Ethanol Feeding Causes Inactivation of Both State 1 and State 2 Rat Hepatic Asialoglycoprotein Receptors

Previous studies have shown that ethanol feeding in rats causes inactivation and redistribution of ˜50% of the total asialoglycoprotein receptors (ASGPRs) in hepatocytes (Tworek et al., J. Biol. Chem. 271:2531, 1996), and that two equal populations of hepatic ASGPRs mediate ligand uptake and processing via two functionally different pathways (Weigel in Glycoconjugates: Composition, Structure and Function , Marcel Dekker, 1992, p. 421). The purpose of this study was to determine if ethanol feeding causes preferential inactivation of only one of these two ASGPR populations, which have been designated state 1 and state 2 ASGPRs. The state 2, but not state 1, ASGPRs are inactivated in isolated hepatocytes by a variety of drugs and inhibitors. State 2 ASGPRs can also be inactivated in permeable cells by ATP treatment and then reactivated by treatment with fatty acyl coenzyme As. In the present study, permeable cell assays for state 2 ASGPR inactivation and reactivation were used to assess whether hepatocytes from ethanol-fed rats contain inactive state 2 ASGPRs. The results show that preferential inactivation of one ASGPR population does not occur after ethanol feeding. That inactive ASGPRs could not be reactivated by treatment with palmitoyl-coenzyme A to a greater extent in ethanol-fed versus control cells indicates there is not a larger pool of inactivated state 2 ASGPRs in treated cells. We conclude that ethanol feeding causes equal inactivation of both state 1 and state 2 ASGPRs. Ethanol feeding may represent the first treatment found to inactivate state 1 ASGPRs.     

Vasodepressor reactions after orthotopic cardiac transplantation: Relationship to reinnervation status

Ventricular vagal nerve endings are thought to trigger vasodepressor syncope. Reports of vasodepressor reactions associated with donor bradycardia after cardiac transplantation have led to speculation that vagal reinnervation occurs. We assessed reinnervation status in seven patients 23–36 months (median 24 months) post-transplantation. Heart rate responses to vagal manoeuvres (respiration, Valsalva) and sympathetic stimuli (exercise and injection of tyramine into the coronary artery supplying the sinus node) were measured. All patients underwent 60 min of 60° head-up tilt with foot plate support. During tilt four of the seven had vasodepressor reactions with a fall in mean arterial pressure of 20–90 mmHg. During vasodepression two patients had falls in donor heart rate of 13 and 40% relative to peak heart rate during tilt. These two patients had evidence of functional sympathetic reinnervation. By contrast the two patients without donor bradycardia during vasodepression had only limited or no evidence of sympathetic reinnervation. No patient had consistent evidence of parasympathetic reinnervation as judged by the heart rate response to vagal manoeuvres. Headup tilt can thus produce vasodepressor reactions with donor bradycardia after cardiac transplantation in the absence of consistent evidence of vagal reinnervation. Left ventricular nerve endings may not be the only mediators of tilt-induced vasodepressor reactions in man. Donor bradycardia during vasodepression may reflect sympathetic withdrawal and not vagal reinnervation.     

The structure of wandering in dementia

‘Wandering’ is one of the most troublesome of behavioural problems in dementia. The term ‘wandering’ covers many different types of behaviour. We examined the hypothesis that the different types of wandering behaviour seen in dementia from a scale using data collected on 83 elderly subjects suffering from either Alzheimer's disease or multiinfarct dementia. We reject the scaling hypothesis. Our data suggest that there are three main categories of wandering behaviour, and that one of these categories is usefully divided into four subcategories.     

Nasal polyposis: prevalence of positive food and inhalant skin tests.

OBJECTIVES: To investigate the etiology of nasal polyps and its relationship to allergy. The prevalence of positive food and inhalant skin tests in patients with nasal polyps and nonatopic controls was compared. STUDY DESIGN AND SETTING: Prospective controlled study in tertiary referral rhinology clinic. RESULTS: Seventy percent (70%) of the patients with nasal polyps had positive skin tests to an average of four foodstuffs, compared to 34 percent of controls (P = 0.006). Only 35 percent of the nasal polyp patients also had positive inhalant skin tests. Overall, the prevalence of positive inhalant skin tests was similar in the nasal polyp patients and controls. CONCLUSIONS: These findings suggest that the positive skin tests to foods are not merely a reflection of the general atopic status of patients with nasal polyps. It may be that non-IgE-mediated hypersensitivities, such as to ingested foods, play a role on the basis of a significant number of patients with positive intradermal skin tests to foods. SIGNIFICANCE: Evaluation of the allergic status of patients with polyposis is important. Dietary manipulation may be indicated, though its role needs further investigation.     

Premature failure of small-sized Shelhigh No-React porcine pulmonic valve conduit model NR-4000.

OBJECTIVE: Given the limited availability of small-sized cryopreserved pulmonary homografts, we implanted a series of Shelhigh No-React porcine pulmonic valve conduits (SPVC). The aim of this study was to evaluate the short-term performance following implantation. METHODS: From February 2000 to September 2000, the SPVC was implanted 25 times in 24 patients in the right ventricular outflow tract (RVOT) to correct congenital anomalies. The anatomical malformations were TOF/PA in eight patients, TGA/VSD/PS in four, truncus arteriosus in four, IAA/VSD/AS or AA in four, l-TGA/VSD in two and other in two. Age at operation was 2.8+/-3.9 years (mean+/-SD), including 12 patients under 1 year. The median conduit size was 14mm (range, 10-18). RESULTS: At a mean follow-up of 23+/-5 months, two late deaths (8%) have occurred. Although they were not primarily conduit related, both showed severe conduit stenosis. Twenty-one conduits (84%) showed mild to severe conduit stenosis, regurgitation or both. Two patients underwent balloon dilatation for distal conduit stenosis. Twelve conduits (48%) in 11 patients were removed at a median of 12 months (range, 2-18 months) due to RVOT obstruction in 11 and free conduit insufficiency with pseudoaneurysm in one. The typical findings of the explanted conduits were prominent intimal peel formation at the distal anastomosis without calcification. The actuarial freedom from reintervention at 18 months was 48+/-10%. CONCLUSIONS: Our experience of the SPVC with the diameter of 14mm or less has revealed a high incidence of distal conduit stenosis due to intimal peel formation resulting in early conduit failure. These findings have led us to abandon its use when other options are available.     

Selective abstraction of 2H from C-5'' of thymidylate in an oligodeoxynucleotide by the radical center at C-6 of the diradical species of neocarzinostatin: chemical evidence for the structure of the activated drug-DNA complex.

Use has been made of the mechanism of DNA deoxyribose damage by the ene-diyne-containing chromophore of the antitumor antibiotic neocarzinostatin to provide chemical evidence for the structure of the activated drug-DNA complex. Radical centers at C-2 and C-6 of the diradical form of the glutathione-activated chromophore abstract hydrogen atoms from C-1' of the C residue and C-5' of the T residue in AGC.GCT to generate a bistranded lesion consisting of an abasic site at C and a strand break at T. This laboratory has proposed a molecular model for the drug-DNA interaction in which the naphthoate moiety of the chromophore intercalates between A.T and G.C, placing the diradical core in the minor groove, so that the radical centers at C-6 and C-2 are close to C-5' of T and C-1' of C, respectively. To determine which radical center abstracts one of the hydrogen atoms from C-5', the self-complementary oligodeoxynucleotide GCAGCGCTGC was synthesized with 2H at both 5' positions of the T residue and treated with glutathione-activated chromophore. Sequencing-gel electrophoresis showed that drug attack was limited to the T and C residues and that abstraction of 2H from C-5' exhibited a small isotope selection effect of 1.25. 1H NMR spectroscopic examination of the reacted chromophore, isolated by HPLC, indicated that 2H was selectively abstracted by C-6, providing experimental corroboration of the model and further elucidating the chemical mechanism. Since direct strand breakage at the T residue exceeds (44% more) abasic site formation at the C residue, other models of drug-DNA interaction leading to only single-strand breaks are also considered.     

Computed tomography and plain radiography in experimental fracture healing

We evaluated the relative contribution of plain radiographs and computed tomography to the assessment of fracture healing under experimental circumstances. In 15 sheep, we performed midshaft femoral osteotomies and internal fixation of the resultant segmental fractures. Radiographs were obtained preoperatively and immediately postoperatively. Animals were sacrificed at 3 weeks, 6 weeks, 12 weeks, 24 weeks, and 36 weeks after surgery, and the femoral specimens radiographed. After removal of the internal fixation devices, computed tomographic scans of the specimens were performed.By 3 weeks, callus was visible, but at 6 weeks, a trabecular pattern in the callus was seen on plain films but not on computed tomography. There was progressive organization of the callus on both studies. At 24 weeks, computed tomography demonstrated fracture lines not seen due to overlying callus on plain films and also more accurately showed incomplete union. By 36 weeks, healing was essentially complete according to both modalities, although there still were small gaps in the callus detectable on computed tomography but not on plain films.Computed tomography may be of value in the evaluation of fractures of long bones in those cases in which clinical examination and plain radiographs fail to give adequate information as to the status of healing.     

Preventive care: do we practice what we preach?

We used insurance claims from enrollees in the Rand Health Insurance Experiment to determine the amount of selected components of preventive care received by a representative sample of the non-aged population in the United States and to determine whether insurance coverage was an important determinant of that amount. Only 45 percent of infants received timely immunization for DPT and polio; 93 per cent received some well child care by 18 months of age. In the three-year experimental period, only 4 per cent of adults had a tetanus shot, 66 per cent of women aged 17-44 and 57 per cent aged 45-65 received a Pap smear, and 2 per cent of women aged 45-65 had a mammogram. Cost sharing was associated with even less preventive care: 60 per cent of children on the free plan and 49 per cent on cost sharing plans received preventive care of any type. For adults, women on the free plan received more preventive care of several kinds, and those aged 45-65 received more Pap smears than those on cost-sharing plans. Even with free care, most enrollees did not receive adequate preventive care. Thus, free care alone, while significant, is not a sufficient incentive to providing recommended levels of preventive care. The average per person insurance charge for increasing the amount of preventive care to a level consistent with that recommended would be $22 for a complete set of immunizations by age 18 months, $9 for a Pap smear every three years, and $97 for a Pap test and mammogram every three years.