Histamine inhibits 5-hydroxytryptamine release from the porcine small intestine: involvement of H3 receptors.

Strips of the porcine small intestine were incubated in vitro, and the release of 5-hydroxytryptamine (5-HT) was determined by high-pressure liquid chromatography with electrochemical detection. Removal of the mucosa resulted in a large reduction (95%) of tissue 5-HT, suggesting that enterochromaffin cells are the main source of 5-HT. The release of 5-HT was reduced by 70% after omission of calcium. Tetrodotoxin and hexamethonium reduced the release of 5-HT by 30%-40% in a nonadditive manner, indicating a spontaneous neuronal (nicotinic) excitatory input to the enterochromaffin cells. Histamine inhibited the release of 5-HT by about 50%. This effect was not affected by mepyramine or cimetidine but was effectively blocked by thioperamide, indicating the involvement of H3 receptors. The selective H3-receptor agonist R-alpha-methyl-histamine also inhibited 5-HT release. Because the effect of R-alpha-methyl-histamine was also observed in the presence of tetrodotoxin, an indirect, neuronally mediated action could be excluded. Therefore, the inhibitory H3 receptors may be localized directly at the enterochromaffin cells.     

Propranolol disposition in the rat: variation in hepatic extraction with unbound drug fraction.

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three- to fourfold as albumin and alpha 1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.     

Peptides for calling? An immunohistochemical study of the avian n. intercollicularis.

We used two phylogenetically distant avian species (dark-eyed junco, hyemalis, Passeriformes; domestic pigeon, Columba livia, Columbiformes) to determine the immunocytochemical distribution of opioid (leucine-enkephalin, dynorphin B) and non-opioid (adrenocorticotropic hormone) peptides in the n. intercollicularis (ICo), a midbrain region which plays a central role in the control of vocalizations. We found that, in both species, the peptides under study are present as fibers and terminal-like structures, and are similarly distributed. The n. dorsomedialis intercollicularis division contains much less immunoreactivity than the rest of the ICo. Based on this and previous studies, we propose that opioid peptides, possibly transported from the preoptic and hypothalamic regions of the diencephalon to the ICo, regulate vocal behavior by altering respiratory function rather than syringeal mechanisms.     

Effect of clonidine and atropine on rest tremor in the MPTP monkey model of parkinsonism

The purported alpha 2-adrenergic agonist clonidine was found to inhibit rest tremor at doses of 0.023-0.1 mg/kg in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of parkinsonism. The effect was dose dependent, but sedation and reduced mobility were observed. Atropine at doses of 0.1-1 mg/kg also reduced tremor in a dose-dependent fashion, but side-effects in the form of agitation, dilated pupils, and dry mouth were seen. When the two drugs were combined, however, we saw a significant potentiation of the antitremor effect. We could even abolish tremor with doses of atropine and clonidine that by themselves were without effect. The side-effects were almost eliminated by the combination.     

Controversies in the diagnosis and treatment of early carcinoma of the larynx

Patients in whom the diagnosis of early carcinoma of the larynx is made and treated as outlined below have a good to excellent outlook (from 85 to 95% survival for glottic lesions). Metastases from lesions of the free edge of the vocal cord usually do not occur because of the paucity of lymphatics, whereas lesions of the supraglottis are more apt to metastasize to regional lymph nodes and local spread. The subglottic area on the other hand by in large has a more ominous prognosis. Carcinoma in situ is treated mainly by endoscopic surgery, whereas T1 lesions of the glottis can either be treated by surgery or radiation with comparable results. This author prefers conservation surgery for the majority of T1 lesions. Radiotherapy is utilized for selected patients with T1 glottic lesions.     

Cancer risks associated with 10 inorganic dusts: results from a case-control study in Montreal

A multicancer site, multifactor case-control study was undertaken to generate hypotheses about possible occupational carcinogens. Probing interviews were carried out with eligible cases, comprising all incident cases of 20 types of cancer who were male, aged 35-70 years, and a resident in Montreal. The interview was designed to obtain detailed lifetime job histories and information on potential confounders. Each job history was reviewed by a team of chemists and industrial hygienists who translated it into a history of occupational exposures. These occupational exposures were then analyzed as potential risk factors in relation to the sites of cancer included; 3,726 cases were interviewed. For each site of cancer analyzed, controls were selected from among the other sites in the study. This report concerns the associations between the 12 main types of cancer in our series and 10 inorganic dusts that are found mainly in construction and metal industries. All site-exposure combinations were investigated. After intensive control for confounding, nonadenocarcinoma (NAC) of the lung was associated with long duration-high level exposure to silica (odds ratio [OR] = 1.4), excavation dust (OR = 1.9), concrete dust (OR = 2.5), abrasives dust (OR = 1.4), and alumina (OR = 1.5). It was difficult to disentangle the relative effects of those substances, and confounding among them was a distinct possibility. Although residual confounding by some uncontrolled factors may explain the elevated ORs, the results were compatible with the hypothesis of a nonspecific relation between NAC of the lung and respirable inorganic dusts as a class. Other associations that remained suggestive after in-depth analysis were silica and stomach cancer (OR = 1.2) and concrete dust and lymphoma (OR = 2.9).     

Resection of the inferior vena cava and tumor of the excretory duct: diagnostic and prognostic problems

The authors present a case of transitional cell carcinoma of the renal pelvis with inferior vena cava involvement. Two types of vena cava involvement are discussed: thrombus or nodes. The CT scan appears to be the best examination to preoperatively diagnose the type of invasion in order to be able to select the optimal treatment. However, these two types of involvement have a poor prognosis and surgery abstention may be justified. Chemotherapy may be useful in these cases.     

VEGF: a key therapeutic target for the treatment of cancer-insights into its role and pharmacological inhibition

Angiogenesis, the formation of new blood vessels from existing vessels, is required for tumor growth, proliferation, and metastasis. Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis, activating signaling pathways that in tumors result in immature blood vessels that are disorganized, tortuous, and leaky. Inhibiting VEGF has the potential to reduce vessel abnormalities and inhibit tumor growth. Preclinical and clinical data show that anti-VEGF agents produce a number of effects on the tumor vasculature, including regression of tumor vessels, “normalization” of the surviving vessels, and inhibition of neovascularization. Normalization reduces the characteristically high intratumoral pressure that impairs the delivery of chemotherapy to tumors; this should improve the effectiveness of chemotherapy. These vascular effects are proposed to be dynamic, providing early and continued (late) clinical benefits. Early clinical effects are thought to be reflected by a consistent improvement in response rate with anti-VEGF agents used alone or in combination with standard therapies. In addition, anti-VEGF agents are proven to extend survival and delay disease progression, illustrating continued (late) effects.     

Gaining insight into the Clinical Practice Guideline development processes: qualitative study in a workshop to implement the GRADE proposal in Spain

Background  

The GRADE method represents a new approach to grading the quality of evidence and strength of recommendations in the preparation of Clinical Practice Guidelines (CPG). In the context of a pilot study to assess the implementability of the system in Spain, we considered it relevant to gain an insight into the significance of the perceptions and attitudes expressed by the actual experts participating in the system try-out.