Hybrid choice model dataset of a representative Swiss online panel survey on peoples' preferences related to mixed renewable energy scenarios in landscapes and the effect of landscape-technology fit.

We present stated preference data based on a national representative Swiss online panel survey related to preference of mixed renewable energy infrastructure in landscapes. Data were collected between November 2018 and March 2019 via an online questionnaire and yielded 1026 responses. The online questionnaire consisted of two main parts - (1) questions covering meanings related to landscapes, nature and renewable energy infrastructure and questions regarding the "fit" of landscape/renewable energy infrastructure (REI) combinations and (2) a stated choice experiment. While in the first part of the questionnaire we asked respondents about their personal connection to certain landscapes, to nature and to specific REI, we also asked them to evaluate the fitting of seven different Swiss landscapes (near natural alpine areas, northern alps, touristic alpine areas, agricultural plateau, urban plateau, Jura ridges, urban alpine valley) with five different REI (wind, PV ground/agricultural, PV ground/other, PV roof, power lines) combinations. In the second part of the questionnaire, the stated choice experiment confronted respondents with 15 consecutive choice tasks, with each task involving a choice between two "energy system transformation" options and an opt-out option (none). Each choice option (beside the opt-out option) included four unlabeled attributes (landscape, wind energy infrastructure, photovoltaic energy infrastructure, high voltage overhead power line infrastructure) with varying levels. Due to data cleaning procedures (item nonresponse) the number of responses used within hybrid choice modeling and analysis was n = 844 (12,660 choice observations). An analysis of the hybrid choice model and further insights are presented in the article "How landscape-technology fit affects public evaluations of renewable energy infrastructure scenarios. A hybrid choice model."

Low plasma adiponectin concentration is associated with myocardial infarction in young individuals.

OBJECTIVE: The importance of adiponectin in coronary heart disease remains to be elucidated. Therefore, the associations between plasma adiponectin levels and i) myocardial infarction and ii) genetic variation within the adiponectin gene were investigated. METHODS: The study included young survivors (age <60 years) of a first myocardial infarction and gender- and age-matched controls (244 pairs). Adiponectin concentrations were analysed by radioimmunoassay. Two polymorphisms, rs266729 and rs1501299, of the adiponectin gene ADIPOQ were genotyped. RESULTS: Adiponectin levels were inversely associated with myocardial infarction [odds ratio (OR) 9.3, 95% confidence interval (CI) 4.7-18.2, for the lowest quartile compared to the highest quartile]. This persisted after adjustment for history of hypertension, HDL cholesterol, smoking and body mass index (BMI) (OR 3.1, 95% CI 1.3-7.6). The rs266729 polymorphism was associated with adiponectin levels. Plasma adiponectin concentrations were lower in individuals with the rare G/G genotype [median 4.3 mg/L, [corrected] interquartile range (IQR) 2.8-6.2] compared to the C/G (median 5.8 mg/L), [corrected] IQR 3.9-8.0; P = 0.035) and C/C genotypes (median 5.5 mg/L, [corrected] IQR 4.0-7.5; P = 0.083). CONCLUSION: Low plasma adiponectin concentrations are associated with myocardial infarction in individuals below the age of 60, and this remains significant after adjustment for history of hypertension, HDL cholesterol, smoking and BMI. In addition, adiponectin levels differ according to rs266729 genotype.

Evidence for immunosurveillance in intestinal premalignant lesions.

The immunosurveillance theory argues that the immune system recognizes tumour-specific antigens expressed by transformed cells, which results in the destruction of cancer precursors before they become clinically manifest. As a model for the development of cancer, we set out to study premalignant lesions and immune responses in sentinel lymph nodes from patients with long-standing ulcerative colitis and progression of mucosal dysplasia. Mesenteric lymph nodes draining dysplastic and normal intestinal segments were identified by sentinel node technique during surgery in 13 patients with ulcerative colitis who were subjected to colectomy because of intestinal dysplasia. T cells were extracted from the lymph nodes and analysed by flow cytometry, and lymphocyte proliferation assays were set up in the presence of extracts from dysplastic and normal intestinal mucosa. Increase in CD4/CD8 ratio was observed in sentinel lymph nodes draining dysplastic epithelium compared to normal mucosa. The increase in CD4(+) T cells in relation to CD8(+) T cells correlated with the degree of dysplasia reflected by a significant increase in the ratio against low-grade dysplasia compared to indefinite dysplastic lesions. The T-cell response was specific to antigens from dysplastic epithelial lining as seen in proliferation assays. The observation suggests an important surveillance role for the immune system against premalignant intestinal lesions in patients with long-standing ulcerative colitis.

COORDINATION OF MANAGEMENT OF THE ACUTE RADIATION SYNDROME.

The acute radiation syndrome (ARS) constitutes the most challenging, immediate medical consequence of exposure to high doses of ionizing radiation in an emergency situation. This report highlights some of the currently available medical guidelines and recommendations on the clinical management of ARS, comments recent trends regarding the approval of targeted pharmaceuticals for ARS, and suggests further initiatives for international collaboration aiming at continuously updating the medical knowledge base of this syndrome.

In vitro inhibition of chick embryo lysyl hydroxylase by homogentisic acid. A proposed connective tissue defect in alkaptonuria.

Homogentisic acid inhibits the in vitro activity of chick embryo lysyl hydroxylase, a microsomal enzyme which catalyzes the transformation of certain lysyl residues in collagen to hydroxylysine. Chick embryo lysyl hydroxylase activity was measured as specific tritium release as tritium water from a [4,5-(3)H]lysine-labeled unhydroxylated collagen substrate prepared from chick calvaria. Kinetic studies revealed a linear, noncompetitive type of inhibition with respect to collagen substrate with a Ki of 120-180 muM. The inhibition by homogentisic acid was reversible in that enzyme activity could be restored after dialysis of preincubated mixtures of homogentisic acid with enzyme or substrate. The inhibition by homogentisic acid was competitive with respect to ascorbic acid, and the addition of reducing agents, such as ascorbic acid or 1,4-dithiothreitol, protected lysyl hydroxylase activity from homogentisic acid inhibition.In organ cultures of embryonic chick calvaria, biosynthesis of hydroxylysine-derived intermolecular collagen cross-links was inhibited in a dose-dependent manner by 0.5-5 mM homogentisic acid. Because homogentisic acid inhibits the formation of hydroxylysine in a cell-free assay and in organ cultures, this compound must pass into the cells of calvaria to inhibit intracellular hydroxylysine formation and subsequently to diminish the reducible intermolecular cross-links of the newly synthesized collagen. We propose that the inhibition of lysyl hydroxylase and the resulting hydroxylsine-deficient, structurally modified collagen may be clinically significant in the defective connective tissue found in alkaptonuric patients.

The collagen of heart valve.

A hydroxylysine-rich type I collagen has been isolated from pepsin-digested porcine heart valve. The ratio of alpha1 to alpha2 in the isolated molecule was 2:1. The component alpha chains exhibited unusual chromatographic behavior in comparison to corresponding chains from human dermis and lathyritic rat skin collagen. The composition of component cyanogen bromide peptides identified the alpha chains as authentic type I chains and demonstrated hydroxylysine enrichment throughout the length of the chain. delta6-Dehydro-5,5'dihydroxylysinonorleucine, a collagen cross-link derived from two hydroxylysyl residues and ordinarily found in hard tissue collagens was found to be the predominant cross-link in heart valve.

Regulation of pancreatic beta-cell mass and proliferation by SOCS-3.

Growth hormone and prolactin are important growth factors for pancreatic beta-cells. The effects exerted by these hormones on proliferation and on insulin synthesis and secretion in beta-cells are largely mediated through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Suppressors of cytokine signaling (SOCS) proteins are specific inhibitors of the JAK/STAT pathway acting through a negative-feedback loop. To investigate in vivo effects of SOCS-3 in growth hormone (GH)/prolactin signaling in beta-cells we generated transgenic mice with beta-cell-specific overexpression of SOCS-3. The relative beta-cell proliferation and volume in the mice were measured by morphometry. Beta-cell volume of transgenic female mice was reduced by over 30% compared with beta-cell volume in wild-type female mice. Stimulation of transgenic islets in vitro with GH showed a reduced tyrosine phosphorylation of STAT-5 when compared with wild-type islets. Transduction of primary islet cultures with adenoviruses expressing various SOCS proteins followed by stimulation with GH or glucagon-like peptide-1 (GLP-1) revealed that SOCS-3 inhibited GH- but not GLP-1-mediated islet cell proliferation, indicating that the decreased beta-cell volume observed in female transgenic mice could be caused by an inhibition of GH-induced beta-cell proliferation by SOCS-3. In spite of the reduced beta-cell volume the transgenic female mice exhibited enhanced glucose tolerance compared with wild-type littermates following an oral glucose-tolerance test. Together these data suggest that SOCS-3 modulates cytokine signaling in pancreatic beta-cells and therefore potentially could be a candidate target for development of new treatment strategies for diabetes.

Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins.

In this study we have investigated the role of suppressor of cytokine signaling (SOCS) proteins in GH receptor-mediated signaling. GH-induced transcription was inhibited by SOCS-1 and SOCS-3, while SOCS-2 and cytokine inducible SH2-containing protein (CIS) had no effect By using chimeric SOCS proteins it was found that the ability of SOCS proteins to inhibit GH-mediated transcription was located in the amino-terminal 40-80 amino acids. In SOCS-3, 46 amino acids C-terminal to the SH2 domain were required for the inhibitory activity, while a truncated SOCS-1 having only 2 amino acids C-terminal to the SH2 domain was able to inhibit GH-mediated transcription. Both SOCS-1 and SOCS-3 were able to inhibit GH-induced STAT5 (signal transducer and activator of transcription) activation. SOCS-1 inhibited the tyrosine kinase activity of Janus kinase 2 (JAK2) directly, while SOCS-3 only inhibited JAK2 when stimulated by the GH receptor. All four SOCS proteins were able to bind to a tyrosine-phosphorylated glutathione-S-transferase-GH receptor fusion protein, and SOCS-3 required the same 46 C-terminal amino acids for GH receptor binding as it did for inhibition of GH-mediated transcription and STAT5 activation. These data suggest that SOCS-1 and -3 can suppress GH-induced transcriptional activity, presumably by inhibiting the kinase activity of JAK2 either directly in the case of SOCS-1 or via binding to the tyrosine-phosphorylated GH receptor in the case of SOCS-3.

In vitro inhibition of collagen cross links by catechol analogs.

Catechol analogs inhibit the formation of hydroxylysine-derived intermolecular collagen cross links in tissue cultures of chick embryo calvaria. Formation of intermolecular collagen cross links was measured following incorporation of [14C]lysine, reduction with sodium borohydride, and elution from an ion exchange column with a pyridine-formate gradient. Cultures grown in the presence of 10(-3) M catechol, 10(-3) M dopamine, 10(-3) M L-dopa, or 10(-3) M D,L-serine-(2,3,4-trihydroxybenzyl)-hydrazide demonstrated between 43 and 84% inhibition of hydroxylysine formation. Collagen biosynthesis was not diminished in these cultures as compared to controls without additions or with beta-aminopropionitrile when measured by collagenase digestion. The formation of hydroxylysine-derived intermolecular cross links was inhibited 34 to 93% for 5,5'-dihydroxylysinonorleucine and 7 to 71% for 5-hydroxylysinonorleucine. The catechol analogs also inhibit the activity of lysyl hydroxylase as measured by specific tritium release as triated water from an L-[4,5-3H]lysine-labeled unhydroxylated collagen substrate prepared from chick calvaria. Since catechol analogs inhibit the formation of hydroxylysine in a cell-free assay, these compounds must pass into the cells of calvaria in this culture system to inhibit intracellular hydroxylysine formation and subsequently to diminish the reducible intermolecular cross links of the newly synthesized collagen.

Growth hormone and prolactin stimulate the expression of rat preadipocyte factor-1/delta-like protein in pancreatic islets: molecular cloning and expression pattern during development and growth of the endocrine pancreas.

GH and PRL have been shown to stimulate proliferation and insulin production in islets of Langerhans. To identify genes regulated by GH/PRL in islets, we performed differential screening of a complementary DNA library from neonatal rat islets cultured for 24 h with human GH (hGH). One hGH-induced clone had 96% identity with mouse preadipocyte factor-1 (Pref-1, or delta-like protein (Dlk)]. The size of Pref-1 messenger RNA (mRNA) in islets was 1.6 kilobases, with two less abundant mRNAs of 3.7 and 6.2 kilobases. The Pref-1 mRNA content of islets from adult rats was only 1% of that in neonatal islets. Pref-1 mRNA was markedly up-regulated in islets from pregnant rats from day 12 to term compared with those from age-matched female rats. Two peaks in mRNA expression were observed during gestation, one on day 14 and the other at term, whereafter it decreased to nonpregnant levels. Pref-1 mRNA was up-regulated 3- to 4-fold in neonatal rat islets of Langerhans after 48-h culture with hGH, as found also with bovine GH or ovine PRL. During the development of pancreas from embryonic day 12 (E12) to postnatal day 4, we observed a 2-fold increase in Pref-1 mRNA on E17 and a 5-fold increase at birth, followed by a rapid decline on postnatal day 4. Pref-1 immunoreactivity was found in a subpopulation of insulin cells of neonatal islets of Langerhans. At an early embryonal stage (E13), most cells of the pancreatic anlage were Pref-1 positive, becoming predominantly restricted to the insulin-producing cells during development. In conclusion, these findings suggest that Pref-1 is involved in both differentiation and growth of beta-cells.

Human corneal and conjunctival epithelia produce a mucin-like glycoprotein for the apical surface.

PURPOSE: The authors have determined that the corneal and conjunctival epithelia of the rat produce a mucin-like glycoprotein at the apical surface of the epithelium. The purpose of this study was to determine if human ocular surface epithelium produces similar glycoproteins. METHODS: Because our initial attempts at production of monoclonal antibodies yielded blood type A-specific antibodies, corneal epithelia from blood type O donor eyes were used for the production of monoclonal antibodies. Screening of hybridoma products was accomplished by immunofluorescence microscopy of cryostat sections of blood type O donor eyes. The monoclonal antibody produced was used for immunofluorescence microscopy and immunoelectron microscopy to determine tissue and cellular distribution, respectively. Immunoblot analysis of SDS-PAGE-separated proteins from corneal epithelial tissue and from cultured human corneal epithelium was used to determine molecular weight range and epitope binding after periodate oxidation, N-glycanase, and O-glycanase treatment. RESULTS: A monoclonal antibody, designated H185, that binds to apical cell layers of human corneal, conjunctival, laryngeal, and vaginal epithelium was produced. The antibody binds to apical membranes of apical cells, particularly at the tips of microplicae. In subapical cells, the antibody binds to small cytoplasmic vesicles. Cultured human corneal epithelium produces H185 antigen. By immunoblot analysis, H185 binds a high molecular weight protein, > 205 kD, from corneal epithelium and cultured corneal epithelium. The protein band visualized by immunoblot analysis cannot be stained by Coomassie or silver stain on SDS-PAGE, but it does stain with Alcian blue followed by silver stain, indicating that the protein is highly glycosylated. H185 binding to blotted proteins is destroyed by sodium periodate treatment and O-glycanase incubation, suggesting that the epitope of H185 is an O-linked carbohydrate. CONCLUSION: Human corneal and conjunctival epithelia produce a molecule, similar in size, cellular localization, and distribution to the mucin-like glycoprotein of rat ocular surface epithelium. These data suggest that the entire ocular surface epithelium produces mucins for the tear film.

In vitro propagation of human ocular surface epithelial cells for transplantation.

PURPOSE: To examine the possibility that ocular surface epithelial cells might be grown in culture for use as grafts. METHODS: The proliferative capacity of epithelial cells cultured from the conjunctiva, limbus, and central cornea of normal human eyes was compared. Single cells disaggregated from approximately 1 mm2 biopsy specimens were serially cocultured with lethally irradiated mouse 3T3 fibroblasts. To study the cells' ability to reform a stratified epithelium, confluent limbal cultures were released as an intact cell sheet with the enzyme Dispase and transplanted to a dermal connective tissue bed in nude mice. Attachment and differentiation properties of the reconstituted epithelium were examined immunohistochemically. RESULTS: Central corneal epithelial cells could not be propagated; they senesced in first or second passage. In contrast, limbal epithelial cells exhibited a substantial (i.e., mean of 23 population doublings) and conjunctival cells a moderate (i.e., mean of 11 population doublings) proliferative capacity. Within 4 days of transplantation to the nude mouse dermis, cultured limbal epithelial cells formed an epithelium 5-6 cell layers thick. The epithelium adhered firmly to the graft bed, and deposition of the basement membrane and anchoring fibril protein collagens IV and VII and laminin was detectable immunohistochemically. The transplanted epithelium displayed limbuslike compartmental expression of keratins K3, K13, and K19, and of the enzyme enolase. CONCLUSIONS: These results support the concept that corneal epithelial stem cells are located in the limbus and indicate that cultured autologous limbal cells may function as grafts to permanently restore the corneal epithelium after severe ocular surface injury.

Multicenter evaluation of a kit for activated protein C resistance on various coagulation instruments using plasmas from healthy individuals. The APC Resistance Study Group.

Recently a new hemostatic disorder has been described which appears to be an important risk factor for familial thromboembolism. The disorder is characterized by a poor anticoagulant response to activated Protein C (APC) and has been shown to be due to lack of an APC cofactor activity which is a property of factor V. A kit for determining the response of plasma samples towards addition of APC in an APTT-based assay--COATEST APC Resistance-has been evaluated on 35 coagulation instruments in a multicenter study involving 32 laboratories. A lyophilized normal plasma and identical plasma aliquotes from 20 individuals, one of whom had a borderline resistance to APC, were analysed in each laboratory and the sensitivity of each plasma to APC was determined as the ratio between the clotting times obtained in the presence and absence of APC (APC ratio). The plasma from the individual with a borderline resistance to APC activity was correctly classified as the lowest responder in each laboratory, with an APC ratio in the range 1.6-2.4. In comparison, plasmas from individuals with a pronounced response to APC activity resulted in APC ratios above 3.4 in most cases. Interestingly, although the actual APT time for a plasma from a given individual showed a more than 10s difference due to the type of instrumentation used, the variation in the APC ratio was limited. A similar discrimination was also obtained from evaluation of the actual prolongation of the clotting time in the presence of APC.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological control of human polymorphonuclear leukocyte degranulation by fenamates and inhibitors of receptor-mediated calcium entry and protein kinase C.

The present work was designed to study the mechanism of inhibitory action of flufenamic and tolfenamic acids on the degranulation response of human polymorphonuclear leukocytes (PMNs). We have recently shown that fenamates inhibit PMN degranulation as well as other PMN functions at micromolar drug concentrations. However, the mechanism of their action remains unknown. To clarify this mechanism, the degranulation response was induced by agents known to activate different steps in the activation cascade in PMNs: the receptor-mediated activator fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine); a calcium ionophore (A23187); an inhibitor of calcium-ATPase (thapsigargin); and an activator of protein kinase C (phorbol myristate acetate, PMA). For comparison, SK&F 96365 (an inhibitor of receptor-mediated calcium entry), Ro 31-8220 (an inhibitor of protein kinase C) and ketoprofen (another cyclooxygenase inhibitor) were used. Flufenamic and tolfenamic acids inhibited A23187- and fMLP-induced degranulation in a dose-dependent manner. The thapsigargin-triggered response was reduced only slightly and that induced by PMA remained unaltered. The pattern of the inhibitory action of fenamates differed from those of Ro 31-8220 and ketoprofen. The action of fenamates resembled that of the inhibitor of receptor-mediated calcium entry, SK&F 96365, especially when A23187, fMLP or PMA were used to stimulate the cells. This prompted us to measure the effects of flufenamic and tolfenamic acids on receptor-mediated calcium entry. The two fenamates inhibited the fMLP-induced increase in intracellular free calcium in fura-2 loaded PMNs in the presence but not in the absence of extracellular calcium. The results suggest that the suppressive actions of fenamates on PMN degranulation are neither related to the activity of cyclooxygenase nor PMA-activated protein kinase C. In contrast, fenamates resemble the antagonist of receptor-mediated calcium entry, SK&F 96365, in their antagonistic action on PMN degranulation.

Immortalized cell lines from embryonic avian and murine otocysts: tools for molecular studies of the developing inner ear.

Recently, our studies have focused on genes expressed at the earliest stages of inner ear development. Our aim is to identify and characterize genes that are involved in determining the axes of the semicircular canals, in otic crest delamination and in early innervation of the inner ear. Many elegant studies of auditory development have been done in animal models. However, the need for large amounts of well-characterized embryonic material for molecular studies makes the development of otocyst cell lines with different genetic repertoires attractive. We have therefore derived immortalized otocyst cells from two of the most widely used animal models of ear development: avians and mice. Avian cell isolates were produced from quail otocysts (embryonic stage 19) that were transformed with temperature-sensitive variants of the Rous sarcoma virus (RSV). Among the individual transformed cells are those that produce neuron-like derivatives in response to treatment with 10(-9) M retinoic acid. Mammalian cell isolates were derived from otocysts, of 9 day (post coitus) embryos of the H2kbtsA58 transgenic mouse (Immortomouse), which carries a temperature-sensitive variant of the Simian Virus 40 Tumor antigen. The vast majority of cells of the Immortomouse are capable of being immortalized at 33 degrees C, the permissive temperature for transgene expression, in the presence of gamma-interferon. Several putative clones et these cells differentiated into neuron-like cells after temperature shift and withdrawal of gamma-interferon; another isolate of cells assumed a neuron-like morphology on exposure to brain-derived neurotrophic factor even at the permissive temperature. We describe also a cell isolate that expresses the Pax-2 protein product and two putative cell lines that express the protein product of the chicken equivalent of the Drosophila segmentation gene engrailed. These genes and their protein products are expressed in specific subpopulation of otocyst cells at early stages. Both mouse and quail immortalized cell lines will be used to study inner ear development at the molecular level.

Novel genes expressed in the chick otocyst during development: identification using differential display of RNA.

Differential display of mRNA is a technique that enables the researcher to compare genes expressed in two or more different tissues or in the same tissue or cell under different conditions. The method is based on polymerase chain reaction amplification and comparison of specific subsets of mRNA. We have used this method to clone partial complementary DNAs (cDNAs; amplicons) for genes expressed in the otocyst in order to identify genes that may be involved in development of the inner ear. A full length cDNA was isolated from an embryonic quail head library with an amplicon (KH121) obtained from the otocyst. This avian cDNA encoded a novel, 172-amino acid acidic protein and detected a major transcript of ca 0.8 kb in RNA from chick embryos and several neonatal chick tissues. The full length avian cDNA had high sequence identity to several human cDNAs (expressed sequence tags) from human fetal tissues, including cochlea, brain, liver/spleen and lung, and from placenta. The human homologue of the avian gene encoded a protein that was 183 amino acids long and had 75.6% amino acid sequence identity to the avian protein. These results identified both the avian and human homologues of an evolutionarily conserved gene encoding a small acidic protein of unknown function; however, expression of this gene was not restricted to otocysts.

In vitro studies on the effect of thromboxane receptor blockade on platelet deposition on vascular surfaces.

The efficacy of platelet inhibition by a thromboxane receptor antagonist (Bay U3405) and acetylsalicylic acid was investigated in vitro using a new perfusion system. Rabbit 51Cr-labeled platelets were suspended in saline as perfusate. Vascular grafts, PTFE or Dacron (precoated with blood or uncoated) as well as native aorta were perfused in vitro. Three sets of grafts (vessels) were perfused simultaneously with either acetylsalicylic acid (10(-5) M), Bay U3405 (10(-6) M) treated or untreated (control) labeled platelets. Platelet deposition on the grafts (vessels) was measured in a gamma counter. Values were normalised to graft weight or vessel surface area respectively and to the platelet concentration of perfusate. The results of these experiments indicated that thromboxane receptor inhibition was superior to cyclooxygenase blockade in preventing platelet deposition on synthetic grafts and native aorta vessels in vitro. Whether this is valid in vivo has to be confirmed.

Nitrendipine and mefruside in elderly hypertensives: effects on blood pressure, cardiac output, cerebral blood flow and metabolic parameters.

In this multicentre, randomised, double-blind, cross-over study, we evaluated and compared the effects of nitrendipine (a calcium entry blocker of the dihydropyridine group) and mefruside (a diuretic) on BP, cardiac output, cerebral blood flow and metabolic parameters in 22 elderly hypertensives. Eight weeks of treatment with nitrendipine (27.3 mg daily) and mefruside (30.7 mg daily) significantly reduced BP values to almost the same extent. Heart rate, cardiac output (n = 14), cerebral blood flow (n = 20), renin activity and aldosterone remained unchanged during nitrendipine and mefruside treatment. Nitrendipine did not alter any metabolic parameter (electrolytes, lipid values and blood glucose); in patients treated with mefruside serum potassium fell by 0.4 mmol/l (P < 0.001). Minor adverse events were reported in both treatment groups, mostly due to vasodilation. We conclude that both drugs possess potent and comparable haemodynamic and anti-hypertensive properties. They reduce BP by reducing total peripheral vascular resistance with maintained autoregulation of cerebral blood flow. The metabolic disturbances induced by mefruside seem to be less pronounced than that observed with other thiazide diuretics.

Comparative studies of DNA adduct formation in mice following dermal application of smoke condensates from cigarettes that burn or primarily heat tobacco.

A new cigarette (Eclipse) that primarily heats rather than burns tobacco has been developed. Since Eclipse primarily heats tobacco, the smoke chemistry is much simplified, consisting of 80% glycerol and water. With the simplified smoke chemistry, it would be expected that toxicological activity would be reduced. Smoke and smoke condensate from Eclipse have consistently yielded markedly reduced mutagenicity and cytotoxicity in in vitro tests when compared to smoke and smoke condensate from the 1R4F Kentucky reference cigarette, which is representative of typical low 'tar' cigarettes sold in the U.S. today. The objective of the present study was to evaluate the potential of mainstream cigarette smoke condensate (CSC) of Eclipse to produce DNA adducts in lung, heart and skin tissue of dermally-exposed mice and to compare the results with those obtained with CSC from the 1R4F Kentucky reference cigarette. CSC from Eclipse or 1R4F cigarettes was applied dermally to SENCAR mice three times a week for 30 weeks. Amounts of CSC applied were 30, 60 or 120 mg 'tar' per animal per week. Tissues were collected after 1, 4, 14 and 29 weeks of CSC application. DNA adducts were analyzed in lung, heart and skin tissues using the 32P-postlabeling method with P1 nuclease modification. Distinct time and dose-dependent diagonal radioactive zones (DRZ) were observed in the DNA from lung, heart and skin tissues of animals treated with 1R4F CSC. The relative adduct labeling (RAL) values of lung, heart and skin DNA from reference CSC-treated animals were significantly greater (p<0.05) than those of the solvent control animals. No corresponding DRZs were observed at any dose from the DNA of animals treated with CSC from Eclipse or solvent control (acetone) and the RAL values observed following application of Eclipse were not increased relative to the solvent control. These results provide additional evidence that the smoke condensate from the Eclipse cigarette is markedly less genotoxic than smoke condensate from tobacco-burning cigarettes representative of those currently sold in the U.S.

Comparison of sucrose-sucrose to sucrose-ethanol concurrent responding in the rat: reinforcement schedule and fluid concentration effects.

Rats maintained at 80% of their ad lib body weight were trained on a two bar concurrent fixed ratio 8-fixed ratio 8 schedule with sucrose solutions presented at schedule completion. When the solutions were available on the same schedule of reinforcement, rats consistently responded more on the lever associated with the higher sucrose concentration over either less concentrated sucrose solutions or water. However, when a preferred 20% sucrose solution was placed on a high fixed ratio requirement (FR64) and a less preferred 2% sucrose solution remained on the lower ratio requirement (FR8), the rats were observed to increase their responding on the lever associated with presentation of the 2% sucrose solution. Response rates for the low concentrated sucrose solution increased to levels comparable to those seen when that solution was paired with water. These results were compared to prior studies using ethanol and sucrose as the available fluids.