The novel inotropic agent CGP 48506 alters force primarily by Ca(2+)-independent mechanisms in porcine skinned trabeculae

OBJECTIVES: The aim was to determine whether, and by what mechanism(s), a novel inotropic agent 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3, 6-methano-1,5-benzodiazocine-2,4-dione (BA 41899) and its enantiomers directly alter the Ca2+ sensitivity of cardiac myofilaments. METHODS: Porcine ventricular trabeculae were permeabilised with Triton X-100. The relationship between force and pCa (-log[Ca2+]) was determined in the presence and absence of ATP. Troponin I was extracted, using vanadate, to produce unregulated maximally activated myofilaments. Force and actomyosin ATPase activity were measured simultaneously to determine tension cost (ATPase activity/tension). The effects of the (+) enantiomer (CGP 48506) on the twitch of intact muscle were demonstrated using rat papillary muscle. RESULTS: 100 microM BA 41899 had a pronounced Ca2+ sensitising effect on force production by porcine skinned cardiac fibres, increasing the pCa required for 50% maximal activation by 0.64 units, while suppressing maximum force by 18.3%. Resting tension was unaffected. These actions were primarily caused by CGP 48506 and were concentration dependent. At concentrations less than 100 microM, CGP 48506 also increased twitch amplitude in intact papillary muscles with no effect on resting tension, whereas 100 microM CGP 48506 increased resting force due to a slowing of relaxation. 100 microM CGP 48506 potentiated Ca(2+)-independent rigor tension in skinned trabeculae, indicating a Ca2+ sensitising mechanism unrelated to Ca2+ binding to troponin C. Tension cost was unaffected by 100 microM CGP 48506 over the entire range of activating Ca2+ concentrations. Suppression of maximum force by CGP 48506 was independent of both Ca2+ concentration and the regulatory troponin complex. CONCLUSIONS: Both the increase in Ca2+ sensitivity during submaximal activation and the depression of maximum force which are induced by CGP 48506 in skinned trabeculae occur at least partly through Ca(2+)-independent mechanisms.     

Morphological variations of the human gastric mucosa after omeprazole treatment: a scanning electron microscopic study

The effects of antiepileptic drugs on cognitive function in 48 healthy volunteers were assessed using event-related potentials (ERP) and the Attention Index included in the Wechsler Memory Scale, revised edition (WMS-R). The study was conducted over 1 week, using a double-blind design. Four drugs, carbamazepine (CBZ), phenytoin (PHT), valproate (VPA) and zonisamide (ZNS) were tested. Using an auditory oddball task, ERP measurements were made under two conditions with different tone intensities: Condition 1 used 70 db SPL; and Condition 2 used 30 db SPL. Results showed that CBZ prolonged target N1 and P3 latencies in Condition 1, and reduced frequent N1 amplitude in Condition 2, which suggests that CBZ may cause a change in sensory memory and prolong stimulus evaluation time. It is suggested that under a low stimulus intensity level, the sensory function itself was affected. Phenytoin was found to prolong target N1 latency in Condition 2, which also indicates a change in the sensory memory function. However, VPA did not significantly affect ERP components, except for the shortened frequent N1 latency, which could not be explained due to the limited information. It was found that ZNS augmented P3 amplitude in Condition 2, and reduced scores on the Attention Index. It is suggested that the augmentation of P3 amplitude was caused by the reduction of processing negativity as a result of the detrimental effect of ZNS on subjects' attention. However, the apparent difference between the ERP and behavioral indices suggests that caution should be exercised in assessing the results obtained only from ERP measurements.     

Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

Ascitic fluid analysis in hepatocellular carcinoma

BACKGROUND: Ascites in patients with hepatocellular carcinoma (HCC) is a poorly characterized subgroup of malignancy-related ascites. Not only the underlying liver disease, but also the tumor growth and spread contributes to the ascites formation. The authors differentiated ascites in HCC from other types of ascites. METHODS: The authors analyzed the ascitic fluid of 185 consecutive patients (89 liver cirrhosis, 33 HCC, 31 peritoneal carcinomatosis, 22 liver metastases, 10 spontaneous bacterial peritonitis). RESULTS: Each subgroup showed a typical pattern. Compared with the cirrhotic patients, those with HCC showed a higher frequency of positive cytologic findings (4 of 33 versus 0/89, P < 0.004), elevated fibronectin concentration (10/33 versus 8/89, P < 0.004), and elevated polymorphonuclear cell count (10/33 versus 5/89 P < 0.004). CONCLUSIONS: A significant number of patients with ascites and HCC patients showed signs of peritoneal infiltration with positive cytologic findings and increased concentration of fibronectin. Moreover, neutrocytic ascites without signs of superinfection is relatively common (30%).     

Multiresidue method for pesticides in drinking water using a graphitized carbon black cartridge extraction and liquid chromatographic analysis

A general liquid-solid extraction procedure for the isolation of pesticides from groundwater and drinking water for high-performance liquid chromatography (HPLC) is presented. This simple and rapid procedure involved passing a 2-L sample through a 250-mg graphitized carbon black (Carbopack B) cartridge at a flow rate of 150-160 mL/min. By taking advantage of the presence of positively charged active centers on the Carbopack B surface, a stepwise elution system allowed the complete separation of base-neutral pesticides from acidic ones. After partial solvent removal, the components in the two fractions were separated and quantified by gradient elution, reversed-phase HPLC with ultraviolet (UV) detection. The performance of the Carbopack cartridge was compared with that of a 500-mg C-18 bonded silica cartridge. With the Carbopack cartridge, the grand mean measurement accuracy of the 35 pesticides considered was 95%. With the C-18 cartridge, the grand mean measurement accuracy of the analytes was 76%. Compared to the C-18 cartridge, additional advantages of using a Carbopack cartridge are that the extraction procedure is about 7 times shorter, no pH adjustment of the environmental sample is necessary for trapping acidic compounds, and one cartridge instead of two suffices to extract base-neutral and acidic pesticides, making the Carbopack cartridge more adaptable than the C-18 one for field use. The detection limits by this method of all the pesticides considered were between 0.003 and 0.07 micrograms/L.     

Primary lymphoma of the breast. Three cases of non-Hodgkin lymphoma

Primary and sole breast lymphoma is a very rare disease. With the review of our series of 616 cases operated on for breast cancer, only 3 cases (0.48%) of primary breast non-Hodgkin lymphoma (LNH) have been observed. The authors outline the problems concerning diagnosis and therapy of this rare disease: pathological and immunohistochemical aspects are discussed. They stress the importance of staging in order to plan a correct multidisciplinary approach.     

Spinal reflex pattern to foot nociceptive stimulation in standing humans

We describe here the results of a screening program conducted to discover inhibitors of the type-I interleukin-1 receptor (IL-1RI) from samples of microbial origin. An innovative approach, based on automated, nonradioactive receptor binding assays has been employed. Specially prepared cell-free systems have allowed the use of high concentrations of microbial metabolites in the reaction mixtures with a low percentage of false positives. More than 30,000 microbial samples from different species of soil isolates have been tested and two interesting activities have been purified and characterized. One of these, isolated from Streptomyces sp. GE48009, was identified as niphimycin, an antifungal agent also known as scopafungin. Preliminary evidence suggests that this molecule and azalomycin F, a structural analogue, inhibit IL-IRI by virtue of their long-chain guanidinium moiety. The other activity, isolated from Aspergillus sp. GE49752, was identified as flavipin, a substituted o-phthalaldehyde.     

Enhancement Effects in the Percutaneous Absorption of Alprazolam Through Human Skin in vitro

The enhancement effects of some chemicals on the percutaneous absorption of alprazolam through human skin was investigated in vitro. Linoleic acid, oleic acid, Comperlan F® (linoleic acid diethanolamide), Comperlan KD® (coconut fatty acid diethanolamide) and Ethomeen C12® (bis-(2-hydroxyethyl)cocamine) were evaluated for their enhancing effect either as neat solvents or combined with propylene glycol. The effects of skin pretreatment with the enhancers on the percutaneous absorption of alprazolam from a drug suspension in an aqueous gel were also investigated: skin pretreatment with some enhancers has shown potentially interesting aspects. The determination of alprazolam partitioning into untreated and pretreated horny layer supported the idea that, with oleic and linoleic acid, a contribution to the modification of the diffusional resistance of the skin was given by an increase of the drug solubility in the stratum coraeum.