Neuroprotective activity of a nanoparticulate formulation of the glycineB site antagonist MRZ 2/576 in transient focal ischaemia in rats

The objective of the present study was to characterise the neuroprotective activity of the novel glycineB site NMDA (N-methyl-D-aspartate) receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-l-oxo- 1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt, CAS 202807-80-5) in a rodent model of focal cerebral ischaemia. Since the solubility of MRZ 2/576 at a physiological pH, is minimal and adequate concentrations can be achieved only at relatively high basic pH the in vivo use of the substance is substantially limited. Therefore, a special nanoparticle formulation was developed to provide means for lengthy i.v. administration of experimentally relevant doses within the physiological range of pH. Focal ischaemia of 75 min duration was induced in rats by a reversible occlusion of the middle cerebral artery (MCAo). MRZ 2/576 (18 mg/kg over 10 min followed by 18 mg/kg/h over 6 h) or placebo treatment was initiated immediately after onset of MCAo. Neurological deficit was evaluated daily for 3 consecutive days and then brain infarct analysis was performed. MRZ 2/576 significantly improved the neurological score at 24 h and 72 h post stroke (p < 0.05 vs. placebo). It also produced a 53.0% reduction of total infarct size, 60.4% of cortical and 42.3% of striatal infarction (p < 0.05 vs. placebo). Temporary drug-induced hypothermia and ataxia were observed during infusions. This leads to the conclusion that prolonged administration of the glycineB site antagonist MRZ 2/576 in form of the nanoparticle suspension ameliorates ischaemic damage induced by the transient MCAo in rats. The results suggest that nanoparticles hold promise as an effective strategy e.g. for substances with physico-chemical characteristics that otherwise would preclude them from pre-clinical development and/or clinical application.     

The impact of a cardioprotective protocol on the incidence of cardiac complications after aortic abdominal surgery

We analyzed a local database including 468 consecutive patients who underwent elective aortic abdominal surgery over an 8-yr period in a single institution. A new cardioprotective perioperative protocol was introduced in January 1997, and we questioned whether perioperative cardiac outcome could be favorably influenced by the application of a stepwise cardiovascular evaluation based on the American College of Cardiology/American Heart Association guidelines and by the use of antiadrenergic drugs. Clonidine was administered during surgery, and beta-blockers were titrated after surgery to achieve heart rates less than 80 bpm. We compared data of two consecutive 4-yr periods (1993-1996 [control period] versus 1997-2000 [intervention period]). Implementation of American College of Cardiology/American Heart Association guidelines was associated with increased preoperative myocardial scanning (44.3% vs 20.6%; P < 0.05) and coronary revascularization (7.7% vs 0.8%; P < 0.05). During the intervention period, there was a significant decrease in the incidence of cardiac complications (from 11.3% to 4.5%) and an increase in event-free survival at 1 yr after surgery (from 91.3% to 98.2%). Multivariate regression analysis showed that the combined administration of clonidine and beta-blockers was associated with a decreased risk of cardiovascular events (odds ratio, 0.3; 95% confidence interval, 0.1-0.8), whereas major bleeding, renal insufficiency, and chronic obstructive pulmonary disease were predictive of cardiac complications. In conclusion, cardiac testing was helpful to identify a small subset of high-risk patients who might benefit from coronary revascularization. Sequential and selective antiadrenergic treatments were associated with improved postoperative cardiac outcome. IMPLICATIONS: Implementation of American College of Cardiology/American Heart Association guidelines and use of antiadrenergic drugs were associated with better cardiac outcomes after major vascular surgery.     

Expression and function of prostate-apoptosis-response-gene-4 in lymphatic cells

Inhibition of apoptosis contributes to the pathogenesis of lymphatic malignancies. In particular, the elevated expression of Bcl-2 is considered to be a marker of poor prognosis, since increased levels of Bcl-2 confer longevity as well as chemoresistance. After demonstrating an inverse expressional pattern of Bcl-2 and prostate-apoptosis-response-4 (Par-4) in ex vivo cells of patients suffering from acute lymphatic leukemia (ALL) as well as a deregulated expression of Par-4 in acute and chronic lymphatic neoplasias, the molecular mechanisms underlying these results were investigated. Thus, it was demonstrated that in neoplastic lymphatic cells Par-4 exerts a proapoptotic role augmenting chemosensitivity by down-regulating Bcl-2, promoting disruption of mitochondrial membrane potential and enforcing caspase-activation. Moreover, Par-4 enables cells to circumvent inhibition of the central executioner caspase-3 by alternative activation of caspases following a decrease in expression levels of inhibitors of apoptosis proteins (IAP).     

hKAP1.6 and hKAP1.7, two novel human high sulfur keratin-associated proteins are expressed in the hair follicle cortex

Hair fiber differentiation involves the expression of both hair keratin intermediate filament proteins and their associated proteins, termed keratin-associated proteins. In this study, cDNA clones encoding two novel keratin-associated proteins were isolated from human hair follicle mRNA. The predicted amino acid sequence derived from these clones revealed that these proteins represent members of the human keratin-associated protein 1 family. They show strong sequence homology to two previously described keratin-associated protein 1 family members hKAP1.1 A and hKAP1.1B. We have called these new proteins hKAP1.6 and hKAP1.7, respectively. RNA in situ hybridization studies of human anagen hair follicles using a conserved probe for these four keratin-associated protein 1 members demonstrated the expression of this group in the differentiated portions of the hair cortex.     

Neuropsychological profile of acute alcohol intoxication during ascending and descending blood alcohol concentrations.

Numerous studies have investigated the effects of alcohol on motor processes during rising and declining blood alcohol concentrations (BAC), however, relatively little research has examined the alcohol-induced impairment of cognitive performance on the two limbs of the BAC curve. This experiment administered a neuropsychological test battery to assess the degree to which rising and declining BACs during an acute dose of alcohol impair nine cognitive processes within an individual. In all, 20 healthy male social drinkers (university students) were assigned to one of two groups (n = 10) who received a beverage containing either 0.0 g/kg (placebo) or 0.65 g/kg alcohol and performed the test battery when BAC was increasing and was decreasing. Comparisons of alcohol and placebo groups revealed impairment (slower response and/or increased errors) in seven of the cognitive processes: long-term verbal memory; information processing; declarative memory; inhibitory control; short-term visual memory; long-term visual memory, and visual-spatial working memory. However, some processes were impaired only during rising BACs whereas the impairment of others during declining BACs was evident only by an increase in errors. These results show cognitive tasks performed by an individual are not similarly affected by rising and declining BACs, and call attention to the importance of assessing both speed and accuracy on both limbs of the BAC curve. The particular cognitive processes differentially affected by rising vs declining BACs raised the possibility that acute alcohol intoxication may impair one cerebral hemisphere to a greater degree than the other, and this could be explored by neuroimaging techniques.     

Acetyl-11-keto-β-boswellic acid, a constituent of a herbal medicine from Boswellia serrata resin, attenuates experimental ileitis

The gum resin extract from Boswellia serrata (H15), an herbal product, was recently shown to have positive therapeutic effects in inflammatory bowel disease (IBD). However, the mechanisms and constituents responsible for these effects are poorly understood. This study examined the effect of the Boswellia extract and its single constituent acetyl-11-keto-beta-boswellic acid (AKBA) on leukocyte-endothelial cell interactions in an experimental model of IBD. Ileitis was induced by two subcutaneous injections of indomethacin (7.5 mg/kg) in Sprague-Dawley rats 24 h apart. Rats also received oral treatment with the Boswellia extract (H15) or AKBA at two different doses (low and high) equivalent to recommendations in human disease over 2 days. Controls received only the carriers NaHCO3 (subcutaneously) and tylose (orally). Effects of treatment were assessed by intravital microscopy in ileal submucosal venules for changes in the number of rolling and adherent leukocytes and by macroscopic and histological scoring. Increased leukocyte-endothelial cell adhesive interactions and severe tissue injury accompanied indomethacin-induced ileitis. Treatment with the Boswellia extract or AKBA resulted in a dose-dependent decrease in rolling (up to 90%) and adherent (up to 98%) leukocytes. High-dose Boswellia extract as well as both low- and high-dose AKBA significantly attenuated tissue injury scores. Oral therapy with the Boswellia extract or AKBA significantly reduces macroscopic and microcirculatory inflammatory features normally associated with indomethacin administration, indicating that the anti-inflammatory actions of the Boswellia extract in IBD may be due in part to boswellic acids such as AKBA.     

Prognosis of extrahepatic bile-duct atresia after hepatoportoenterostomy

 Clinical and histologic findings from 206 patients operated upon for extrahepatic biliary atresia (EHBA) are analyzed in order to define the prognosis of patients with EHBA. The prospective study took into consideration both initial fibrosis of the liver and the morphology of the porta hepatis (PH) at surgery. Kaplan-Meier survival estimates and statistical calculations demonstrated a relationship between long-term survival and histologic findings in the liver and porta hepatis. The efficacy of HPE is significantly influenced by the morphology of the PH and to a lesser extent by the initial liver fibrosis. Surgery should thus achieve pattern 1 morphology of the PH, but this is problematic because of the close relationship of the vascular and biliary structures in its two lateral zones. Accepted: 8 November 1999