Hepatic apolipoprotein and LDL receptor gene expression in the genetically hypercholesterolemic (RICO) rat

Up and down-regulation of calcium and potassium conductances are associated with several forms of short-term synaptic modulation. Detailed investigation of synaptic plasticity in the marine gastropod Aplysia, and in other mollusks, indicates that synaptic transmission can be influenced in a number of ways by modulatory neurotransmitters acting through several second-messenger cascades. Modulation at the synapse itself occurs by means of the regulation of calcium current as well as through effects on processes directly involved in transmitter mobilization and exocytosis. Modulation of potassium current plays a major role in controlling neuronal excitability and may contribute to a lesser extent to the regulation of transmitter release through actions on the resting potential and on action potential configuration.     

Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE-1) in breast carcinomas

The concurrent external validity of the diagnosis of cocaine abuse, based on the DSM criteria, is shown to be established to an unexpectedly high degree, based on a method of determining the association between a summary score derived by quantifying the DSM criteria and another summary score derived from weighting several measures of frequency of use of cocaine and a measure of its mode of use. The degree of validity was cross-validated by performing the same analysis on two study samples: one of inpatients (N = 179) and one of urban-community African-Americans (N = 204).     

The untranslated first exon ''exon 0S'' of the rat estrogen receptor (ER) gene

Occasionally, ipsilateral ischemia develops following the groin insertion of an intra-aortic balloon catheter. Various treatment options have evolved, and include replacing the catheter in the opposite groin, removing it completely, or performing a femorofemoral bypass to deliver blood flow below the catheter. Outlined in this paper is a simple method to restore blood flow to a threatened limb, during femoral artery exploration, in the presence of an intra-aortic balloon. This method is also appropriate for optimal positioning of the balloon catheter prior to femorofemoral bypass.     

Human papillomavirus type 16 E6 protein up-regulates the expression of the high mobility group protein HMG-I(Y) gene in mouse 10T1/2 cells

Signs of acute respiratory distress were reported in moulting grey seals (Halichoerus grypus) hauled out on Lady's Holm, Shetland, following the Braer oil spill in January, 1993. Behavioural observations carried out between 16 January and 13 February 1993 showed that the proportion of animals exhibiting a discharge of nasal mucus was significantly higher than the proportion at a control site in the north (Papa Stour). The proportion of animals affected on Lady's Holm increased for up to one month following the spill. However, the time lag between exposure and peak response was approximately 30 days, longer than may be expected for an acute effect. The proportion of non-specific signs of respiratory distress in unexposed Shetland seals was assessed from observations made between 16 January and 25 January 1994. Symptoms similar to those seen in 1993 were also reported during this period, but the proportion of affected animals was higher in 1993. Symptoms were not observed at a grey seal moult site on the east coast of England in March 1993 and 1994. Grey seals moulting in Shetland during the time of the oil spill may have been acutely affected by exposure to hydrocarbons, but without sufficient baseline data on the occurrence of respiratory distress in grey seals it is difficult to determine the proportion attributable to other causes.     

Thrombin induces thrombomodulin mRNA expression via the proteolytically activated thrombin receptor in cultured bovine smooth muscle cells

We propose that a long-term cure for the recalcitrant chronic venous ulcer must involve a dual surgical approach including (1) wide excision of the ulcer and surrounding liposclerotic tissue bed, and (2) replacement by a free flap containing multiple, competent microvenous valves with a normal microcirculation. Advantages of free flaps over skin grafting include improvement of the underlying pathophysiology; increase in blood supply to the area; ability to cover exposed bone, joint, or tendon; and a lower incidence of recurrence. During the past 8 years, 20 consecutive muscle free flaps were performed in 18 patients for 19 recalcitrant venous ulcers (two "sequential" flaps to the ipsilateral leg in 1 patient and a repeat flap after initial failure in 1 patient). Twelve males and 6 females ranged in age from 17 to 76 years (mean, 44 years). Nontraumatic, nonosteomyelitic venous ulcers had been present for an average of 3.5 years (range, 1-10 years) and failed an average of 2.4 skin grafts (range, 0-6 grafts). Defects ranged from 100 to 600 cm2 (mean, 238 cm2). Donor tissues included rectus abdominis (N = 13), latissimus dorsi (N = 5), gracilis (N = 1), and serratus (N = 1) muscles. Recipient vessels included posterior tibial (N = 12), anterior tibial (N = 6), and peroneal (N = 2). In all instances except one, only one vein, usually one of the venae comitantes, was anastomosed in end-to-end fashion. Successful free tissue transfer was accomplished in 18 of 20 flaps (90%). Complications included infection with partial flap and/or skin graft loss (three flaps), and partial skin graft loss (two flaps). There were no recurrences within the flaps; however, breakdown occurred at the junction between the flap and residual adjacent liposclerotic skin in 1 patient. Follow-up average 32.7 months (range, 8-65 months); 3 patients were lost to follow-up. Free muscle transfer can provide a long-term cure for the recalcitrant venous ulcer by replacing the diseased tissue bed with healthy tissue containing multiple, competent microvenous valves and a normal microcirculation. This can be accomplished in one reconstructive procedure with excellent long-term results.     

Withdrawal of [corrected] estrogen increases hypothalamic neuropeptide Y (NPY) mRNA expression in ovariectomized obese rat

We determined the changes in neuropeptide Y (NPY) mRNA expression of the arcuate nucleus (ARC) in sham-operated (SHAM) and bilaterally ovariectomized (OVX) rats with estradiol (E2) supplement. Ovariectomy increases body weight gain for 3 weeks, accompanied by an increase of daily food intake. Ovariectomy significantly reduced serum corticosterone levels. E2 supplement reversed the effects of ovariectomy on body weight gain, food intake and serum corticosterone levels. Ovariectomy significantly increased NPY mRNA expression in the ARC. E2 supplement decreased NPY mRNA expression in the ARC of OVX rats. The present findings indicated that hypothalamic NPY mRNA expression, which involves the regulation of feeding behavior, are in parallel with circulating estrogen levels. Hypothalamic NPY mRNA expression may be important in the induction of hyperphagia after the withdrawal of estrogen by bilateral ovariectomy.     

Differential regulation of GABA(A) receptor gene expression by ethanol in the rat hippocampus versus cerebral cortex

Previous research has shown that chronic ethanol consumption dramatically alters GABA(A) receptor alpha1 and alpha4 subunit gene expression in the cerebral cortex and GABA(A) receptor alpha1 and alpha6 subunit gene expression in the cerebellum. However, it is not yet known if chronic ethanol consumption produces similar alterations in GABA(A) receptor gene expression in other brain regions. One brain region of interest is the hippocampus because it has recently been shown that a subset of GABA(A) receptors in the hippocampus is responsive to pharmacologically relevant concentrations of ethanol. Therefore, we directly compared the effects of chronic ethanol consumption on GABA(A) receptor subunit gene expression in the hippocampus and cerebral cortex. Furthermore, we investigated whether the duration of ethanol consumption (14 or 40 days) would influence regulation of GABA(A) receptor gene expression in these two brain regions. Chronic ethanol consumption produced a significant increase in the level of GABA(A) receptor alpha4 subunit peptide in the hippocampus following 40 days but not 14 days. The relative expression of hippocampal GABA(A) receptor alpha1, alpha2, alpha3, beta(2/3), or gamma2 was not altered by either period of chronic ethanol exposure. In marked contrast, chronic ethanol consumption for 40 days significantly increased the relative expression of cerebral cortical GABA(A) receptor alpha4 subunits and significantly decreased the relative expression of cerebral cortical GABA(A) receptor alpha1 subunits. This finding is consistent with previous results following 14 days of chronic ethanol consumption. Hence, chronic ethanol consumption alters GABA(A) receptor gene expression in the hippocampus but in a different manner from that in either the cerebral cortex or the cerebellum. Furthermore, these alterations are dependent on the duration of ethanol exposure.     

Bone marrow transplantation in apolipoprotein E-deficient mice. Effect of ApoE gene dosage on serum lipid concentrations, (beta)VLDL catabolism, and atherosclerosis

Apolipoprotein E (apoE), a high-affinity ligand for lipoprotein receptors, is synthesized by the liver and extrahepatic tissues, including cells of the monocyte/macrophage lineage. Inactivation of the apoE gene in mice leads to a prominent increase in serum cholesterol and triglyceride levels and the development of premature atherosclerosis. In this study, the role of monocyte/macrophage-derived apoE in lipoprotein remnant metabolism and atherogenesis was assessed. The influence of apoE gene dosage on serum lipid concentrations was determined by transplantation of homozygous apoE-deficient (apoE-/-), heterozygous apoE-deficient (apoE+/-), and wild-type (apoE+/+) bone marrow in homozygous apoE-deficient mice. The concentration of apoE detected in serum was found to be gene dosage dependent, being 3.52 +/- 0.30%, 1.87 +/- 0.17%, and 0% of normal in transplanted mice receiving either apoE+/+, apoE+/-, or apoE-/- bone marrow, respectively. These low concentrations of apoE nevertheless dramatically reduced serum cholesterol levels owing to a reduction of VLDL and, to a lesser extent, LDL, while HDL levels were slightly raised. After 4 months on a "Western-type" diet, atherosclerosis was evidently reduced in mice transplanted with apoE+/+ bone marrow, compared with control transplanted mice. To study the mechanism of the lipoprotein changes on bone marrow transplantation, the in vivo turnover of autologous serum (beta)VLDL was studied. The serum half-life of (beta)VLDL in transplanted mice, compared with control apoE-deficient mice, was shortened mainly as a consequence of an increased recognition and uptake by the liver. Analysis of the relative contribution of the liver parenchymal cells, endothelial cells, and Kupffer cells (liver tissue macrophages) indicated an increased uptake by parenchymal cells, while the relative contribution to Kupffer cells was decreased. In conclusion, macrophage-derived apoE can dose-dependently reduce hypercholesterolemia in apoE-deficient mice owing to increased recognition and uptake of (beta)VLDL by parenchymal liver cells, leading to a decreased susceptibility to atherosclerosis.     

An essential E box in the promoter of the gene encoding the mRNA cap-binding protein (eukaryotic initiation factor 4E) is a target for activation by c-myc

The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF4E]) binds the m7 GpppN cap on mRNA, thereby initiating translation. eIF4E is essential and rate limiting for protein synthesis. Overexpression of eIF4E transforms cells, and mutations in eIF4E arrest cells in G, in cdc33 mutants. In this work, we identified the promoter region of the gene encoding eIF4E, because we previously identified eIF4E as a potential myc-regulated gene. In support of our previous data, a minimal, functional, 403-nucleotide promoter region of eIF4E was found to contain CACGTG E box repeats, and this core eIF4E promoter was myc responsive in cotransfections with c-myc. A direct role for myc in activating the eIF4E promoter was demonstrated by cotransfections with two dominant negative mutants of c-myc (MycdeltaTAD and MycdeltaBR) which equally suppressed promoter function. Furthermore, electrophoretic mobility shift assays demonstrated quantitative binding to the E box motifs that correlated with myc levels in the electrophoretic mobility shift assay extracts; supershift assays demonstrated max and USF binding to the same motif. cis mutations in the core or flank of the eIF4E E box simultaneously altered myc-max and USF binding and inactivated the promoter. Indeed, mutations of this E box inactivated the promoter in all cells tested, suggesting it is essential for expression of eIF4E. Furthermore, the GGCCACGTG(A/T)C(C/G) sequence is shared with other in vivo targets for c-myc, but unlike other targets, it is located in the immediate promoter region. Its critical function in the eIF4E promoter coupled with the known functional significance of eIF4E in growth regulation makes it a particularly interesting target for c-myc regulation.