Effect of peroxisome proliferator-activated receptor gamma agonist, rosiglitazone, on dedifferentiated thyroid cancers

BACKGROUND AND METHOD: As genetic alterations in the gene for the peroxisome proliferator-activated receptor gamma (PPARgamma) have been described and PPAR agonists have been shown to redifferentiate thyroid cancers in animal models, we performed a pilot study in five patients with thyroglobulin-positive and I scan-negative thyroid cancers using the PPARgamma agonist rosiglitazone. RESULTS: Although thyroglobulin levels increased in four of the five patients after 3 months of treatment with rosiglitazone, the I scan remained negative in four patients and became only faintly positive in one patient for two lung metastases that could be correlated with metabolically active lung metastases shown by F-fluorodeoxyglucose positron emission tomography (F-FDG PET) and by computed tomography (CT). F-FDG PET, performed in four patients, revealed metastases of significant size in two patients, including the patient mentioned above and in a second patient confirmed by surgery. CONCLUSIONS: Treatment with rosiglitazone increased the production of thyroglobulin in some patients with thyroid cancers, but only rarely restored scintigraphically significant iodine trapping. It remains to be shown whether longer treatment periods might result in a more efficient redifferentiating effect.     

Lipid atherogenic risk markers can be more favourably influenced by the cis-9,trans-11-octadecadienoate isomer than a conjugated linoleic acid mixture or fish oil in hamsters

The aim of our present study was to compare the efficiency of conjugated linoleic acids (CLA) and fish oil in modulating atherogenic risk markers. Adult male hamsters were given a cholesterol-rich diet (0.6 g/kg) for 8 weeks; the diet was supplemented with 5 g cis-9,trans-11-CLA isomer/kg, 12 g CLA mixture (CLA-mix)/kg, 12 g fish oil/kg or 12 g fish oil+12 g CLA-mix/kg. The plasma cholesterol status was improved only with the cis-9,trans-11-CLA (HDL-cholesterol and HDL-cholesterol:LDL-cholesterol ratio, P<0.05), but was of borderline significance for CLA-mix (HDL-cholesterol:LDL-cholesterol ratio, P=0.06), with an increase (33-40 %) in the liver lipoprotein receptors (scavenger receptor-type I and LDL ApoB/E receptor) and HDL-binding protein 2 (P<0.05). A 100 % pigment gallstones incidence and a slight insulin resistance (homeostatic model assessment index) were observed in the CLA-mix-fed hamsters (P=-0.031). In comparison, fish-oil feeding alone improved merely the scavenger receptor-type I and HDL-binding protein 2 liver status and faeces sterol output. For most of our present observations, the concomitant intake of fish oil and CLA-mix gave dominant effects that were exclusive and specific to one or the other oil. In conclusion, part of the beneficial effects of CLA in the present study can be ascribed to the cis-9,trans-11-isomer, and these did not generally overlap with those of fish oil. In addition, the CLA-mix effects are clearly affected by the marine (n-3) fatty acids.     

Population pharmacokinetics of ibuprofen enantiomers in very premature neonates

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.     

No facilitation of amphetamine- or cocaine-induced hyperactivity in adult rats after various 192 IgG-saporin lesions in the basal forebrain

Lesions of basal forebrain cholinergic neurons by intracerebroventricular (i.c.v.) injections of 192 IgG-saporin increased the locomotor response to 0.5 and 1.5 mg/kg of D-amphetamine in adult rats [A. Mattsson, S.O. Ogren, L. Olson, Facilitation of dopamine_mediated locomotor activity in adult rats following cholinergic denervation, Exp Neurol. 174 (2002) 96-108.]. In the present study, adult male rats were subjected to bilateral injections of 192 IgG-saporin either into the septum (Sp), the nucleus basalis magnocellularis (Nbm), both structures (SpNbm) or i.c.v. Locomotor activity was assessed in the home cage 23 days after surgery, and, subsequently, thrice after an intraperitoneal injection of D-amphetamine (1 mg/kg) and twice after an injection of cocaine (15 mg/kg). Analysis of AChE-stained material showed that Sp lesions induced preferentially hippocampal denervation, Nbm lesions induced preferentially cortical denervation, while both SpNbm and i.c.v. lesions deprived the hippocampus and the cortex of almost all AChE-positive reaction products. The spontaneous and drug-induced locomotor activity of all lesioned rats did not differ significantly from that of control rats, except in rats subjected to i.c.v. injections, in which the locomotor response was significantly increased after the second administration of cocaine. In addition, in Nbm and SpNbm rats, the locomotor reaction to cocaine was weaker right after the second injection. The present results do not confirm the report by Mattsson et al. on the potentiation of amphetamine-induced locomotion by i.c.v. injections of 192 IgG-saporin, but suggest that cocaine-induced locomotion can be increased by such lesions and, to some respect, attenuated by cholinergic damage in the Nbm.     

Characterization of Drosophila fruitless-gal4 transgenes reveals expression in male-specific fruitless neurons and innervation of male reproductive structures

The fruitless (fru) gene acts in the central nervous system (CNS) of Drosophila melanogaster to establish male sexual behavior. Genetic dissection of the locus has shown that one of the fru gene's promoter, P1, controls the spatial and temporal expression of male-specific FruM proteins critical to determining stereotypical male sexual behavior. By using the Gal4-expression system, we show that a 16-kb fragment of the fru P1 promoter's 5' regulatory region drives the expression of Gal4 in a subset of FruM-expressing neurons within both the pupal and adult CNS. Colocalization of FruM and a Gal4-responsive reporter shows that the fru(P1)-gal4 fusion construct generates expression in both previously characterized FruM-expressing neurons as well as within cells of both the CNS and the peripheral nervous system that have not been demonstrated as FruM-expressing. Gal4-expressing neurons are shown to innervate abdominal organs directly relevant to fru function; specifically, the muscle of Lawrence (MOL) and the male internal reproductive organs. Innervations of the latter are shown to originate from identified FruM-serotonergic neurons. Furthermore, we show that the MOL neuromuscular junction is sexually dimorphic. Finally, we describe Gal4 expression in neurites innervating male reproductive structures that are hypothesized to be targets of fru function. Isolation of the regulatory sequences controlling the expression of fru in the CNS, therefore, provides a potent tool for the manipulation of FruM-expressing neurons and for understanding the cellular basis of Drosophila reproductive behavior.     

In situ-Forming Pharmaceutical Organogels Based on the Self-Assembly of L-Alanine Derivatives

PURPOSE: To characterize novel pharmaceutical organogels based on the self-assembly of L-alanine derivatives in hydrophobic vehicles. METHODS: The gelation properties of N-lauroyl-L-alanine (LA) and N-lauroyl-L-alanine methyl ester (LAM) were investigated in the presence of various solvents. Gel-sol and sol-gel transitions were evaluated by the inverse flow method, and gelation kinetics were determined by turbidimetry. The in vitro release kinetics of labeled dextran physically dispersed in the oil-based organogel was assessed in phosphate-buffered saline. In situ formation of the implants was evaluated in rats by subcutaneously injecting a solution containing LAM, an oil, and a water-diffusible inhibitor of self-assembly (ethanol). RESULTS: The LAM-containing formulations showed a hysteretic gelling behavior with transition temperatures between 10 and 55 degrees C. Gelation kinetics exhibited a lag time of 10 and 30 min at 25 and 37 degrees C, respectively. In vitro, fluorescein isothiocyanate-dextran was released from the gel in a sustained manner with less than 6% released after 20 days. The addition of ethanol to the LAM/oil mixture inhibited gelation and allowed subcutaneous injection of the solution at room temperature. After injection, ethanol diffusion led to the formation of a solid implant. CONCLUSIONS: Low-molecular weight self-assembling organogelators may allow the preparation of novel in situ-forming hydrophobic implants.     

Detection and false-positive rates of maternal serum markers for Down syndrome screening according to maternal age in women over 35 years of age. A study of the agreement of eight dedicated software packages

Maternal serum markers for trisomy 21 screening (MSS) can be assayed in women > or =35 years in an attempt to reduce the need for invasive procedures and thereby avoid their side effects. Our objective was to compare, in women > or =35, eight different software packages dedicated to second trimester MSS, thus providing reliable data for patient counselling. A simulation study was carried out on 189 sera from women with Down syndrome fetuses and 11 962 sera from mothers of unaffected babies. The first step was to estimate the joint distribution of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (beta-hCG). The second step was to calculate trisomy 21 detection and false-positive rates for each software according to maternal age (35-45 years), using the usual 1:250 risk threshold. Agreement between software packages was measured using 2 x 2 kappa coefficients. Detection rates and false-positive rates increased with maternal age. Depending on the software, 57-71% detection rates were achieved at 35 years with 12-18% false-positive rates. At 45 years, 61-100% detection rates were achieved with 66-95% false-positive rates. Up to 39 years, all softwares were concordant (kappa coefficients >0.75). In the range 35-45 years, false-positive and detection rates increased substantially with maternal age and differences between software packages are observed.     

Choroid plexectomy reduces neurosurgical intervention in patients with hydranencephaly

INTRODUCTION: The removal of the choroid plexus from the lateral ventricles was attempted by Dandy in the early 20th century but later discarded as complications arose and other methods of cerebrospinal fluid (CSF) diversion were introduced. We compare our experience with a variation of this operation to CSF diversion in patients with hydranencephaly or near hydranencephaly. METHODS: The hospital and office charts of patients with a diagnosis of hydranencephaly were reviewed from the two institutions spanning the career of the senior author. Thirteen patients were identified, of whom 9 underwent CSF diversionary procedures (group A) and 4 underwent choroid plexectomy (group B). RESULTS: The mean number of reoperations (2 in group A, 0 in group B), neurosurgical readmissions (1.5 in group A, 0 in group B) and days of hospitalization related to neurosurgical readmissions (43.5 in group A, 0 in group B) were all less in patients who underwent choroid plexectomy. The total incidence of complications related to surgery was also lower in this group (7 in group A, 0 in group B). CONCLUSION: In our experience, choroid plexectomy in patients with hydranencephaly reduces the incidence of reoperation and readmission, the number of days of hospitalization related to the surgical procedure and the total number of complications in comparison to patients undergoing CSF diversion. Further neurosurgical intervention is minimized as is the financial burden from multiple emergency department visits and radiological procedures for shunt evaluation. Choroid plexectomy is a viable alternative to CSF diversion in patients with hydranencephaly and a rapidly enlarging head. It avoids the chronic issues and complications surrounding CSF diversion in this difficult group of patients.