Thermogenic effects of dihydrocodeine in the rat

The object of this study was to assess the effects of dihydrocodeine on thermogenesis and brown adipose tissue activity in the rat from measurements of oxygen consumption and blood flow. Acute injection of dihydrocodeine tartrate (s.c.) stimulated resting oxygen consumption (VO2) in Sprague-Dawley rats in a dose-dependent manner (0.5-50 mg/kg), with a peak response (40-45% increase) occurring at 10-25 mg/kg. This effect was also observed in urethane-anaesthetized rats (although the effect was reduced) and in conscious animals following gastric intubation with the drug. Pretreatment of rats with either a beta-adrenergic antagonist (propranolol, 20 mg/kg), ACTH (4 g/kg), or an opiate antagonist (WIN44441-1, 2 mg/kg) significantly reduced the response to dihydrocodeine, whereas corticosterone injection (5 mg/kg) enhanced the effect. Surgical adrenalectomy or hypophysectomy (HYPX) almost completely abolished the thermogenic effect of dihydrocodeine. Dihydrocodeine also stimulated VO2 in lean (58% increase) and genetically obese Zucker rats (69% increase), and in both Zucker genotypes these responses were only slightly affected by HYPX, but enhanced in HYPX rats treated daily with corticosterone (1 mg/kg). Tissue blood flow, assessed from the distribution of radiolabelled microspheres, was unaffected in white adipose tissue, skeletal muscle, testes, kidney, brain, and liver (arterial supply) after a single injection of dihydrocodeine (25 mg/kg), but flow to interscapular and perirenal brown adipose tissue was increased by 9- to 10-fold. Surgical sympathectomy of brown adipose tissue prevented the increase in blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Drug transport by reconstituted P-glycoprotein in proteoliposomes. Effect of substrates and modulators, and dependence on bilayer phase state.

The P-glycoprotein multidrug transporter (Pgp) is an active efflux pump for chemotherapeutic drugs, natural products and hydrophobic peptides. Pgp is envisaged as a 'hydrophobic vacuum cleaner', and drugs are believed to gain access to the substrate binding sites from within the membrane, rather than from the aqueous phase. The intimate association of both Pgp and its substrates with the membrane suggests that its function may be regulated by the biophysical properties of the lipid bilayer. Using the high affinity fluorescent substrate tetramethylrosamine (TMR), we have monitored, in real time, transport in proteoliposomes containing reconstituted Pgp. The TMR concentration gradient generated by Pgp was collapsed by the addition of either the ATPase inhibitor, vanadate, or Pgp modulators. TMR transport by Pgp obeyed Michaelis--Menten kinetics with respect to both of its substrates. The Km for ATP was 0.48 mM, close to the K(m) for ATP hydrolysis, and the K(m) for TMR was 0.3 microM. TMR transport was inhibited in a concentration-dependent fashion by verapamil and cyclosporin A, and activated (probably by a positive allosteric effect) by the transport substrate colchicine. TMR transport by Pgp reconstituted into proteoliposomes composed of two synthetic phosphatidylcholines showed a highly unusual biphasic temperature dependence. The rate of TMR transport was relatively high in the rigid gel phase, reached a maximum at the melting temperature of the bilayer, and then decreased in the fluid liquid crystalline phase. This pattern of temperature dependence suggests that the rate of drug transport by Pgp may be dominated by partitioning of drug into the bilayer.     

Meningitis caused by Rhodotorula.

A case of rhodotorula meningitis in a 21 year old male compromised with acute lymphoblastic leukemia is reported. The yeast was identified as Rhodotorula rubra (Demme) Lodder.     

Simple shifts in the voltage dependence of sodium channel gating caused by divalent cations

The effect of elevated divalent cation concentration on the kinetics of sodium ionic and gating currents was studied in voltage-clamped frog skeletal muscle fibers. Raising the Ca concentration from 2 to 40 mM resulted in nearly identical 30-mV shifts in the time courses of activation, inactivation, tail current decay, and ON and OFF gating currents, and in the steady state levels of inactivation, charge immobilization, and charge vs. voltage. Adding 38 mM Mg to the 2 mM Ca bathing a fiber produced a smaller shift of approximately 20 mV in gating current kinetics and the charge vs. voltage relationship. The results with both Ca and Mg are consistent with the hypothesis that elevated concentrations of these alkali earth cations alter Na channel gating by changing the membrane surface potential. The different shifts produced by Ca and Mg are consistent with the hypothesis that the two ions bind to fixed membrane surface charges with different affinities, in addition to possible screening.     

Changes in mortality patterns and temperature dependence of lifespan in Drosophila melanogaster caused by inbreeding

After an inbreeding event, lifespan can be curtailed through the expression of deleterious alleles. This will impact on both mortality patterns and interactions with the environment as visualised in reaction norms. We have established the effects of inbreeding on the temperature dependence of lifespan and on mortality patterns in Drosophila melanogaster. Four inbred lines displaying severely decreased lifespan and five outbred controls were assessed for male adult survival at three temperatures. As expected, all inbred lines showed a shorter lifespan than noninbred lines. The mechanisms behind this, however, appeared to be very diverse. Two inbred lines showed a significantly decreased temperature dependence of lifespan compared to the control lines. Analysis of variance on the mortality parameters over all lines showed that inbreeding changes the age-independent mortality but not the age-dependent mortality, whereas temperature does the opposite. This suggests that gene-by-environment interaction caused by inbreeding is the result of changes in the processes of lifespan determination. Importantly, for the two other inbred lines, a particular temperature regime triggered the expression of conditional lethal alleles. Mortality was concentrated in short lethal phases early in adult life. These conditionally expressed lethal alleles affecting lifespan demonstrate line specificity for inbreeding depression and will help ageing studies as such alleles may serve as candidate genes for ageing processes and age-related pathologies in humans.     

Onychomycosis caused by Aspergillus terreus.

Four cases of onychomycosis caused by Aspergillus terreus are presented. The clinical characteristics consisted of spotted and striated leuconychia, dark spots and fragility of the nails. The mycology is described, and is shown that A. terreus has an inhibitory effect on the growth of dermatophytes and Scopulariopis brevicaulis. Topical treatment with 1% Pimafucin in a mixture of 60% dimethylsulfoxide (DMSO) and 40% water as well as 9% aqueous solution of sodium benzoate were both effective. The literature concerning onychomycosis caused by A. terreus is summarized.