Age-associated alterations in calcium current and its modulation in cardiac myocytes

Stimulatory effects of several types of adjuvants on secondary antibody response to inactivated Newcastle disease virus (iNDV) were examined in chickens. For this purpose, animals were primed with iNDV without adjuvant resulting in a low but significant antibody response, boosted with iNDV plus adjuvant 3 weeks later, and analysed for specific antibody titres in serum 3 weeks after the booster. Water-in-mineral oil emulsion (W/O) caused significant increase in antibody titres measured in an indirect enzyme-linked immunosorbent (ELISA), haemagglutination inhibition (HI), and virus neutralisation (VN) assay. The adjuvants tested included three oil-in-water emulsions (i.e. mineral oil-in-water, sulpholipo(SL)-Ficoll400/squalane-in-water and sulpholipo-cyclodextrin/squalane-in-water), three negatively-charged polymers with high molecular weight (i.e. polyacrylate, polystyrenesulphonate and sulpho(S)-Ficoll400) and two surface-active agents (i.e. dimethyldioctadecylammonium bromide (DDA) and Quil A). These adjuvants enhanced significantly the secondary immune response but none reached the titre obtained with W/O. Combinations of adjuvants with distinct physicochemical properties, i.e. polyacrylate and DDA revealed only slight, beneficial effects. We concluded that the various types of adjuvants tested can stimulate secondary immune responses in primed animals but that W/O is superior.     

Multicenter prospective study of the current status of treatment for bleeding ulcer in Germany

The current state of ulcer treatment in Germany was analysed in a prospective multi-centre study. It was based on 1139 consecutive patients admitted to the participating hospitals because of upper gastrointestinal bleeding. The source of the bleeding was identified by diagnostic endoscopy in 1075 patients (94%), from a gastric and/or duodenal ulcer in 546 of them (mean age 62 +/- 18 years). Using Forrest's classification, 4% of patients were in bleeding stage Ia, 17% in stage Ib, 16% stage IIa, 30% stage IIb and 33% stage III. An attempt to arrest bleeding through the endoscope was made in 233 patients (43%): more often with tissue-preserving substances (epinephrine +/- NaCl in 36%, fibrin glue +/- epinephrine in 24%) than with tissue-damaging procedures (epinephrine + polidocanol +/- NaCl in 26%, epinephrine + thermocoagulation in 7%). Primary haemostasis was achieved in 219 patients (94%). There was a total of 66 recurrences of bleeding (12%), but the rate was 18% after endoscopic haemostasis. 64 patients (12%) required operative intervention, including initial emergency operations. Severe complications (infections, organic failure) occurred in 82 patients (16%). 114 of the 546 patients were in the high risk group (older than 60 years; high amount of bleeding). Their bleeding recurrence and mortality rates (27 and 22%, respectively) were significantly higher (P < 0.01) than those of the total group. Overall mortality rate was 11% (58 patients). The mortality rate depended on the severity of initial bleeding (26% for Forrest group Ia). After recurrent bleeding the mortality rate was 34% with conservative and 33% with operative treatment. 7% of all deaths were the direct result of bleeding. The following factors prognostically closely correlated with mortality rate: age of patient (P < 0.01); haemoglobin < 8 g/dl on admission (P < 0.05); initial severity of bleeding (Forrest group I; P < 0.05); and recurrence of bleeding (P < 0.001).     

Synthesis and structure elucidation of estrogen quinones conjugated with cysteine, N-acetylcysteine, and glutathione

A micromechanical model for predicting the densification of particulate matter under hydrostatic loading was developed to account for the time-dependent response of materials to applied loads. Viscoelastic material response used in the analysis was based upon a standard three-parameter rheological model. Compaction data under closed die conditions were collected using an Instron analyzer for different rates of applied load. Densification during the loading phase of PMMA/coMMA powder, a pharmaceutical polymeric coating material, was well predicted by the proposed algorithm, which contrasts with the prediction implied through a static indentation model. Secondary factors which affect compaction such as die-wall friction are also briefly discussed.     

Vitamin E modifies neither fructosamine nor HbA1c levels in poorly controlled diabetes

OBJECTIVE: To examine the effects of vitamin E on total serum protein glycation (fructosamine), hemoglobin glycation (HbA1c), and serum levels of glucose, total cholesterol, triglycerides, LDL-C, HDL-C, apolipoprotein A1 and apolipoprotein B. MATERIAL AND METHODS: Sixty poorly controlled diabetic patients were randomly assigned to receive either 1200 mg/day of vitamin E or identical placebo capsules during a two month period following a double blind cross-over design with a four week wash-out period between regimens. RESULTS: Seven patients were excluded from the study because of reasons not related to the medication. In the remaining 53 patients, the levels of serum glucose, fructosamine, HbA1c, total cholesterol, HDL-C, LDL-C, Apo A1 and Apo B did not vary significantly with vitamin E as compared with placebo. CONCLUSIONS: No significant effects of vitamin E on any of the parameters evaluated were observed in poorly controlled diabetic patients.     

Prodrugs of nitroxyl and nitrosobenzene as cascade latentiated inhibitors of aldehyde dehydrogenase

The prototypic aromatic C-nitroso compound, nitrosobenzene (NB), was shown previously to mimic the effect of nitroxyl (HN=O), the putative active metabolite of cyanamide, in inhibiting aldehyde dehydrogenase (AlDH). To minimize the toxicity of NB in vivo, pro-prodrug forms of NB, which were designed to be bioactivated either by an esterase intrinsic to AlDH or the mixed function oxidase enzymes of liver microsomes, were prepared. Accordingly, the prodrug N-benzenesulfonyl-N-phenylhydroxylamine (3) was further latentiated by conversion to its O-acetyl (1a), O-methoxycarbonyl (1b), O-ethoxycarbonyl (1c), and O-methyl (2) derivatives. Similarly, pro-prodrug forms of nitroxyl were prepared by derivatization of the hydroxylamino moiety of methanesulfohydroxamic acid with N, O-bis-acetyl (7a), N,O-bis-methoxycarbonyl (7b), N, O-bis-ethoxycarbonyl (7c), and N-methoxycarbonyl-O-methyl (7d) groups. It was expected that the bioactivation of these prodrugs would initiate a cascade of nonenzymatic reactions leading to the ultimate liberation of NB or nitroxyl, thereby inhibiting AlDH. Indeed, the ester pro-prodrugs of both series were highly active in inhibiting yeast AlDH in vitro with IC50 values ranging from 21 to 64 microM. However, only 7d significantly raised ethanol-derived blood acetaldehyde levels when administered to rats, a reflection of the inhibition of hepatic mitochondrial AlDH-2.     

Symptomatic and functional outcome of surgical treatment of cervical dystonia

OBJECTIVES: Previous studies of surgical treatment for cervical dystonia have reported highly variable rates of postoperative symptomatic benefit and morbidity. Little is known about functional improvement and long term results. This study evaluates the symptomatic and functional outcome of surgical treatment of cervical dystonia in a consecutive series of 46 patients. METHODS: The most affected muscles were selected for denervation after clinical examination and confirmation by four channel EMG studies. Surgical treatment, aiming at selective elimination of pathological activity while preserving normal motor function and avoiding side effects, was achieved by using a broad scope of techniques including intradural denervation, extradural denervation, and myotomy. Rather than carrying out standard operations, the treatment was tailored to the needs of the patient according to the individual pattern of dystonic activity. Long term benefit was assessed with a global outcome score, and a modified Toronto western spasmodic torticollis rating scale (TWSTRS) in those 34 patients who were available for a recent follow up evaluation. RESULTS: The 46 patients underwent a total of 70 procedures with intradural approaches in 33 instances, extradural approaches in 21, and muscle sections (singly or combined) in 22 instances. Transient mild postoperative side effects occurred in 10% of the procedures. The mean duration of long term follow up was 6.5 years. The global outcome was rated as excellent in nine patients (21%), as marked in 12 (27%), as moderate in nine (21%), as mild in nine (21%), and as no improvement in five (11%). A persistent side effect consisting of mild difficulty with balance was noted in one case. There were highly significant changes of the preoperative and postoperative mean values for almost all TWSTRS subscores for severity of cervical dystonia, functional disability, and pain. Patients with excellent outcome underwent a higher number of surgical procedures on average than those patients who achieved no benefit. CONCLUSIONS: Surgical treatment tailored to the specific pattern of dystonic activity in the individual patient is a valuable alternative in the long term management of cervical dystonia.