Nicotine reinforcement in rats with histories of cocaine self-administration

Few reports have described conditions under which nicotine self-administration occurs in rats. In this study, rats which initially lever pressed for cocaine infusion (0.05 mg/kg) during 1 h experimental sessions continued to obtain similar infusion numbers when nicotine (0.03 mg/kg) was available. When saline was substituted for nicotine, infusions decreased from 11.8±4.5/h to 5.4±1.1/h but returned to pre-saline levels when it was reintroduced (12.0±5.5/h). These results indicate that nicotine can serve as a positive reinforcer for rats under the historical and schedule conditions described.     

Metabolism and pharmacokinetics of p-(3,3-dimethyl-1-triazeno) benzoic acid in M5076 sarcoma-bearing mice

Summary The pharmacokinetics of the anticancer agent p-(3,3-dimethyl-1-triazeno) benzoic acid (pCOOH-DMT), a drug now in phase I clinical trial in Europe, was investigated in C57 Bl female mice with M5076 reticulum-cell sarcoma that were treated i.v. with 200 mg/kg pCOOH-DMT. The drug disappeared from plasma with a terminal half-life of about 2.5 h. Plasma clearance was approximately 6 ml/min per kg. Distribution studies showed some differences in drug levels in different tissues. The highest levels were found in the tumor, liver, kidney and lung; lower levels were found in the spleen and gut, and the lowest, in the brain. The N-desmethyl derivative of pCOOH-DMT was not detectable in plasma or tissues of mice treated with the drug. Therefore, the previous evidence of low N-demethylation of pCOOH-DMT was confirmed. pCOOH-DMT glucuronide was identified by mass spectrometry and quantified by high-performance liquid chromatography (HPLC) in plasma, tissues and urine samples. pCOOH-DMT glucuronide appears to be the major urinary metabolite of pCOOH-DMT in mice. Another metabolite identified by mass spectrometry and quantified by HPLC in some tissues and urine was pCOOH-DMT glycinate.Abbreviations DTIlC 5-(3,3-dimethyl-l-triazeno)imidazole-4-carboxamide - pCOOH-DMT p-(3,3-dimethyl-l-triazeno)benzoic acid - pCOOH-MMT p-(3-methyl-l-triazeno)benzoic acid - pCONH₂-DMT p-(3,3-dimethyl-l-triazeno)carboxamide - BSTFA N,O-bis(trimethylsilyl)trifluoroacetamide - TMCS trimethylchlorosilane - TLC thin-layer chromatography - FAB fast atom bombardment - EI electron impact - M5 M5076 reticulum-cell sarcoma - t_1/2 beta-half-life - C₀ concentration time 0 - AUC area under the concentration vs time curve - Cl total clearance - V volume of distribution     

Persistent productive HIV infection in EBV-transformed B lymphocytes

The susceptibility to HIV infection of 14 B-cell lines established from five healthy HIV seronegative and from six HIV seropositive subjects by lymphocyte transformation with EBV and/or by lymphocyte cultivation with cyclosporin A was studied. Although the cell lines contained different proportions of CD4-positive cells, as shown by flow cytometry, all of them could be infected with the SF-2 strain of HIV. Infection was blocked by a monoclonal antibody directed against the viral attachment site of the CD4 molecule, even in a line that lacked demonstrable CD4 receptors. B-cell lines with high proportions of CD4-expressing cells produced HIV p24 antigen more rapidly and at higher concentrations than cell lines with low CD4 expression. Although HIV infection resulted in some cytopathic effects, it was possible to cultivate the infected cells for more than 8 months without refeeding the cultures with uninfected cells. Even in long-term cultures, there was a continuous production of infectious HIV, as detected by transfer of culture supernatants to other susceptible cell lines. The production of viral antigens was consistently more pronounced in the B-cell line with the highest CD4 positivity than it was in a permissive T-cell line (HUT-78) infected in the same manner. These results indicate that HIV can chronically and productively infect transformed B cells via interaction with CD4 molecules. Thus it is possible that B cells may constitute a source of infectious virus in HIV-infected EBV-positive individuals.     

Do environmental and occupational exposure to pyrethroids and organophosphates affect human semen parameters? Results of a systematic review and meta-analysis

Our purpose was to review and analyse the impact of pyrethroids and organophosphates exposure on human semen parameters. A comprehensive literature search was performed through MEDLINE via PubMed, Scopus and Webscience. Only cohort studies examining semen parameters in workers or general populations exposed to pyrethroids or organophosphates were included. Ejaculate volume, sperm count, concentration, motility, viability, normal morphology and seminal pH alterations were pooled using the Cochran–Mantel–Haenszel Method with the random effect model and expressed as weighted mean difference, risk ratios, 95% confidence intervals and p-values. Seven cross-sectional studies regarding pyrethroids were included. Four of them were eligible for meta-analysis. The only parameter affected by pyrethroid exposure was normal sperm morphology (WMD-7,61%, 95%CI –11,92 to −3,30;p = 0,0,005). Nine studies were selected to evaluate the impact of organophosphates on semen parameters with six of them eligible for meta-analysis. A significant reduction was detected for the following: ejaculate volume (WMD −0,47ml, 95%CI −0,69 to −0,25; p < 0,0001), sperm count (WMD-40,03, 95%CI −66,81 to −13,25;p = 0,003), concentration (WMD-13,69 x10⁶/mL, 95%CI −23, 27 to-4,12;p = 0,005) and motility (WMD −5,70%, 95%CI −12,89 to 1,50;p = 0,12). Despite the increase in sperm abnormality, it has been shown that pyrethroids are unrelated to reduced sperm quality. However, the negative association of organophosphates with spermatogenesis is noteworthy.     

Virtual Changes of the Shape of the Lips

Many of the unsatisfactory results in cosmetic surgery are due not to the technique employed itself but to the virtual changes that our work has imposed in other areas. These changes are especially evident in the face, due to the small dimensions of its organs. The surgeon should do a thorough evaluation of the area to be treated prior to the surgery and make her/him notice not only the usual existing asymmetries, but also the modifications which probably will be noticed in the neighboring parts after surgery, to avoid later problems. The surgeon will discover then the many irregularities a patient may have, which have not been noticed by the patient before. These, if not detected in time, are weapons that may act as a boomerang against the surgeon later.     

A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells

Background

Mutations of the p53 oncosuppressor gene are amongst the most frequent aberration seen in human cancer. Some mutant (mt) p53 proteins are prone to loss of Zn(II) ion that is bound to the wild-type (wt) core, promoting protein aggregation and therefore unfolding. Misfolded p53 protein conformation impairs wtp53-DNA binding and transactivation activities, favouring tumor growth and resistance to antitumor therapies. Screening studies, devoted to identify small molecules that reactivate mtp53, represent therefore an attractive anti-cancer therapeutic strategy. Here we tested a novel fluorescent curcumin-based Zn(II)-complex (Zn-curc) to evaluate its effect on mtp53 reactivation in cancer cells.

Methods

P53 protein conformation was examined after Zn-curc treatment by immunoprecipitation and immunofluorescence assays, using conformation-specific antibodies. The mtp53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The intratumoral Zn-curc localization was evaluated by immunofluorescence analysis of glioblastoma tissues of an ortothopic mice model.

Results

The Zn-curc complex induced conformational change in p53-R175H and -R273H mutant proteins, two of the most common p53 mutations. Zn-curc treatment restored wtp53-DNA binding and transactivation functions and induced apoptotic cell death. In vivo studies showed that the Zn-curc complex reached glioblastoma tissues of an ortothopic mice model, highlighting its ability to crossed the blood-tumor barrier.

Conclusions

Our results demonstrate that Zn-curc complex may reactivate specific mtp53 proteins and that may cross the blood-tumor barrier, becoming a promising compound for the development of drugs to halt tumor growth.