Ru 41.740 triggers human mononuclear blood cells to release tumor growth inhibitory factors in vitro.

Ru 41.740 (Biostim) is an immunostimulating drug of microbial origin which may stimulate human mononuclear blood cells (mainly monocytes) to release soluble factors which inhibit replication of several tumor cell lines in vitro. Since this effect may be of clinical importance in the treatment of cancer a number of tests have been conducted in order to find methods to augment this secretion. In vitro tests suggested that this non-specific antitumor activity of Biostim may not be enhanced by concomitant treatment of patients with inhibitors of cyclo-oxygenase and lipoxygenases or by interferons alpha, beta, gamma or the hemopoietic growth factors GM-CSF and G-CSF.     

Two statins and cromolyn as possible drugs against the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides: a comparative study by advanced computer simulation methods

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET₃₅, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood–brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood–brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations.     

Effect of initial shock wave voltage on shock wave lithotripsy-induced lesion size during step-wise voltage ramping

OBJECTIVE

To determine if the starting voltage in a step‐wise ramping protocol for extracorporeal shock wave lithotripsy (SWL) alters the size of the renal lesion caused by the SWs.

MATERIALS AND METHODS

To address this question, one kidney from 19 juvenile pigs (aged 7–8 weeks) was treated in an unmodified Dornier HM‐3 lithotripter (Dornier Medical Systems, Kennesaw, GA, USA) with either 2000 SWs at 24 kV (standard clinical treatment, 120 SWs/min), 100 SWs at 18 kV followed by 2000 SWs at 24 kV or 100 SWs at 24 kV followed by 2000 SWs at 24 kV. The latter protocols included a 3–4 min interval, between the 100 SWs and the 2000 SWs, used to check the targeting of the focal zone. The kidneys were removed at the end of the experiment so that lesion size could be determined by sectioning the entire kidney and quantifying the amount of haemorrhage in each slice. The average parenchymal lesion for each pig was then determined and a group mean was calculated.

RESULTS

Kidneys that received the standard clinical treatment had a mean (sem ) lesion size of 3.93 (1.29)% functional renal volume (FRV). The mean lesion size for the 18 kV ramping group was 0.09 (0.01)% FRV, while lesion size for the 24 kV ramping group was 0.51 (0.14)% FRV. The lesion size for both of these groups was significantly smaller than the lesion size in the standard clinical treatment group.

CONCLUSIONS

The data suggest that initial voltage in a voltage‐ramping protocol does not correlate with renal damage. While voltage ramping does reduce injury when compared with SWL with no voltage ramping, starting at low or high voltage produces lesions of the same approximate size. Our findings also suggest that the interval between the initial shocks and the clinical dose of SWs, in our one‐step ramping protocol, is important for protecting the kidney against injury.     

Immediate diagnosis of ventriculits: evaluation of parameters independent of microbiological culture

Background  

Generally accepted reference values in CSF diagnostics are not valid in cerebrospinal fluid (CSF) containing large amounts of blood. Residual blood may obscure ventriculitis as diagnostics largely depend on parameters such as cell count, lactic acid and total protein measurement. We sought to improve the diagnostics by evaluating a cytokine panel and soluble CD62L as markers of ventriculitis. In addition, we tested an algorithm of established parameters to predict ventriculitis in a specific patient collective.     

Potential mechanism for Calvados-related oesophageal cancer

The old Normandian habit of consumption of hot Calvados is associated with an increased risk of oesophageal cancer compared to other alcoholic beverages. The role of alcohol consumption in the risk of oesophageal cancer is well established. The first metabolite of alcohol, acetaldehyde is a potential local carcinogen in humans. Accordingly, different acetaldehyde concentrations in different beverages could account for some of the variations in cancer risk with regard to the type of alcoholic beverage. Eighteen samples of farm-made Calvados were collected in Normandy. Samples of commercially available beverages were purchased, including factory-made Calvados, other spirits, wines, beer and cider. The samples were analysed gas-chromatically for acetaldehyde and ethanol concentrations. All results are expressed as mean ± SD. The mean acetaldehyde concentration of all Calvados samples (1781 ± 861 μM, n = 25) differed highly significantly (p < 0.001) from that of all wine samples (275 ± 236 μM), from all other spirits samples (1251 ± 1155 μM, p < 0.05), and from all beer and cider samples (233 ± 281 μM, p < 0.001). Farm-made Calvados and farm-made cognac had the highest mean acetaldehyde concentration of the measured beverages. The high concentration of acetaldehyde combined with possible effects of the high temperature at which Calvados is consumed could account for the increased risk of Calvados-related oesophageal cancer.     

RB-reconstituted human retinoblastoma cells form RB-positive intraocular and intracerebral but not subcutaneous tumors in scid mice

WERI-Rb 27 human retinoblastoma cells were reconstituted with an intact RB gene by retrovirus-mediated gene transfer, in order to study the phenotypic effects of the protein in vitro and in vivo. Extensive morphological changes were observed, dominated by the formation of multinucleated giant cells. Six weeks after retroviral infection, the giant cells began to die and small cells emerged, resembling the parental non-reconstituted line. They expressed RB and continued to grow, although they showed an increased sensitivity to serum starvation. The original RB-negative cells grew progressively after subcutaneous inoculation into SCID mice, whereas the reconstituted cells failed to grow. RB-positive cells grew progressively in the corpus vitreum of the eye and in the brain, however. The RB-reconstituted cells grew more slowly and were less invasive than the parental cells and cells infected with a firefly luciferase (LUX) gene carrying retrovirus, used as controls. RB-reconstituted cells re-explanted from the intraocular and intracranial tumors continued to express full-length RB protein. RBeye2, an RB-positive cell line established from an eye tumor, was still unable to grow subcutaneously. The reduced tumorigenicity of the RB-reconstituted cells in the subcutaneous space may be due to the influence of locally acting growth-controlling signals or the absence of microenvironment-specific trophic factors. Alternatively, it may reflect the action of residual immune effectors in the SCID mice. If this is the case, these would have to be more effective at the subcutaneous site than in the eye or brain. © 1995 Wiley-Liss, Inc.     

A Swedish case-control network for studies of drug-induced morbidity--acute pancreatitis

OBJECTIVE: To evaluate risk factors - notably drugs - for developing acute pancreatitis. METHODS: A population-based, case-control study, encompassing 1.4 million inhabitants aged 20-85 years from four regions in Sweden between 1 January 1995 and 31 May 1998. A total of 462 cases were hospitalised in surgical departments with their first episode of acute pancreatitis without previously known biliary stone disease. From a population register, 1781 controls were randomly selected. Information was obtained from medical records and through telephone interviews. RESULTS: Fifty-seven percent of the cases were males. An expert group found evidence for biliary stones in 50% of the cases, alcohol intake in 23%, but in 29% neither of these factors were present. In all, "other" factors, e.g. drugs, could have contributed to the development of acute pancreatitis in 52% of the cases. In a multivariate analysis, the adjusted odds ratios (ORs) for H(2) antagonists were 2.4 (95% CI 1.2-4.8) for proton pump inhibitors (PPIs), 2.1 (1.2-3.4) for non-steroidal anti-inflammatory drugs (NSAIDs), 2.3 (1.3-4.0) for those derived from acetic acid and 1.9 (1.1-3.2) for antibacterials for systemic use. Significant ORs were found for a history of gastrointestinal tract disorders [1.5 (1.1-1.9)] and inflammatory bowel disease (IBD) [3.4 (1.5-7.9)]. Smoking was significantly associated with acute pancreatitis [1.7 (1.2-2.1)] and, for those smoking more than 20 cigarettes per day, the OR was 4.0 (2.2-7.5). Alcohol in moderate amounts did not increase the risk, but for those drinking more than 420 g alcohol per week the OR was 4.1 (2.2-7.5). CONCLUSION: In addition to cholelithiasis, smoking and heavy alcohol use, drugs may be an important risk factor for acute pancreatitis.     

A novel high-through-put assay for screening of pro-apoptotic drugs

Screening for anti-cancer substances iscommonly conducted using viability assays.An inherent problem with this approach isthat all compounds that are toxic andgrowth inhibitory, irrespective ofmechanism of action, will score positive.It would be beneficial to be able to screenfor compounds that specifically induceapoptosis. We here describe an ELISA-assaybased on a monoclonal antibody (M30) whichrecognizes a neo-epitope on cytokeratin 18exposed after cleavage by caspases duringapoptosis. We show that this assay detectsapoptosis in epithelial cells and that thesensitivity is sufficient for screening inthe 96-well format. We used the M30-ELISAassay to screen 500 low molecular weightcompounds from a chemical library from theNational Cancer Institute and identified 16drugs with strong pro-apoptotic activity,suggesting that the assay is a useful toolfor discovery of pro-apoptotic drugs.     

Neuronal and glial differentiation within expanded glial cultures derived from the lateral and medial ganglionic eminences

Attached glial-like cell cultures were established from the lateral and medial ganglionic eminences (LGE and MGE) and from the neocortex (Cx) of E13.5 mouse embryos, and expanded over four to five passages under epidermal growth factor (EGF) stimulation. Following removal of EGF and serum, we analysed the generation of neurons and glial cells within the cultures. Significant numbers of betaIII-tubulin-positive neurons were generated in both the LGE (about 7% of total cell numbers) and the MGE (around 2%). However, only few betaIII-tubulin-positive cells with neuronal morphologies were detected in the differentiated Cx cultures. The newly formed neurons were to a large extent GABAergic, and many of the MGE-derived, but not the LGE-derived, cells expressed the MGE-marker NKX2.1. Most cells in all cultures still appeared astroglial-like, expressing glial fibrillary acidic protein (GFAP), but in addition, CNPase-positive cells with oligodendroglial morphologies were present in the MGE (0.68%), and, to a lesser extent (0.2%), in the LGE cultures. The present results demonstrate that cells of expanded glial cultures from both the LGE and MGE can give rise to significant and, to a certain extent, region-specific neuronal and glial cell types under differentiating conditions.     

Lactulose reduces intracolonic acetaldehyde concentration and ethanol elimination rate in rats

BACKGROUND: Normal colonic bacteria possessing alcohol dehydrogenase activity can oxidize ethanol to acetaldehyde. Acetaldehyde recently has been shown to be a local carcinogen in humans. The aim of the study was to examine the effect of lactulose feeding on fecal and cecal pH, intracolonic acetaldehyde concentration, and total ethanol elimination rate in rats. METHODS: Sixty Wistar rats were divided into four groups. Groups 2 and 4 received lactulose daily (11 g/kg body weight for 14 days). On days 7 and 14, groups 1 and 2 received ethanol (1.5 g/kg body weight) intraperitoneally, whereas groups 3 and 4 received saline. RESULTS: Fecal and cecal pH values decreased significantly after lactulose treatment compared with the controls. Lactulose feeding reduced the total ethanol elimination rate by 13.8% (257 +/- 0.008 mg/kg/hr vs. 298 +/- 0.003 mg/kg/hr, p < 0.001) and the intracecal acetaldehyde concentration by 66.2% after ethanol (49 +/- 29 microM vs. 145 +/- 47 microM, p = 0.03) compared with the controls. CONCLUSION: Lactulose feeding to rats significantly reduces ethanol elimination rate and intraluminal acetaldehyde concentration in the colon after ethanol administration. This prebiotic thus could be used as an effective agent to block the microbial production of carcinogenic acetaldehyde in the large intestine.