Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity.
Conjugation of gonadotropin-releasing hormone (GnRH) analogues GnRH-III, MI-1544, and MI-1892 through lysyl side chains and a tetrapeptide spacer, Gly-Phe-Leu-Gly (X) to a copolymer, poly(N-vinylpyrrolidone-co-maleic acid) (P) caused increased antiproliferative activity toward MCF-7 and MDA-MB-231 breast, PC3 and LNCaP prostate, and Ishikawa endometrial cancer cell lines in culture and against tumor development by xenografts of the breast cancer cells in immunodeficient mice. MCF-7 cells treated with P-X-1544 and P-X-1892 displayed characteristic signs of apoptosis, including vacuoles in the cytoplasm, rounding up, apoptotic bodies, bleb formation, and DNA fragmentation. Conjugates, but not free peptides, inhibited cdc25 phosphatase and caused accumulation of Ishikawa and PC3 cells in the G2/M phase of the cell cycle after 24 h at lower doses and in the G1 and G2 phases after 48 h. Since P-X-peptides appear to be internalized, the increased cytotoxicity of the conjugates is attributed to protection of peptides from proteolysis, enhanced interaction of the peptides with the GnRH receptors, and/or internalization of P-X-peptide receptor complexes so that P can exert toxic effects inside, possibly by inhibiting enzymes involved in the cell cycle. The additional specificity of P-X-peptides compared with free peptides for direct antiproliferative effects on the cancer cells but not for interactions in the pituitary indicates the therapeutic potential of the conjugates. (+info
Low mortality rates in industrial cohort studies due to selection for work and survival in the industry.
Occupational groups are often described as being relatively healthy because their mortality rates are lower than those of the national average. Although correct this confuses the issue for those who are interested in assessing the effects of exposure to a particular chemical. In a further analysis of data collected in a study of all men ever exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain, three factors have been shown to contribute to the low mortality rates that were observed. The three factors: the selection of a healthy population for employment, the survival in the industry of the healthier men, and the length of time that this population has been pursued, have been quantified. The mortality experience within five years of entering this industry was shown to be as low as 37% of that expected; for circulatory disease and respiratory disease it was as low as 21%. There was a progressive increase in standardized mortality ratio with the length of time since entry so that the effect had almost disappeared 15 years after entry. To avoid confounding the selection effect with the survival effect the latter was measured by separating men who survived 15 years after entering the industry according to whether or not they were still in the industry after this period. Those who had left experienced an overall standardized mortality ratio some 50% higher than those still in the industry. This effect, although consistent in the age groups between 25 and 74 years and for all cause groups studied, was greatest in those aged between 25 and 44 years and for lung cancer and respiratory disease. (+info
Role of elevated plasma transforming growth factor-beta1 levels in wound healing.
Transforming growth factor (TGF)-beta1 plays a central role in wound healing. Wounds treated with neutralizing antibody to TGF-beta1 have a lower inflammatory response, reduced early extracellular matrix deposition, and reduced later cutaneous scarring, indicating the importance of local tissue TGF-beta1. By contrast, increasing the local, tissue levels of TGF-beta1 increases the early extracellular matrix deposition but does not alter scar formation. Increased levels of plasma TGF-beta1 correlate with increased fibrogenesis in the lung, kidneys, and liver. The aim of the present study was to investigate the role of elevated systemic levels of TGF-beta1 on wound healing. We used transgenic mice that express high levels of active TGF-beta1 and have elevated plasma levels of TGF-beta1 and wild-type mice of the same strain as controls. Incisional wounds and subcutaneously implanted polyvinyl alcohol (PVA) sponges were analyzed. Surprisingly, cutaneous wounds in transgenic, TGF-beta1-overexpressing mice healed with reduced scarring accompanied by an increase in the immunostaining for TGF-beta3 and TGF-beta-receptor RII and a decrease in immunostaining for TGF-beta1 compared with wounds in control mice. By contrast, the PVA sponges showed the opposite response, with PVA sponges from transgenic mice demonstrating an enhanced rate of cellular influx and matrix deposition into the sponges accompanied by an increase in the immunostaining for all three TGF-beta isoforms and their receptors compared with PVA sponges from control mice. Together, the data demonstrate that increased circulating levels of TGF-beta1 do not always result in increased expression or activity in selected target tissues such as the skin. The two wound models, subcutaneously implanted PVA sponges and cutaneous incisional wounds, differ significantly in terms of host response patterns. Finally, the data reinforce our previous observations that the relative ratios of the three TGF-beta isoforms is critical for control of scarring. (+info
Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers.
The cohort of workers employed in a Swedish vinyl chloride/poly(vinyl chloride) plant since its start in the early 1940's has been followed for mortality and cancer morbidity patterns. Only 21 of the 771 persons could not be traced. Difficulties in establishing exposure levels at different work areas in the past makes an evaluation of dose-effect relationships impossible. A four- to fivefold excess of pancreas/liver tumors was found, including two cases later classified as angiosarcomas of the liver. The number of brain tumors and suicide do not deviate significantly from expected. Cardiovascular and cerebrovascular diseases, on the other hand, differ significantly from the expected. The discrepancies between previous reports on VCM/PVC workers and this report are discussed. The possible etiology of the cardiovascular deaths is also discussed. (+info
Malignant tumors of the liver and lungs in an area with a PVC industry.
The incidence of malignant tumors of the lung and bronchus and of cytologically confirmed primary malignant tumor of the liver was analyzed for a 4-yr period in a city with several factories, including a PVC industry. Prior to the study two cases of angio-sarcoma of the liver were diagnosed in workers employed in PVC production. The total incidence of analyzed tumors was only slightly higher than predicted. The tumors of the liver recorded did not show any dependence on place of work or residence. During the period of observation, malignant tumors of the bronchus (lung) were not recorded in the PVC industry. Their rate in the area in which the PVC industry is situated was approximately the same as that for the entire city area. The study does not indicate that the occurrence of malignant tumors other than angiosarcoma is associated with exposure to vinyl chloride. (+info
Partial blocking of NMDA receptors reduces plastic changes induced by short-lasting classical conditioning in the SI barrel cortex of adult mice.
The effect of blockade of N-methyl-D-aspartate (NMDA) receptors in the barrel cortex upon the learning-induced changes of the cortical body map was examined in adult mice. We have previously found that three sensory conditioning sessions, in which stimulation of a row of vibrissae was paired with a tail shock, produced an enlargement of the functional representation of a row of vibrissae stimulated during training. Implantation of the slow release polymer Elvax, containing 2-amino-5-phosphonovalerate (APV, 50 mM), in the vicinity of the barrel cortex was performed 1 day before conditioning to block NMDA receptors. The cortical representation of a trained row of vibrissae was visualized with 2-deoxyglucose (2DG) functional brain mapping 1 day after the completion of the conditioning procedure. The partial blockade of NMDA receptors within the barrel cortex reduced (by half) the expansion of the cortical representation of a trained row of vibrissae as compared to the enlargement of the cortical representation of a trained row found in untreated (60%) and Elvax-PBS implanted (47%) mice. The results provide evidence that the learning-induced processes of cortical map reorganization involve mechanisms that depend on NMDA receptor activation. (+info
The hazards of vinyl glove ingestion in the mentally retarded patient with pica: new implications for surgical management.
OBJECTIVE: To report experience with the treatment of complications of vinyl glove ingestion in mentally retarded patients with pica. DESIGN: A retrospective case series. SETTING: Two university-affiliated hospitals. PATIENTS: Five mentally retarded patients, 4 with a history of pica, who were admitted for the management of complications resulting from the ingestion of vinyl gloves. MAIN OUTCOME MEASURES: Type of complication, treatment and operative outcome. FINDINGS: The patients ranged in age from 26 to 46 years. One patient died while awaiting surgical consultation of massive gastrointestinal bleeding from a large gastric ulcer caused by a vinyl glove bezoar (VGB). Four VGBs were removed surgically. Endoscopic removal was difficult or impossible because the gloves had become hardened and matted. CONCLUSIONS: VGB should be considered in institutionalized mentally retarded people with a history of pica when they present with gastrointestinal symptoms. VGBs should be removed directly by laparotomy, gastrotomy or enterotomy. Endoscopic removal is not recommended. (+info
Intradermal irritation of dental bleaching agents in rats.
AIM: To evaluate the irritative potential of three dental bleaching agents (hydrogen oxide, carbopol, and carbamide peroxide). METHODS: In rats, Evans blue (2.5%, 1 mL.L-1) was injected i.v. and later each test solution was injected intradermally on the back. After the concentration of the dye in the stained skin area was determined by spectrophotometric analysis. RESULTS: All the dental bleaching agents caused increase of vascular permeability and the intensity varied with the time. CONCLUSION: Dental bleach agents had a great potential for irritating soft tissues. (+info