TP53 polymorphism at exon 4 in caucasian women from eastern France: lack of correlation with HPV status and grade of cervical precancerous lesions

OBJECTIVE: To investigate the codon 72 TP53 polymorphism in women from eastern France with normal or abnormal cervical cytology.STUDY DESIGN: We analyzed the TP53 allele distribution by denaturant gradient gel electrophoresis assay and the human papillomaviruses (HPV) infection in 138 cervical smears: 50 normal, 20 atypical squamous cells of undetermined significance, 40 low grade squamous intraepithelial lesions, 28 high grade squamous intraepithelial lesions.RESULTS: The viral DNA prevalence increased with cytological abnormalities. The rates of arginine (Arg) and proline (Pro) homozygosity and Arg/Pro heterozygosity were 49, 0.72, and 51%, respectively. No association was found between HPV status and TP53 polymorphism. No differences were observed in the frequency of the TP53 genotypes according to cytology.CONCLUSION: The TP53 Arg/Arg genotype does not appear to represent a risk factor in the progression of HPV associated cervical lesions. We were not able to confirm that the TP53 genotype increases the susceptibility to be infected by HPV or to develop HGSIL, and a fortiori invasive carcinoma of the cervix.     

Ventilatory responses to hypercapnia and hypoxia in heterozygous c-ret newborn mice

The c-ret proto-oncogene encodes a tyrosine-kinase receptor involved in survival and differentiation of neural crest cell lineages. Previous studies have shown that homozygous c-ret-/- mice die soon after birth and have impaired ventilatory responses to hypercapnia. Heterozygous c-ret +/- mice develop normally, but their respiratory phenotype has not been described in detail. We used whole-body flow plethysmography to compare baseline breathing and ventilatory and arousal responses to chemical stimuli in unrestrained heterozygous c-ret +/- newborn mice and their wild-type c-ret +/+ littermates at 10-12 h of postnatal age. The hyperpnoeic and arousal responses to hypoxia and hypercapnia were not significantly different in these two groups. However, the number and total duration of apnoeas and periodic breathing episodes were significantly higher in c-ret +/- than in c-ret +/+ pups during hypoxia and post-hypoxic normoxia. These results are further evidence that respiratory control at birth is heavily dependent on genes involved in the neural determination of neural crest cells.     

Comparative Analysis of Bupivacaine and Ropivacaine for Infiltration Analgesia for Bilateral Breast Surgery

Local anesthesia infiltration has been established as a preferred method of perioperative analgesia in many cosmetic operations. In an attempt to maximize the risk-benefit ratio of local anesthesia, a study was conducted to compare efficacy of two local anaesthetic agents. Bupivacaine was compared to ropivacaine in a bilaterally symmetrical breast surgery model. A local anaesthetic solution containing either bupivacaine or ropivacaine was infiltrated into each of the breasts of 15 patients undergoing either breast augmentation or breast reduction. Both surgeon and patient were blinded to the nature of local anaesthetic agent injected. Patients were requested to score their pain at 1, 2, 6, and 10 hours after surgery on a visual analog scale. The results were analyzed statistically using a cross-sectional time-series regression model employing the random effects option of the xtreg command from Strata Release 6 statistical software. We found that overall analgesia achieved with bupivacaine and ropivacaine infiltrations was not statistically different. The use of a higher dose of ropivacaine is likely to have removed the clinical advantage noted for the bupivacaine group. There was, however, a statistical and clinical difference in the efficacy of local anaesthetic infiltration of both agents in breast augmentation patients as compared to breast reduction patients, local anaesthetic being less effective in patients who had submuscular breast augmentation than in patients who had breast reduction. In view of these findings, it appears reasonable to recommend the use of ropivacaine in high-dose infiltration breast analgesia, as it is reported to be less cardiotoxic than bupivacaine. Serious attention needs also to be given to the adequacy of field infiltration of local anesthesia in submuscular breast augmentation.     

Neutralising immunogenicity of a polyepitope antigen expressed in a transgenic food plant: a novel antigen to protect against measles

Transgenic carrot plants were developed expressing a designer polyepitope combining tandem repeats of a protective loop-forming B cell epitope (H386-400) of the measles virus hemagglutinin protein with a human promiscuous, measles-unrelated T cell epitope (tt830-844). Despite the sensitivity of the loop conformation to its molecular environment, proper folding was confirmed by conformation-dependent monoclonal antibodies. The antibodies also reacted with the boiled antigen in Western blot. Immunisation of mice peritoneally with carrot plant extracts induced high titers of antibodies that crossreacted strongly with the virus. Furthermore, the sera neutralised field isolates of different geographic origins and genotypes in a modified plaque reduction neutralisation assay performed on CD150-transfected Vero cells. These results demonstrate that transgenic carrot plants can serve as an efficient expression system to produce highly immunogenic, randomly assembled polyepitope antigens. The combined features of the selected epitopes and the potential of the plant expression system may pave the way towards new vaccines against measles.     

Mirtazapine orally disintegrating tablet versus sertraline: a prospective onset of action study

This multinational, randomized, double-blind study was specifically designed to prospectively compare the onset of antidepressant efficacy of mirtazapine orally disintegrating tablets and sertraline at dosages commonly used in clinical practice. A total of 345 patients with major depressive episode (DSM-IV) received mirtazapine (30-45 mg/d) or sertraline (50-150 mg/d) for 8 weeks. Mirtazapine was administered in the newly developed fast dissolving, orally disintegrating tablet formulation. Assessments were performed at baseline and on days 4, 7, 10, 14, 28, 42, and 56. The primary efficacy variable (mean absolute change from baseline in the Hamilton Depression Rating Scale [HAMD] total score [17 items]) showed that mirtazapine was significantly (P < 0.05) more effective than sertraline at all assessments during the first 2 weeks of the study. After this time, HAMD total scores were similar in both groups. These findings were supported by analysis of the HAMD response rate (ie, > or =50% reduction in HAMD total score from baseline), HAMD remission rate (HAMD total score of < or =7), and the Montgomery-Asberg Depression Rating Scale (MADRS). Both treatments were well tolerated. In addition, mirtazapine had a greater effect than sertraline on sexual functioning. In conclusion, this first prospective onset of action study using the orally disintegrating tablet indicates that mirtazapine has a faster onset of therapeutic effect than sertraline. The orally disintegrating tablet formulation of mirtazapine used in this study is known to enhance the convenience and compliance by the patient.     

Reg IV,a new member of the regenerating gene family,is overexpressed in colorectal carcinomas

A better understanding of the mechanisms by which colon tumor cells are able to survive exposure to drugs would be valuable for the development of new therapeutic strategies. We used differential display-PCR to compare gene expression in the drug-sensitive HT-29 colon cancer cell line and 3 drug-resistant subpopulations derived from this parental cell line. One of the genes identified is a new gene, Regenerating IV gene (Reg IV), and was strongly overexpressed in HT-29 drug-resistant cells. Other drug-resistant cell lines expressed Reg IV at a high level, whereas a low expression was noted in sensitive cell lines. Northern blot and real-time PCR analysis showed that Reg IV is more strongly expressed in 71% of colorectal tumors (in particular in mucinous carcinomas) than in normal colon tissues. The comparison of Reg IV expression with that of other REG genes, Regenerating Ialpha or (Reg Ialpha), Regenerating Ibeta (Reg Ibeta) and Pancreatitis-associated protein (PAP), highlights its predominant expression in colorectal tumors. Reg IV mRNA-positive tumor cells display different phenotypes: mucus-secreting, enterocyte-like or undifferentiated. Interestingly, whereas Reg IV expression is low in normal colon, its level in normal small intestine is similar to that in some colorectal tumors. In normal tissue, Reg IV mRNA-positive cells are mostly enteroendocrine cells and goblet cells. Our results point out the potential role of Reg IV in colorectal tumors and its subsequent interest as a pronostic indicator of tumor survival.     

Musculoskeletal manifestations in cystic fibrosis

Although bone and joint manifestations are common in children with cystic fibrosis (CF), they have received little attention in adults. As compared to healthy individuals, bone mineral density is low, even with calcium intakes greater than 1500 mg/d. Nevertheless, calcium and phosphate levels in blood and urine are often normal, and vitamin D levels vary. Short stature with a low body mass index and central hypogonadism are the rule in these patients. Fractures and kyphosis are often reported. CF arthropathy occurs in 2-8.5% of patients. Arthritis develops, and there may be skin eruptions. Non-steroidal antiinflammatory drug therapy is effective. Hypertrophic osteoarthropathy associated with respiratory failure is present in 2-7% of patients. Rheumatoid arthritis, spondyloarthropathies, sarcoidosis, and amyloidosis have been reported in association with CF. Knee pain due to patellofemoral syndrome, quinolone-induced arthropathy, and mechanical back pain have been described. Rheumatoid factor titers are higher than in healthy controls, particularly in patients with episodic arthritis. No data are available on antiperinuclear factor or antikeratin antibody titers. Tests for antinuclear antibody are usually negative. Circulating immune complex levels and antibodies to heat shock proteins may be elevated. Antineutrophil cytoplasmic antibody of the bactericidal/permeability-increasing protein (BPI) or azurocidin (AZ) type has been reported, often in high titers (up to 40%).     

Behavioral changes are not directly related to striatal monoamine levels, number of nigral neurons, or dose of parkinsonian toxin MPTP in mice

Behavioral analyses of mice intoxicated by the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) have generated conflicting results. We therefore analyzed the relationship between behavioral changes, loss of monoamine levels, and loss of dopaminergic cell bodies in groups of mice intoxicated with acute or subchronic MPTP protocols. Despite a higher degree of neuronal loss in the mice intoxicated using subchronic protocols, dopamine loss was severe and homogeneous in the striatum in all groups. Dopamine levels were less severely reduced in the frontal cortex in the three groups of MPTP-intoxicated mice. Norepinephrine and serotonin levels in the striatum were decreased only in the mice intoxicated with the acute protocol. The most surprising result was that the mice intoxicated with the subchronic protocols were more active than the saline-treated mice. As reported in rats with dopamine depletion in the prefrontal cortex, the hyperactivity observed in our mice could be due to the reduced dopamine levels detected in this structure.