组织中成纤维细胞数量和胶原含量的变化。结果 :粉防己碱治疗组瘢痕组织中成纤维细胞数量与胶原含量均明显减少 ,呈剂量效应关系 ;与生理盐水对照组比较 ,有极显著差异 (P <0 .0 1) ;与去炎松对照组比较无显著差别 (P >0 .0 5 )。结论 :粉防己碱抑制瘢痕组织中成纤维细胞增殖 ,并使胶原合成减少 ,从而抑制瘢痕组织生长 ,有望成为防治病理性瘢痕的新药物