May cannabinoids prevent the development of chemotherapy-induced diarrhea and intestinal mucositis? Experimental study in the rat.

BACKGROUND: The antineoplastic drug 5-fluoruracil (5-FU) is a pirimidine analog, which frequently induces potentially fatal diarrhea and mucositis. Cannabinoids reduce gastrointestinal motility and secretion and might prevent 5-FU-induced gut adverse effects. Here, we asked whether cannabinoids may prevent diarrhea and mucositis induced by 5-FU in the rat. METHODS: Male Wistar rats received vehicle or the non-selective cannabinoid agonist WIN 55,212-2 (WIN; 0.5 mg kg-1 injection-1 , 1 injection day-1 , 4 consecutive days) by intraperitoneal (ip) route; on the first 2 days, animals received also saline or 5-FU (150 mg kg-1 injection-1 , cumulative dose of 300 mg kg-1 ). Gastrointestinal motor function was radiographically studied after barium contrast intragastric administration on experimental days 1 and 4. Structural alterations of the stomach, small intestine and colon were histologically studied on day 4. PAS staining and immunohistochemistry for Ki67, chromogranin A and CD163 were used to detect secretory, proliferating, and endocrine cells, and activated macrophages respectively. KEY RESULTS: As shown radiographically, 5-FU induced significant gastric emptying delay (on days 1 and 4) and diarrhea (on day 4). WIN did not significantly alter the motility curves obtained for either control or 5-FU-treated animals but tended to reduce the severity of 5-FU-induced diarrhea and increased permanence of barium from day 1 to the beginning of day 4 in 5-FU-treated animals. 5-FU-induced mucositis was severe and not counteracted by WIN. CONCLUSIONS AND INFERENCES: 5-FU-induced diarrhea, but not mucositis, was partly prevented by WIN at a low dose. Cannabinoids might be useful to prevent chemotherapy-induced diarrhea.

Prior aspirin use in unstable angina patients with modified plasma inflammatory markers and endothelial nitric oxide synthase in neutrophils.

BACKGROUND: Prior use of aspirin in patients with acute coronary syndrome has been associated with a lower incidence of acute myocardial infarction. The aim of this study was to explore if prior aspirin therapy in unstable angina (UA) patients could modify systemic inflammatory markers such as interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) and the expression of endothelial nitric oxide synthase (eNOS) in neutrophils. MATERIALS AND METHODS: Unstable angina was defined as transient S-T segment changes without significant increases in CK and CK-MB. We studied 50 consecutive patients admitted to hospital within 24 h after the onset of chest pain. The number of patients with prior aspirin was significantly higher (n = 32) than those not taking aspirin (n = 18) on admission. RESULTS: Plasma levels of IL-6 and ICAM-1 were significantly increased in the UA patients when compared with the healthy control volunteers (n = 20) used as a reference for normal values. Plasma levels of both IL-6 and ICAM-1 were reduced in patients taking aspirin. There were no differences in the plasma levels of TNF-alpha between the UA patients and the control volunteers. The eNOS protein expression was also higher in neutrophils from the UA patients taking aspirin than in those not taking aspirin. CONCLUSION: Patients taking aspirin before UA showed a lower systemic inflammatory response and higher eNOS protein expression in their neutrophils

[Doxazosin and soluble guanylate cyclase in a rat model of hypertension]. / Doxazosina y guanilato ciclasa soluble en un modelo de ratas hipertensas.

BACKGROUND: Although different studies have evaluated the ability of endothelial cells to produce NO in the setting of the endothelial dysfunction associated with hypertension, less it is known about the soluble guanylate cyclase system. AIM: To analyze the level of expression of sGC in the vascular wall in Stroke-prone spontaneously hypertensive rats (SHRSP). Moreover, the effect of treatment with an alpha1 adrenergic antagonist, doxazosin, on sGC expression was also evaluated. METHODS: The study was performed in 24 untreated 20-week-old SPSHR and 12 SPSHR treated orally with doxazosin (10 mg/Kg bw/day; for 15 days). A group of normotensive Wistar-Kyoto (WKY) rats were used as controls (n = 12). RESULTS: Isolated aortic segments from SHRSP showed impaired response to SNP. Doxazosin treatment prevented impaired vasodilatory response to SNP. Expression of the beta1 sGC in the vascular wall of SHRSP determined by Western blot and immunohistochemistry was markedly reduced with respect to that of WKY. Doxazosin treatment increased of beta1 sGC expression in treated SHRSP particularly at the medium level with respect to that of untreated SHRSP. CONCLUSION: SHRSP showed reduced expression of beta1 sGC in the vascular wall and an impaired vasodilator response to SNP which improved with doxazosin treatment. These results suggest the role the sGC system may play in the global treatment of endothelial dysfunction.

Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin.

Patients with heterozygous familial hypercholesterolemia (hFH) are at very high risk for premature coronary heart disease. In the last decade, treatment with statins has reduced cardiovascular mortality in these patients. The aim of this study was to analyze arterial endothelial function assessed as flow-mediated dilatation (FMD) and soluble E-selectin (sE-selectin) levels in patients with hFH under a long-term lipid-lowering treatment. Twenty-five patients who completed the study received a dose of simvastatin to achieve a treatment goal of at least 30% reduction in serum low-density lipoprotein (LDL)-cholesterol (LDL-C) for 52 weeks. Functional and biochemical measurements were taken at entry, and at week 12 and 52 of treatment. FMD was measured by vascular ultrasound of the brachial artery. sE-selectin, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 were determined by enzyme linked immunosorbent assay (ELISA). LDL-C levels were significantly reduced by treatment at week 12 and maintained at week 52 (reduction vs. baseline, 44+/-12 and 43+/-11%, respectively, P<0.0001). A significant improvement in endothelial function, measured as FMD (baseline, 4.7+/-6.2%; 12 weeks, 12.3+/-5.9%; 52 weeks, 9.7+/-4.7%; P<0.005) and a reduction in sE-selectin levels (baseline, 16.2+/-3.4 ng/ml; 12 weeks, 11.0+/-3.2 ng/ml; 52 weeks, 12.3+/-4.2 ng/ml; P<0.01) were observed. Endothelial-independent relaxation induced by nitroglycerin was not modified during the study. Our results indicate that a long-term treatment with simvastatin produced a sustained beneficial effect in endothelial function in hFH patients.

[Spontaneous meningitis caused by gram-negative bacilli]. / Meningitis espontánea por bacilos gramnegativos.

OBJECTIVE: To analyze the causative factors, clinical and microbiological characteristics, and prognosis in spontaneous meningitis caused by Gram-negative rods in adult patients. METHODS: Descriptive and retrospective study of all clinical records and microbiological findings in patients diagnosed of meningitis by Gram-negative bacilli, from 1973 to 1995, at Fundación Jiménez Díaz. RESULTS: Twenty patients had spontaneous meningitis caused by Gram-negative bacilli (2.1% of all diagnosed meningitis during this period). Fourteen patients were older than 65 years (range: 36-81; p < 0.05). Ninety-five percent of cases had an extranosocomial origin (p < 0.001). Ninety percent of patients had some underlying disease (p < 0.001). Twelve patients were immunosuppressed. Seven patients had changes in the urinary tract or repeated UTI infections. The most common clinical symptoms were a decrease in consciousness level, fever, and neck stiffness. Cerebrospinal fluid (CSF) in 18 patients showed cellular and biochemical changes. The CSF smear revealed the presence of Gram-negative bacilli in 15 patients. E. coli was the microorganism recovered most frequently. Immunosuppression (p < 0.05), septic shock (p < 0.001) and antimicrobial therapy not including a third generation cephalosporin (p < 0.01) were independently associated with mortality. CONCLUSIONS: Spontaneous meningitis by Gram-negative bacilli is an uncommon infection. It occurs mainly in immunosuppressed patients older than 65 years or with changes in the urinary tract. It usually has an extranosocomial origin. The investigation of CSF is a highly effective for diagnosis. Therapy with third generation cephalosporins has notably improved its prognosis.

Cervical epidural abscess: approaches to diagnosis.

We report on two cases of cervical epidural abscess (CEA). Their clinical presentation included fever, neck pain and symptoms of neural compression, and the presence of epidural abscess was documented by surgery. Several imaging methods were used to establish a prompt diagnosis of CEA in both patients. Magnetic Resonance image provided a noninvasive means of visualize both extent in the spinal canal and paravertebral locations. None of the other currently used imaging modalities could provide the same information alone. The role of these techniques in diagnosing this condition is discussed.

Localization of human immunodeficiency virus antigens in infected cells by scanning/transmission-immunogold techniques.

An application of high resolution scanning/transmission electron microscopy (STEM) and gold-labelling techniques for the rapid detection of human immunodeficiency virus (HIV) in infected cells has been developed. Experimental in vitro studies for detecting two HIV structural proteins, gp41 and p17, were performed following an indirect labeling procedure that uses monoclonal anti-p17 and anti-gp41 antibodies as primary antibodies and 40 nm gold-linked goat antimouse IgG as secondary antibodies. The cells were then studied by STEM in the scanning mode. Unambiguous localization of the viral antigens was possible by combining the three-dimensional image provided by the secondary electron image and the atomic number-dependent backscattered electron image for the identification of the gold marker. This technique combines both the morphological information and the rapid procedures of scanning electron microscopy with the precise and sensitive antigen detection provided by the use of STEM and immunological methods. The preliminary results of its application to the study of peripheral blood mononuclear cells from four anti-HIV-seropositive patients showing the presence of specific labeling in all of them suggest that it might prove useful for early detection of HIV infection before seroconversion, as well as for quantitative studies.

Human immunodeficiency virus and related retroviruses.

This paper summarizes the current knowledge on the human immunodeficiency virus (HIV) and related retroviruses, describing basic characteristics of this new group of viruses such as morphologic and genetic structure, biological and cultural properties, virus growth characteristics, genetic variability and virus replication. The discovery of new human and simian retroviruses has prompted the World Health Organization (WHO) to convene a group of experts to establish criteria for their characterization. This will allow rapid identification of new variants that may arise and allow public health measures to be implemented accordingly. Different approaches are made to nomenclature in view of the evolution of knowledge about these viruses, and a system of nomenclature has been proposed by the WHO working group. This system, inspired by the one developed for the influenza viruses, is practical and descriptive, providing information on the origins of the organism and its type.