Balloon catheter systems for PTCA: the importance of the catheter length

This complex study was designed to measure the transport and excretion characteristics of gadolinium ethoxybenzyl diethylenetriaminepentacetic acid (Gd-EOB-DTPA) in dog's livers following bolus and infusion. Simultaneous T1 magnetic resonance imaging was performed to measure maximum signal enhancement. Anaesthetized dogs had cannulation of the common bile duct and urinary bladder for collections and cannulation of the femoral artery and vein for monitoring, blood sampling and infusion. Gd-EOB-DTPA was administered by bolus (range 12.5-200 mumol/kg) and infusion (range 0.4-6.4 mumol/min per kg). An hepatic transport maximum 0.09-0.15 mumol/min/kg was achieved with a blood concentration of 0.03-0.06 mumol/mL. Marked hepatic affinity for Gd-EOB-DTPA was demonstrated with measurements of liver concentration. Maximum T1 signal enhancement was achieved with blood Gd-EOB-DTPA concentration of 0.02-0.03 mumol/mL and a liver concentration of 1-2 mumol/g. The transport maximum for Gd-EOB-DTPA in the dog was similar to that for ipodate and iodipamide and effective imaging was achieved with sub-maximal doses. The maximum signal enhancement at blood concentrations less than required for maximum transport suggest a wide latitude for effective clinical imaging.     

Familial aggregation of female sexual orientation

OBJECTIVE: The purpose of this study was to determine whether female homosexuality is familial and whether it is cofamilial with male homosexuality. METHOD: Subjects included 84 homosexual and 79 heterosexual female probands recruited through newspaper advertisements. Probands were asked about their siblings' sexual orientations and were asked for permission to contact siblings to confirm their reports. RESULTS: The authors were able to contact 60% of eligible siblings, and the information they provided about their sexual orientations confirmed that probands' reports were highly accurate. Homosexual probands had a significantly higher proportion of homosexual sisters according to four criteria for rating siblings' sexual orientations. Homosexual probands also had a higher proportion of homosexual brothers; however, this difference was not significant. CONCLUSIONS: Female homosexuality appears to be familial. Further research is required to resolve the question of whether female and male homosexuality are cofamilial.     

The alpha1 and alpha2 isoforms of the AMP-activated protein kinase have similar activities in rat liver but exhibit differences in substrate specificity in vitro

The AMP-activated protein kinase (AMPK) is a heterotrimeric complex composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma). Two isoforms of the catalytic subunit (alpha1 and alpha2) have been identified. We show here that the alpha1- and alpha2-containing complexes contribute approximately equally to total AMPK activity in rat liver. Furthermore, expression of alpha1 or alpha2 with beta and gamma in mammalian cells demonstrates that both complexes have equal specific activity measured with the SAMS peptide. Using variant peptides, however, we show that alpha1 and alpha2 exhibit slightly different substrate preferences, which suggest that the two isoforms could play different physiological roles within the cell.     

Variability in the oral bioavailability of all-trans-retinoic acid

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. PURPOSE: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. METHODS: Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. RESULTS: Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. CONCLUSION: The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.     

Role of conducting polymeric interfaces in promoting biological electron transfer

In this paper, we explore the role that polymer conductivity and functionality play in determining the nature of molecular recognition at artificial polymer interfaces, as evidenced by electron transfer with the small redox protein, cytochrome c. The relationship is investigated electrochemically using cyclic voltammetry in order to assess the degree of molecular recognition between the biological molecule and carboxyl-functionalized beta-substituted poly(thiophenes) and poly(pyrroles), as well as a co-polymer matrix of these derivatives. In the latter case, the co-polymer film was analysed quantitatively using X-ray photoelectron spectroscopy, and it was found that its composition did not reflect the initial molar ratios of the monomers prior to electrodeposition.     

Raman difference studies of GDP and GTP binding to c-Harvey ras

The vibrational spectra of phosphate modes for GDP and GTP bound to the c-Harvey p21(ras) protein have been determined using 18O isotope edited Raman difference spectroscopy. A number of the phosphate stretch frequencies are changed upon GDP/GTP binding to ras, and the results are analyzed by ab initio calculations and through the use of empirical relationships that relate bond orders and bond lengths to vibrational frequencies. Bound GDP is found to be strongly stabilized by its interactions, mostly electrostatic, with the active site Mg2+. Bound GTP also interacts with the active site Mg2+ via its beta-phosphate group, as expected on the basis of crystallographic studies of bound GppNp. The angle between the nonbridging P&bondDot;O bonds of the gamma-phosphate of bound GTP increase by about 1-2 degrees compared to its solution value, thus bringing about a geometry that is closer to planar for these bonds as expected for the putative pentacoordinated transition state geometry of the phosphotransfer reaction. Modeling of the interactions at the nucleotide binding site suggests that the water molecule in-line with the P-O bond is positioned to bring about the change in bond angle. Moreover, a weak fifth bond (about 0.03 vu) appears to be formed between it and the gamma-phosphorus atom of bound GTP with a concomitant weakening of the O-P bond between the GDP leaving group and the gamma-phosphorus atom. Hence, an important role of the active site structure appears to be the strategic positioning of this in-line water. These structural results are consistent with a reaction pathway for GTP hydrolysis in ras of synchronous bond formation between the gamma-phosphorus of GTP and the attacking nucleophile and bond breaking between the gamma-phosphorus and the GDP leaving group.