Percutaneous absorption and disposition of [14C]chlordecone in young and adult female rats

The objective of this study was to evaluate the effect of age and dosage on percutaneous absorption and disposition of [14C]chlordecone (Kepone) and to describe results using a physiological based pharmacokinetic (PBPK) model. Female Fischer 344 rats 33 and 82 days old were used as the young and adult animal models, respectively, and were studied over a 10-fold dose range. [14C]Chlordecone (0.286 micromol/cm2) was applied to dorsal skin (2. 3% BSA) and radioactivity was quantified in selected tissues and excreta up to 120 h. Absorption and disposition were also determined at three dose levels up to 2.68 micromol/cm2; fraction absorbed decreased as dose increased. In vitro percutaneous absorption was measured by static and flow-through methods; these yielded similar penetration rates, which were lower than those obtained in vivo. In vivo percutaneous absorption over 120 h was 14.4+/-0.99 and 14.2+/-1. 5% dose in young and adults, respectively. Organ and tissue content increased over time (carcass>liver>kidney), indicating prolonged absorption. Statistical differences between young and old were found for liver, skin, and urine, but not for absorption. Excretion occurred primarily in feces, but also in urine. A biophysically based percutaneous model was fitted to both young and adult in vivo absorption data. This was embedded in a whole body PBPK model which, upon optimization with SAAM II, estimated apparent tissue partition coefficients, urinary and fecal excretion rates, and parameters characterizing hepatic nonlinear uptake of bound chlordecone. The model reasonably predicted tissue chlordecone content at higher doses, when decreased absorption was accounted for.     

Radiotherapy for non-small-cell bronchial cancers: definitions of volumes, patient selection. Recommendations of the International Association for the Study of Lung Cancer (IASLC)

Chemoradiation is the standard treatment of unresectable, locally advanced non-small cell lung cancer, with a mean dose of 60-66 Gy, excluding escalation dose schemes. The standard treated volume includes primary tumor, ipsilateral hilar and mediastinal nodes, supraclavicular and contralateral nodes as well, regardless of the node status. This work tries to answer the question of the optimal volume to be treated. Drainage routes analysis is in favor of large volumes, while toxicity analysis favors small volumes. Combined modality treatment may increase the observed toxicity. The optimal volume definition is difficult, and requires available conformal therapy tools. Patients selection is another important issue. A volume definition is then attempted, based on the IASLC (International Association for the Study of Lung Cancer) Annecy workshop experience, highlighting the interobservers discrepancies, and suggests basic recommendations to harmonize volume definition.     

Is it possible to improve the quality of life of patients who have undergone pelvic evisceration?

Locally spread cancer makes up considerable percent (20-30%) in statistical structure of rectal tumors. In cases of cancer spread into the area of urine bladder triangle the operation of choice is pelvic evisceration. From 1977 to 1997 in the State research Centre of the Ministry of Health for Coloproctology pelvic evisceration in cancer spread to back wall of urine bladder in the area of triangle was carried out in 22 patients (20 male and 2 female). Mean age was 43.4 (29-56) years, 16 patients have undergone typical infralevator pelvic evisceration. There were no intraoperative lethality. Postoperative lethality made up 6.3%, complications--68.8%, 5-years survival rate--25%. Presence of two fecal fistulas on the anterior abdominal wall has decreased considerably the quality of life of the patients. Since 1993 the conception of preservation and restoration of natural passage of urine and bowel contents was adopted. In 4 cases infralevator pelvic evisceration with various types of ileocystoplasty and pull-through of colon into small pelvis with creation of smooth muscle cuff in perineal colostomy was carried out. In 2 patients evisceration was of supralevator-character cystoplasty of local tissues and performance of coloanal anastomosis were carried out. The application of reconstructive-restorative ways in coloproctology and urology considerably contributed to the improvement of the quality of life of the patients after pelvic evisceration.     

Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory

To explore the role of protein kinase A (PKA) in the late phase of long-term potentiation (L-LTP) and memory, we generated transgenic mice that express R(AB), an inhibitory form of the regulatory subunit of PKA, only in the hippocampus and other forebrain regions by using the promoter from the gene encoding Ca2+/ calmodulin protein kinase IIalpha. In these R(AB) transgenic mice, hippocampal PKA activity was reduced, and L-LTP was significantly decreased in area CA1, without affecting basal synaptic transmission or the early phase of LTP. Moreover, the L-LTP deficit was paralleled by behavioral deficits in spatial memory and in long-term but not short-term memory for contextual fear conditioning. These deficits in long-term memory were similar to those produced by protein synthesis inhibition. Thus, PKA plays a critical role in the consolidation of long-term memory.     

Save our children

This paper reports changes in adrenocorticotrophic hormone (ACTH), insulin and insulin-like growth factor-1 (IGF-1) concentrations in cats from a previously published study. The cats were given oral megestrol acetate (MA, 5 mg once daily for 14 days), subcutaneous proligestone (PRG, 100 mg on two occasions one week apart) or subcutaneous saline (1 ml as for PRG). In the cats given saline (n = 6), basal ACTH, insulin and IGF-1 did not change significantly throughout the following seven weeks. The cats given MA (n = 7) developed significant suppression of plasma ACTH concentrations and hyperinsulinaemia during treatment and for two to four weeks after MA dosage ceased. In the cats given PRG (n = 7), plasma ACTH concentrations were not significantly altered although three cats had markedly suppressed values for some time after PRG treatment had ceased. Serum insulin concentrations were not significantly altered in the PRG-treated cats. The results suggest PRG may be a preferable alternative to MA in some situations.     

Chronic and acute prenatal and postnatal ethanol exposure on lymphocyte subsets from offspring thymic, splenic, and intestinal intraepithelial sources

The overall objective of this study was to analyze the effects of a combined prenatal and postnatal (entire gestational human chronic drinking model) ethanol exposure on T-cell development in mice. Specifically, this study evaluated the effects of chronic exposure to prenatal ethanol on lymphocyte makeup and proliferative capabilities of postnatal offspring's (4 and 12 weeks) peripheral lymphoid tissues. Chronic exposure regimens were conducted over the entire gestational period and through postnatal day 14 or 21. Thymus, spleen, and intestinal intraepithelial lymphocytes were harvested and analyzed by flow cytometry for percentages of T-cell subsets. Splenic lymphocytes were also analyzed for their ability to proliferate in response to a T-cell mitogen. Limited effects of chronic ethanol exposure were seen.