Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers

Background: Alcohol increases body iron stores. Alcohol and iron may increase oxidative stress and the risk of alcohol-related liver disease. The relationship between low or safe levels of alcohol use and indices of body iron stores, and the factors that affect the alcohol-iron relationship, have not been fully characterized. Other aspects of the biological response to alcohol use have been reported to depend on iron status. Methods: We have measured serum iron, transferrin, and ferritin as indices of iron stores in 3375 adult twin subjects recruited through the Australian Twin Registry. Information on alcohol use and dependence and smoking was obtained from questionnaires and interviews. Results: Serum iron and ferritin increased progressively across classes of alcohol intake. The effects of beer consumption were greater than those of wine or spirits. Ferritin concentration was significantly higher in subjects who had ever been alcohol dependent. There was no evidence of interactions between HFE genotype or body mass index and alcohol. Alcohol intake-adjusted carbohydrate-deficient transferrin was increased in women in the lowest quartile of ferritin results, whereas adjusted gamma -glutamyltransferase, aspartate aminotransferase, and alanine aminotransferase values were increased in subjects with high ferritin. Conclusions: Alcohol intake at low level increases ferritin and, by inference, body iron stores. This may be either beneficial or harmful, depending on circumstances. The response of biological markers of alcohol intake can be affected by body iron stores; this has implications for test sensitivity and specificity and for variation in biological responses to alcohol use.

Hormone physiology of pea mutants prevented from flowering by mutations gi or veg1

The veg1 (vegetative) mutant in pea (Pisum sativum L.) does not flower under any circumstances and gi (gigas) mutants remain vegetative under certain conditions. gi plants are deficient in production of floral stimulus, whereas veg1 plants lack a response to floral stimulus. During long days in particular, these non-flowering mutant plants eventually enter a stable compact phase characterised by a large reduction in internode length, small leaves and growth of lateral shoots from the upper-stem (aerial) nodes. The first-order laterals in turn produce second-order laterals and so on in a reiterative pattern. The apical bud is reduced in size but continues active growth. Endogenous hormone measurements and gibberellin application studies with gi-1, gi-2 and veg1 plants indicate that a reduction in gibberellin and perhaps indole-3-acetic acid level may account, at least partially, for the compact aerial shoot phenotype. In the gi-1 mutant, the compact phenotype is rescued by transfer from a 24- to an 8-h photoperiod. We propose that in plants where flowering is prevented by a lack of floral stimulus or an inability to respond, the large reduction in photoperiod gene activity during long days may lead to a reduction in apical sink strength that is manifest in an altered hormone profile and weak apical dominance.

Long-distance signaling and the control of branching in the rms1 mutant of peal

The ramosus (rms) mutation (rms1) of pea (Pisum sativum) causes increased branching through modification of graft-transmissible signal(s) produced in rootstock and shoot. Additional grafting techniques have led us to propose that the novel signal regulated by Rms1 moves acropetally in shoots and acts as a branching inhibitor. Epicotyl interstock grafts showed that wild-type (WT) epicotyls grafted between rms1 scions and rootstocks can revert mutant scions to a WT non-branching phenotype. Mutant scions grafted together with mutant and WT rootstocks did not branch despite a contiguous mutant root-shoot system. The primary action of Rms1 is, therefore, unlikely to be to block transport of a branching stimulus from root to shoot. Rather, Rms1 may influence a long-distance signal that functions, directly or indirectly, as a branching inhibitor. It can be deduced that this signal moves acropetally in shoots because WT rootstocks inhibit branching in rms1 shoots, and although WT scions do not branch when grafted to mutant rootstocks, they do not inhibit branching in rms1 cotyledonary shoots growing from the same rootstocks. The acropetal direction of transport of the Rms1 signal supports previous evidence that the rms1 lesion is not in an auxin biosynthesis or transport pathway. The different branching phenotypes of WT and rms1 shoots growing from the same rms1 rootstock provides further evidence that the shoot has a major role in the regulation of branching and, moreover, that root-exported cytokinin is not the only graft-transmissible signal regulating branching in intact pea plants.

Mutational analysis of branching in pea. Evidence that Rms1 and Rms5 regulate the same novel signal

The fifth increased branching ramosus (rms) mutant, rms5, from pea (Pisum sativum), is described here for phenotype and grafting responses with four other rms mutants. Xylem sap zeatin riboside concentration and shoot auxin levels in rms5 plants have also been compared with rms1 and wild type (WT). Rms1 and Rms5 appear to act closely at the biochemical or cellular level to control branching, because branching was inhibited in reciprocal epicotyl grafts between rms5 or rms1 and WT plants, but not inhibited in reciprocal grafts between rms5 and rmsl seedlings. The weakly transgressive or slightly additive phenotype of the rmsl rms5 double mutant provides further evidence for this interaction. Like rms1, rms5 rootstocks have reduced xylem sap cytokinin concentrations, and rms5 shoots do not appear deficient in indole-3-acetic acid or 4-chloroindole-3-acetic acid. Rms1 and Rms5 are similar in their interaction with other Rms genes. Reciprocal grafting studies with rmsl, rms2, and rms5, together with the fact that root xylem sap cytokinin concentrations are reduced in rms1 and rms5 and elevated in rms2 plants, indicates that Rms1 and Rms5 may control a different pathway than that controlled by Rms2. Our studies indicate that Rms1 and Rms5 may regulate a novel graft-transmissible signal involved in the control of branching.

Can long-distance dispersal be inferred from the New Zealand plant fossil record?

New Zealand is generally thought to have been physically isolated from the rest of the world for over 60 million years. But physical isolation may not mean biotic isolation, at least on the time scale of millions of years. Are New Zealand's present complement of plants the direct descendants of what originally rafted from Gondwana? Or has there been total extinction of this initial flora with replacement through long-distance dispersal (a complete biotic turnover)? These are two possible extremes which have come under recent discussion. Can the fossil record be used to decide the relative importance of the two endpoints, or is it simply too incomplete and too dependent on factors of chance? This paper suggests two approaches to the problem-the use of statistics to apply levels of confidence to first appearances in the fossil record and the analysis of trends based on the entire palynorecord. Statistics can suggest that the first appearance of a taxon was after New Zealand broke away from Gondwana-as long as the first appearance in the record was not due to an increase in biomass from an initially rare state. Two observations can be drawn from the overall palynorecord that are independent of changes in biomass: (1) The first appearance of palynotaxa common to both Australia and New Zealand is decidedly non-random. Most taxa occur first in Australia. This suggests a bias in air or water transport from west to east. (2) The percentage of endemic palynospecies in New Zealand shows no simple correlation with the time New Zealand drifted into isolation. The conifer macrorecord also hints at complete turnover since the Cretaceous.

Deciding who has the right to vote: A comparative analysis of election laws

The paper analyses seven potential restrictions to the right to vote in 63 democracies. Only two of these restrictions have given rise to a near consensus. An overwhelming majority of democracies have decided that the minimum voting age should be 18 and that the right to vote of mentally deficient people should be restricted. There is little consensus about whether the right to vote should be restrcited to citizens, about whether there should be country or electoral district residence requirements, about which electors residing abroad (if any) should retain their right to vote and about which prison inmates (if any) should have the right to vote. The paper also examines two factors that affect right to vote laws: British colonialism and level of political rights. The pattern found with respect to electoral systems, whereby former British colonies emulate their former ruler, is less systematic in the case of right to vote legislation. Finally, “strong” democracies are slightly more inclusive than “weak” ones when deciding who has the right to vote.

Canopy carbon and oxygen isotope composition of 9-year-old hoop pine families in relation to seedling carbon isotope composition, growth, field growth performance, and canopy nitrogen concentration

Carbon isotope composition (delta C-13), oxygen isotope composition (delta O-18), and nitrogen concentration (N-mass) of branchlet tissue at two canopy positions were assessed for glasshouse seedlings and 9-year-old hoop pine (Araucaria cunninghamii Ait. ex D. Don) trees from 22 open-pollinated families grown in 5 blocks of a progeny test at a water-limited and nitrogen-deficient site in southeastern Queensland, Australia. Significant variations in canopy delta C-13, delta O-18, and N-mass existed among the 9-year-old hoop pine families, with a heritability estimate of 0.72 for branchlet delta C-13 from the upper inner canopy position. There was significant variation in canopy delta C-13 of glasshouse seedlings between canopy positions and among the families, with a heritability estimate of 0.66. The canopy delta C-13 was positively related to canopy N-mass only for the upper outer crown in the field (R = 0.62, p < 0.001). Phenotypic correlations existed between tree height and canopy delta C-13 (R = 0.37-0.41, p < 0.001). Strong correlations were found between family canopy delta C-13 at this site and those at a wetter site and between field canopy delta C-13 and glasshouse seedling delta C-13. The mechanisms of the variation in canopy delta C-13 are discussed in relation to canopy photosynthetic capacity as reflected in the N-mass and stomatal conductance as indexed by canopy delta O-18.

Emotional distress induced rhabdomyolysis in an individual with carnitine palmitolytransferase deficiency

A 48-year-old male patient with underlying CPT II enzyme deficiency is described. Emotional stress appeared to precipitate recurrent myalgias, rhabdomyolysis and reversible renal impairment over a 40-year period. Our search of the English literature indicates this to be the first time that the emotional stress has been documented to precipitate the CPT II syndrome. Although the pathogenesis of this syndrome has yet to be established, existing knowledge is briefly reviewed and the likely metabolic and neuroendocrine mechanisms which link emotional stress to muscle metabolism are examined. These mechanisms influence the extent of lipolysis or glycolysis that occurs during the process of muscle ATP generation. It is suggested that neuroendocrine and other stress related changes which favour lipolysis over glycolysis adversely effect muscle energy metabolism in patients whose mitochondria are deficient in CPT II enzyme. Possible treatment strategies are those that favour glycolysis over fatty acid metabolism and include a variety of ways of modulating sympathetic and parasympathetic tone. The use of carbohydrate supplementation P-blockers and anxiolytic agents is discussed.

Cross-talk between caveolae and glycosylphosphatidylinositol-rich domains

Most mammalian cells have in their plasma membrane at least two types of lipid microdomains, non-invaginated lipid rafts and caveolae. Glycosylphosphatidylinositol (GPI)-anchored proteins constitute a class of proteins that are enriched in rafts but not caveolae at steady state. We have analyzed the effects of abolishing GPI biosynthesis on rafts, caveolae, and cholesterol levels. GPI-deficient cells were obtained by screening for resistance to the pore-forming toxin aerolysin, which uses this class of proteins as receptors. Despite the absence of GPI-anchored proteins, mutant cells still contained lipid rafts, indicating that GPI-anchored proteins are not crucial structural elements of these domains. Interestingly, the caveolae-specific membrane proteins, caveolin-1 and 2, were up-regulated in GPI-deficient cells, in contrast to flotillin-I and GM1, which were expressed at normal levels. Additionally, the number of surface caveolae was increased. This effect was specific since recovery of GPI biosynthesis by gene recomplementation restored caveolin expression and the number of surface caveolae to wild type levels. The inverse correlation between the expression of GPI-anchored proteins and caveolin-1 was confirmed by the observation that overexpression of caveolin-1 in wild type cells led to a decrease in the expression of GPI-anchored proteins. In cells lacking caveolae, the absence of GPI-anchored proteins caused an increase in cholesterol levels, suggesting a possible role of GPI-anchored proteins in cholesterol homeostasis, which in some cells, such as Chinese hamster ovary cells, can be compensated by caveolin up-regulation.

The pathogenesis of oral lichen planus

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.

Excited to death: different ways to lose your neurones

The selective loss of neurones in a range of neurodegenerative diseases is widely thought to involve the process of excitotoxicity, in which glutamate-mediated neuronal killing is elaborated through the excessive stimulation of cell-surface receptors. Every such disease exhibits a distinct regional and subregional pattern of neuronal loss. so processes must be locally triggered to different extents to account for this. We have studied several mechanisms which could lead to excitotoxic glutamate pathophysiology and compared them in different diseases. Our data suggest that glutamate can reach toxic extracellular levels in Alzheimer disease by malfunctions in cellular transporters, and that the toxicity may be exacerbated by continued glutamate release from presynaptic neurones acting on hypersensitive postsynaptic receptors. Thus the excitotoxicity is direct. In contrast, alcoholic brain damage arises in regions where GABA-mediated inhibition is deficient, and fails properly to dampen trans-synaptic excitation, Thus the excitotoxicity is indirect. A variety of such mechanisms is possible, which may combine in different ways.

Expression of a truncated Brca1 protein delays lactational mammary development in transgenic mice

To address the hypothesis that certain disease-associated mutants of the breast-ovarian cancer susceptibility gene BRCA1 have biological activity in vivo, we have expressed a truncated Brca1 protein (trBrca1) in cell-lines and in the mammary gland of transgenic mice. Immunofluorescent analysis of transfected cell-lines indicates that trBRCA1 is a stable protein and that it is localized in the cell cytoplasm. Functional analysis of these cell-lines indicates that expression of trBRCA1 confers an increased radiosensitivity phenotype on mammary epithelial cells, consistent with abrogation of the BRCA1 pathway. MMTV-trBrca1 transgenic mice from two independent lines displayed a delay in lactational mammary gland development, as demonstrated by altered histological profiles of lobuloalveolar structures. Cellular and molecular analyses indicate that this phenotype results from a defect in differentiation, rather than altered rates of proliferation or apoptosis. The results presented in this paper are consistent with trBrca1 possessing dominant-negative activity and playing an important role in regulating normal mammary development. They may also have implications for germline carriers of BRCA1 mutations.

GH treatment in adults with chronic liver disease: A randomized, double-blind, placebo-controlled, cross-over study

Patients with chronic liver disease (CLD) are catabolic and GH-resistant. The effects of supraphysiological recombinant human GH (rhGH; 0.2 IU.kg(-1).d(-1)) treatment in adults with CLD were assessed in a randomized, double-blind, placebo-controlled cross-over trial (4-wk dietary run-in, 4-wk treatment, and 2-wk wash-out phases). Nine adults with mild- to moderate-severity CLD participated (median age, 49 yr; three males and six females; Child's classification A in six and B in three). Biopsy-proven etiologies were: alcohol (four patients), primary biliary cirrhosis (three patients), non-A, non-B, non-C hepatitis (one patient), and cryptogenic (one patient). Treatment with rhGH increased serum IGF-I (median increase over placebo, +93 mug.liter(-1); P = 0.004), IGF-binding protein-3 (+0.9 mg.liter(-1): P = 0.004), and acid labile subunit (+10.7 nM; P = 0.004). Total body potassium (+8.0 g; P = 0.023), body weight (+1.6 kg; P = 0.008), and total body water (by bioelectrical impedance; +4.9 kg; P = 0.004) increased. Resting metabolic rate (+313 ml.kg(-1).min(-1); P = 0.004) and lipid oxidation (+1072.0 kcal.d(-1); P = 0.032) increased. Metabolic changes included increased fasting plasma glucose (+1.2 mm; P = 0.008), insulin (+33.8 mU.liter(-1); P = 0.004), C-peptide (+0.7 nM; P = 0.004), and free-fatty acids (+0.1 mEq.liter(-1); P = 0.04). Clinical side effects included worsening edema and ascites. Hepatocellular function did not change. Therefore, rbGH treatment in CLD: 1) overcame hepatic GH resistance; 2) may have improved whole-body protein catabolism; 3) increased lipolysis and lipid oxidation; 4) increased insulin resistance; and 5) had potent antinatriuretic effects. Long-term safety and efficacy require further assessment.

CDT, GGT, and AST as markers of alcohol use: The WHO/ISBRA Collaborative Project

Background: Estimates of the performance of carbohydrate deficient transferrin (CDT) and gamma glutamyltransferase (GGT) as markers of alcohol consumption have varied widely. Studies have differed in design and subject characteristics. The WHO/ISBRA Collaborative Study allows assessment and comparison of CDT, GGT, and aspartate aminotransferase (AST) as markers of drinking in a large, well-characterized, multicenter sample. Methods: A total of 1863 subjects were recruited from five countries (Australia, Brazil, Canada, Finland, and Japan). Recruitment was stratified by alcohol use, age, and sex. Demographic characteristics, alcohol consumption, and presence of ICD-10 dependence were recorded using an interview schedule based on the AUDADIS, CDT was assayed using CDTect(TM) and GGT and AST by standard methods. Statistical techniques included receiver operating characteristic (ROC) analysis. Multiple regression was used to measure the impact of factors other than alcohol on test performance. Results: CDT and GGT had comparable performance on ROC analysis, with AST performing slightly less well. CDT was a slightly but significantly better marker of high-risk consumption in men. All were more effective for detection of high-risk rather than intermediate-risk drinking. CDT and GGT levels were influenced by body mass index, sex, age, and smoking status. Conclusions: CDT was little better than GGT in detecting high- or intermediate-risk alcohol consumption in this large, multicenter, predominantly community-based sample. As the two tests are relatively independent of each other, their combination is likely to provide better performance than either test alone, Test interpretation should take account sex, age. and body mass index.

Effects of vitamin E deficiency on fatigue and muscle contractile properties

Radical-mediated oxidative damage of skeletal muscle membranes has been implicated in the fatigue process. Vitamin E (VE) is a major chain breaking antioxidant that has been shown to reduce contraction-mediated oxidative damage. We hypothesized that VE deficiency would adversely affect Muscle contractile function, resulting in a more rapid development of muscular fatigue during exercise. To test this postulate, rats were fed either a VE-deficient (EDEF) diet or a control (CON) diet containing VE. Following a 12-week feeding period, animals were anesthetized and mechanically ventilated. Muscle endurance (fatigue) and contractile properties were evaluated using an in situ preparation of the tibialis anterior (TA) muscle. Contractile properties of the TA muscle were determined before and after a fatigue protocol. The muscle fatigue protocol consisted of 60 min of repetitive contractions (250 ms trains at 15 Hz; duty cycle = I I %) of the TA muscle. Prior to the fatigue protocol, no significant differences existed in the force-frequency curves between EDEF and CON animals. At the completion of the fatigue protocol, muscular force production was significantly (P