The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Traumatic aneurysm of the internal carotid artery: a late finding presenting as a mass in the sphenoid sinus.

We describe a case of a traumatic aneurysm of the cavernous portion of the internal carotid artery in a patient who had had craniofacial trauma 12 years before. MR and CT revealed a mass in the sphenoid sinus thought to be unrelated to the patient''s symptoms. Carotid angiography gave the correct diagnosis.     

Perinatal 'TORCH' infections identified by serology: correlation with abnormalities in the children through 7 years of age.

A matched case-control methodology was used to assess the risk for a wide range of abnormalities in children associated with serological evidence for 'TORCH' infections in the mothers. Specimens were selected from the large bank of sera from the approximately 54,000 pregnant women who participated in the Collaborative Perinatal Project. There was no clear association between any of the antigens studied and any specific damage to the child. These 'negative' findings are consistent with the absence of frequent significant effects due to these agents in the second and third trimesters of pregnancy.     

The “suffocation alarm” theory of panic attacks: A critical commentary

In 1993 Klein proposed a “false suffocation alarm” theory of panic attacks, claiming that many spontaneous panic attacks are due to a “suffocation monitor” in the brain erroneously signaling a lack of useful air, and triggering an evolved “suffocation alarm system”. He proposed that carbon dioxide acts as a panic stimulus because rising arterial CO₂ suggests suffocation may be imminent. The present paper provides a critical analysis of Klein's theory and concludes that there is neither empirical evidence nor compelling argument to support the assumptions or the proposed neurological mechanism of a “suffocation alarm”, true or false, or a CO₂ “suffocation monitor”. Data relevant to the role of breathing in the phenomenon of panic can be parsimoniously subsumed within the domain of dyspnea.     

Lectin-like cell adhesion molecule 1 mediates leukocyte rolling in mesenteric venules in vivo

During the inflammatory response, granulocytes and other leukocytes adhere to and emigrate from small venules. Before firm attachment, leukocytes are observed rolling slowly along the endothelium in venules of most tissues accessible to intravital microscopy. The molecular mechanism underlying this early type of leukocyte-endothelial interaction is unknown. Leukocyte rolling was investigated in venules (diameter, 40 microns) of the exposed rat mesentery. Micro-infusion of a recombinant soluble chimera (LEC-IgG) of the murine homing receptor lectin-like cell adhesion molecule 1 (LEC-CAM 1; gp90MEL) into individual venules reduced the number of rolling leukocytes by 89% +/- 2% (mean +/- SEM, n = 20 venules), while a similar CD4 chimera (CD4-IgG) had no effect (inhibition 14% +/- 7%, n = 25). Rolling was also greatly reduced by a polyclonal serum against LEC-CAM 1 (inhibition 84% +/- 3%, n = 35); preimmune serum was ineffective (11% +/- 13% inhibition, n = 28). These findings indicate that LEC-CAM 1 mediates the adhesive interaction underlying leukocyte rolling and thus may play an important role in inflammation and in pathologic conditions involving leukocytes.     

Medulloblastoma in adulthood: Prognostic factors influencing survival and recurrence

Summary Thirty adult patients presenting with medulloblastoma between 1974 and 1991 were studied and treated at Puerta de Hierro Clinic. After diagnosis, all patients were treated by surgery followed by radiotherapy and eight of them received adjuvant chemotherapy. We have studied the influence of some factors such as age, sex, location of tumour in the cerebellum, amount of surgical resection and histological variants on survival and recurrence of the disease. Only the histological type has a statistically significant influence on survival and recurrence: we have found that patients presenting classic medulloblastoma have a long survival and a long relapse-free interval.     

LIPOPROTEIN(α) IN HEALTH AND DISEASE

SUMMARY Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).     

High frequency of precancerous lesions of gastric cancer associated with Helicobacter pylori and response to treatment,in Chiapas,Mexico

Stomach cancer is the second cause of death in Mexico in patients with malignant tumors. This disease represents a public health problem. A strong association has been described between chronic infection with Helicobacter pylori and gastric cancer. This malignancy is preceded by a series of preneoplastic conditions, including chronic atrophic gastritis (CAG), intestinal metaplasia (IM), and dysplasia. The objective of this study was to establish the prevalence of preneoplastic conditions associated with infection of Helicobacter pylori in the state of Chiapas and its eradication with antibiotics. Persons infected with Helicobacter pylori and with CAG were identified by serology against CagA protein and serologic levels of gastrin. An endoscopy with biopsy was performed at the beginning of the study, and at 6 weeks and 1 year thereafter. A total of 281 people were enrolled and randomly assigned to treatment or placebo group. CAG was found in 59%, IM in 51%, and dysplasia in 13%. In intent-to-treat and per-protocol analysis, Helicobacter pylori was eliminated in 70 and 76%, respectively. These results indicate high frequency of preneoplastic conditions associated with Helicobacter pylori and an excellent eradication rate. They also offer a possible alternative for preventing gastric cancer.