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At least 739 records · Page 41Linked to original sources
PubMed2003

Antifungal activity of amiodarone is mediated by disruption of calcium homeostasis.

The antiarrhythmic drug amiodarone was recently demonstrated to have novel broad range fungicidal activity. We provide evidence that amiodarone toxicity is mediated by disruption of Ca2+ homeostasis in Saccharomyces cerevisiae. In mutants lacking calcineurin and various Ca2+ transporters, including pumps (Pmr1 and Pmc1), channels (Cch1/Mid1 and Yvc1), and exchangers (Vcx1), amiodarone sensitivity correlates with cytoplasmic calcium overload. Measurements of cytosolic Ca2+ by aequorin luminescence demonstrate a biphasic response to amiodarone. An immediate and extensive calcium influx was observed that was dose-dependent and correlated with drug sensitivity. The second phase consisted of a sustained release of calcium from the vacuole via the calcium channel Yvc1 and was independent of extracellular Ca2+ entry. To uncover additional cellular pathways involved in amiodarone sensitivity, we conducted a genome-wide screen of nearly 5000 single-gene yeast deletion mutants. 36 yeast strains with amiodarone hypersensitivity were identified, including mutants in transporters (pmr1, pdr5, and vacuolar H+-ATPase), ergosterol biosynthesis (erg3, erg6, and erg24), intracellular trafficking (vps45 and rcy1), and signaling (ypk1 and ptc1). Of three mutants examined (vps45, vma3, and rcy1), all were found to have defective calcium homeostasis, supporting a correlation with amiodarone hypersensitivity. We show that low doses of amiodarone and an azole (miconazole, fluconazole) are strongly synergistic and exhibit potent fungicidal effects in combination. Our findings point to the potentially effective application of amiodarone as a novel antimycotic, particularly in combination with conventional antifungals.

Amiodarone↗
PubMed2003

Glucose metabolism and energy homeostasis in mouse hearts overexpressing dominant negative alpha2 subunit of AMP-activated protein kinase.

AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that plays a pivotal role in regulating cellular metabolism for sustaining energy homeostasis under stress conditions. Activation of AMPK has been observed in the heart during acute and chronic stresses, but its functional role has not been completely understood because of the lack of effective activators and inhibitors of this kinase in the heart. We generated transgenic mice (TG) with cardiac-specific overexpression of a dominant negative mutant of the AMPK alpha2 catalytic subunit to clarify the functional role of this kinase in myocardial ischemia. In isolated perfused hearts subjected to a 10-min ischemia, AMPK alpha2 activity in wild type (WT) increased substantially (by 4.5-fold), whereas AMPK alpha2 activity in TG was similar to the level of WT at base line. Basal AMPK alpha1 activity was unchanged in TG and increased normally during ischemia. Ischemia stimulated a 2.5-fold increase in 2-deoxyglucose uptake over base line in WT, whereas the inactivation of AMPK alpha2 in TG significantly blunted this response. Using 31P NMR spectroscopy, we found that ATP depletion was accelerated in TG hearts during no-flow ischemia, and these hearts developed left ventricular dysfunction manifested by an early and more rapid increase in left ventricular end-diastolic pressure. The exacerbated ATP depletion could not be attributed to impaired glycolytic ATP synthesis because TG hearts consumed slightly more glycogen during this period of no-flow ischemia. Thus, AMPK alpha2 is necessary for maintaining myocardial energy homeostasis during ischemia. It is likely that the functional role of AMPK in myocardial energy metabolism resides both in energy supply and utilization.

AMP-Activated Protein Kinases↗
PubMed2003

The Saccharomyces cerevisiae high affinity phosphate transporter encoded by PHO84 also functions in manganese homeostasis.

In the bakers' yeast Saccharomyces cerevisiae, high affinity manganese uptake and intracellular distribution involve two members of the Nramp family of genes, SMF1 and SMF2. In a search for other genes involved in manganese homeostasis, PHO84 was identified. The PHO84 gene encodes a high affinity inorganic phosphate transporter, and we find that its disruption results in a manganese-resistant phenotype. Resistance to zinc, cobalt, and copper ions was also demonstrated for pho84Delta yeast. When challenged with high concentrations of metals, pho84Delta yeast have reduced metal ion accumulation, suggesting that resistance is due to reduced uptake of metal ions. Pho84p accounted for virtually all the manganese accumulated under metal surplus conditions, demonstrating that this transporter is the major source of excess manganese accumulation. The manganese taken in via Pho84p is indeed biologically active and can not only cause toxicity but can also be incorporated into manganese-requiring enzymes. Pho84p is essential for activating manganese enzymes in smf2Delta mutants that rely on low affinity manganese transport systems. A role for Pho84p in manganese accumulation was also identified in a standard laboratory growth medium when high affinity manganese uptake is active. Under these conditions, cells lacking both Pho84p and the high affinity Smf1p transporter accumulated low levels of manganese, although there was no major effect on activity of manganese-requiring enzymes. We conclude that Pho84p plays a role in manganese homeostasis predominantly under manganese surplus conditions and appears to be functioning as a low affinity metal transporter.

Carrier Proteins↗
PubMed2003

The modifier subunit of Drosophila glutamate-cysteine ligase regulates catalytic activity by covalent and noncovalent interactions and influences glutathione homeostasis in vivo.

Glutamate-cysteine ligase (GCL) has a key influence on glutathione homeostasis. It has been proposed that mammalian GCL is regulated by the redox environment, and we show here that cysteine residues in the Drosophila melanogaster GCL modifier subunit (DmGCLM) can form covalent interactions with the catalytic subunit (DmGCLC) and modify its activity. Candidate components of intersubunit disulfides (Cys213, Cys214, and Cys267) were identified using matrix-assisted laser desorption ionization time-of-flight spectroscopy of iodoacetamide-modified DmGCLM as well as examination of the evolutionary conservation of cysteines. Mutation of the 3 cysteine residues allowed DmGCLM to associate with DmGCLC, but inhibited the formation of intersubunit disulfides. This caused a 2-fold reduction in the catalytic efficiency of Drosophila GCL, although activity remained significantly higher than the catalytic subunit alone. The cysteine mutant was also more sensitive to inhibition by glutathione than the unmodified holoenzyme. Notably, human GCLM could substitute for DmGCLM in modification of DmGCLC activity. The role of DmGCLM in vivo was examined by analysis of a Drosophila mutant (l(3)L0580) containing a P-element insertion in Gclm. We found that the P-element is not responsible for the lethal phenotype and separated the recessive lethal mutation from the P-element by recombination. This yielded two fully viable and fertile recombinants bearing the P-element insertion, which Western and Northern blotting indicated is a severely hypomorphic allele of Gclm. Glutathione levels were approximately 2-fold lower in the GclmL0580 mutants than in control strains, demonstrating the importance of DmGCLM in the regulation of glutathione homeostasis in vivo.

Animals↗
PubMed2004

Critical role of calbindin-D28k in calcium homeostasis revealed by mice lacking both vitamin D receptor and calbindin-D28k.

Calbindin (CaBP)-D28k and CaBP-D9k are cytosolic vitamin D-dependent calcium-binding proteins long thought to play an important role in transepithelial calcium transport. However, recent genetic studies suggest that CaBP-D28k is not essential for calcium metabolism. Genetic ablation of this gene in mice leads to no calcemic abnormalities. Genetic inactivation of the vitamin D receptor (VDR) gene leads to hypocalcemia, secondary hyperparathyroidism, rickets, and osteomalacia, accompanied by 90% reduction in renal CaBP-D9k expression but little change in CaBP-D28k. To address whether the role of CaBP-D28k in calcium homeostasis is compensated by CaBP-D9k, we generated VDR/CaBP-D28k double knockout (KO) mice, which expressed no CaBP-D28k and only 10% of CaBP-D9k in the kidney. On a regular diet, the double KO mice were more growth-retarded and 42% smaller in body weight than VDRKO mice and died prematurely at 2.5-3 months of age. Compared with VDRKO mice, the double KO mice had higher urinary calcium excretion and developed more severe secondary hyperparathyroidism and rachitic skeletal phenotype, which were manifested by larger parathyroid glands, higher serum parathyroid hormone levels, much lower bone mineral density, and more distorted growth plate with more osteoid formation in the trabecular region. On high calcium, high lactose diet, blood-ionized calcium levels were normalized in both VDRKO and the double KO mice; however, in contrast to VDRKO mice, the skeletal abnormalities were not completely corrected in the double KO mice. These results directly demonstrate that CaBP-D28k plays a critical role in maintaining calcium homeostasis and skeletal mineralization and suggest that its calcemic role can be mostly compensated by CaBP-D9k.

Animals↗
PubMed2004

Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis.

Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.

Animals↗
PubMed2006

Growth yield homeostasis in respiring yeast is due to a strict mitochondrial content adjustment.

In living cells, growth is the result of coupling between substrate catabolism and multiple metabolic processes taking place during net biomass formation and cell property maintenance. A crucial parameter for growth description is its yield, i.e. the efficiency of the transformation from substrate consumption to biomass formation. Using numerous yeast strains growing on different respiratory media, we have shown that the growth yield is identical regardless of the strain, growth phase, and respiratory substrate used. This homeostasis is the consequence of a strict linear relationship between growth and respiratory rates. Moreover, in all conditions tested, the oxygen consumption rate was strictly controlled by the cellular content of respiratory chain compounds in such a way that, in vivo, the steady state of oxidative phosphorylation was kept constant. Thus, the growth yield homeostasis depends on the tight adjustment of the cellular content of respiratory chain compounds to the growth rate. Any process leading to a defect in this adjustment allows an energy waste and consequently an energy yield decrease.

Adenosine Triphosphate↗
PubMed2006

A Mitogen-activated protein kinase kinase kinase mediates reactive oxygen species homeostasis in Arabidopsis.

Mitogen-activated protein kinase kinase kinases (MAPKKKs) play key roles in intra- and extracellular signaling in eukaryotes. Here we report that the MAPKKK MEKK1 regulates redox homeostasis in Arabidopsis. We show that MEKK1-deficient plants are misregulated in the expression of a number of genes involved in cellular redox control and accumulate reactive oxygen species (ROS). Most strikingly, homozygous mekk1 mutant plants exhibit a lethal phenotype when developing true leaves. MEKK1 kinase activity and protein stability was regulated by H(2)O(2) in a proteasome-dependent manner and mekk1 plants were compromised in ROS-induced MAPK MPK4 activation. Whereas mpk3 and mpk6 knock out plants showed no defects in development or changes in redox control genes, mpk4 null mutant shared several phenotypic and transcript profile features with mekk1 plants. In agreement with the concept that ROS negatively regulates auxin responses in plants, mekk1 and mpk4 mutants show reduced expression of several auxin-inducible marker genes. Overall, our data defines MPK4 as downstream target of MEKK1 and show that MEKK1 functions in integrating ROS homeostasis with plant development and hormone signaling.

Arabidopsis↗
PubMed1985

Intestinal absorption of sorbitol and effects of its acute administration on glucose homeostasis in normal rats.

Intestinal absorption of sorbitol was studied in a duodeno-jejunal loop of anaesthetized rats. The acute effects of exogenous sorbitol on glucose homeostasis were also evaluated in male and female rats. In the presence of lumen concentrations of sorbitol ranging from 1 microM to 200 mM, a fairly constant low percentage (about 12%) of the loop's contents was absorbed after 30 min. This amount increased only slightly with time, but this was not due to sorbitol accumulation in the mucosal layer of the loop. 3-O-methylglucose was absorbed much more quickly than sorbitol, but did not interfere with sorbitol absorption. The latter was not impaired by omission of lumen sodium ions nor by phloridzin, both of which inhibited 3-O-methylglucose absorption. Gastric administration of sorbitol did not affect plasma glucose or insulin levels. Glucose or sucrose administration caused a similar rise in plasma glucose, but the increase in plasma insulin levels was larger after glucose than after sucrose administration. Intravenous administration of sorbitol slightly increased plasma glucose and insulin levels. These changes were, however, considerably smaller than those occurring after glucose administration. In the normal rat, intestinal absorption of sorbitol is passive and proceeds at a low rate. Acute oral administration of sorbitol does not affect glucose homeostasis, which is only slightly disturbed by a large intravenous load of sorbitol.

3-O-Methylglucose↗
PubMed2005

Rats treated with oleoyl-oestrone maintain glucidic homeostasis: comparisons with a pair-fed model.

To determine whether or not the weight (and fat) loss induced by oleoyl-oestrone treatment results only as a consequence of decreased food intake, we compared treated animals with a pair-fed model. To this end, Wistar female rats received daily oral gavages of 10 mumol/kg per d oleoyl-oestrone in sunflower oil, or vehicle alone for 10 or 20 d. A second group of rats received the gavage of sunflower oil and the same amount of food ingested as the oleoyl-oestrone-treated animals (pair-fed group). Rats treated with oleoyl-oestrone maintained glucidic metabolism homeostasis despite a marked decrease in adipose tissue weight (P<0.001). Pair-fed rats exhibited a different pattern, comparable to short-term starvation, with greatly decreased glycogen stores (P<0.0001). The most significant effects were detected in the 10 d period groups. Oleoyl-oestrone affected the activity of the ponderostat system not only by decreasing appetite but also by modifying energy partition: treated animals maintained their glucose and energy homeostasis despite decreased food intake and the massive depletion of lipid stores.

3-Hydroxybutyric Acid↗
PubMed1999

The effect of inactivity on dietary intake and energy homeostasis.

Reduced physical activity commonly occurs in patients with disease or chronic disabilities, in the elderly, and in certain patients with obesity. Surprisingly, information on the effect of inactivity on energy homeostasis is scarce and often difficult to interpret. In models of reduced physical activity, such as space flights, bed-rest and confinement, subjects frequently lose weight (< 5%), predominantly in the form of fat-free mass. In some cases this is compensated by an increase in fat mass, which means that changes in weight are poor indicators of energy balance. The extent to which spontaneous reduction in energy intake (in most studies energy intake is fixed) compensates or overcompensates for the reduction in energy expenditure (mainly physical activity and to a small extent in BMR, typically < 6%) is largely underexamined. Preliminary observations suggesting that there is a preferential selection of low-energy-dense foods (low in fat) require confirmation under carefully controlled experimental conditions. It is concluded that a comprehensive and systematic evaluation is needed to address the effects and relevance of various degrees of physical inactivity to energy homeostasis, in relation to disease and space medicine.

Anorexia↗
PubMed2005

Biochemical homeostasis and body growth are reliable end points in clinical nutrition trials.

Studies of biochemical homeostasis and/or body growth have been included as outcome variables in most nutrition trials in paediatric patients. Moreover, these outcome variables have provided important insights into the nutrient requirements of infants and children, and continue to do so. Examples of the value of such studies in improving parenteral nutrition, in defining essential fatty acid metabolism and requirements of infants and in defining the protein and energy needs of low-birth-weight infants are discussed. Data from such studies have helped to define the mechanism of metabolic acidosis and hyperammonaemia associated with the use of early crystalline amino acid mixture and, hence, how to prevent these disorders. Such studies have allowed the development of parenteral amino acid mixtures that circumvent grossly abnormal plasma concentrations of most amino acids and appear to be utilized more efficiently. These studies have also helped define micronutrient requirements, including requirements for several such nutrients that had not been previously recognized as essential (e.g. Cr, Se, Mo, alpha-linolenic acid). Studies of body growth have been particularly valuable in defining the nutritional requirements of low-birth-weight infants. Finally, studies of metabolic homeostasis coupled with more sophisticated metabolic studies have provided considerable insight into the metabolism of the essential fatty acids, linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3). Although such studies have not defined the amount of the longer-chain PUFA synthesized from each of these essential fatty acids, i.e. arachidonic acid (20:4n-6) and DHA (22:6n-3), they have shown that the rates of conversion are extremely variable from infant to infant, suggesting a possible explanation of why some studies show developmental advantages from intake of these fatty acids while others do not.

Energy Metabolism↗
PubMed2000

Altered calcium homeostasis and membrane destabilization in erythrocytes of hamsters infected with Leishmania donovani.

Homeostatic mechanisms regulating intracellular concentrations of Ca2+ at a low level are prerequisites for maintaining the integral and cytoskeletal structure of erythrocytes under normal physiological conditions. The present study was undertaken to assess the contribution of Ca2+ homeostasis in modifying red-cell stability in hamsters, during the anaemia caused by Leishmania donovani. Erythrocytes from the infected animals became increasingly fragile as infection progressed. This fragility may be the result of a gradual change in membrane permeability, as indicated by enhanced uptake of 45Ca2+. The increase in cytosolic Ca2+ and decrease in membrane-bound Ca2+ observed indicate the release of Ca2+ from the membrane store, leading to [Ca2+]i accumulation in the later stages of the post-infection period. Decline in the efficacy of Ca(2+)-effluxing enzyme may also contribute to the enhanced [Ca2+]i level, with subsequent degradation of membrane proteins in the erythrocytes of the infected animals. Marked inhibition of proteolytic degradation by the Ca(2+)-dependent thiol protease inhibitor leupeptin, with concomitant thiol depletion, indicates the involvement of Ca(2+)-induced thiol protease in the observed degradation of membrane proteins. The results indicate that an altered Ca2+ homeostasis in erythrocytes following leishmanial infection causes enhanced cellular accumulation of Ca2+, which in turn may lead to haemolysis in experimental visceral leishmaniasis.

Animals↗
PubMed1997

Dose-dependent effect of octreotide on nitrogen retention and glucose homeostasis in response to endotoxemia in parenterally fed rats.

OBJECTIVE: This study compared the effect of different doses of octreotide on glucose and protein homeostasis in rats receiving concomitant lipopolysaccharide and parenteral nutrition infusions. METHODS: Sixty-six male Sprague Dawley rats (185 to 220 g) were randomized to receive parenteral nutrition only (PN), PN plus continuous infusion of Escherichia coli 026:B6 lipopolysaccharide at 6 mg/kg/day (LPS), PN plus LPS plus octreotide at 10 micrograms/kg/day (LPS + Oct 10), 100 micrograms/kg/day (LPS + Oct 100), or 1000 micrograms/kg/day (LPS + Oct 1000) for 48 hours. Prior to randomization all animals received isocaloric and isonitrogenous PN (170 kcal/kg/day as glucose and 1.1 g N/kg/day) and were kept nil per os except for water ad libitum. Nitrogen balance, urinary 3-methylhistidine/creatinine ratio, serum glucose concentration, and incidence of glycosuria were compared between groups. Serum urea nitrogen (SUN) changes were incorporated into the cumulative 48 hour nitrogen balance. ANOVA, Duncan's multiple range test, and Fisher's Exact Test were used for statistical analysis. RESULTS: Nitrogen balance (mg/48 hours) was significantly lower in all four groups receiving LPS +/- Oct when compared to the control group receiving PN alone. SUN (mg/dL) was significantly higher in all four groups receiving LPS +/- Oct when compared to control. There were no statistically significant differences in nitrogen balance or SUN among the four groups receiving LPS +/- Oct. The ratio of urinary 3-methylhistidine/ creatinine was significantly higher in the LPS + Oct 1000 group compared to the PN group (0.77 +/- 0.37 vs. 0.42 +/- 0.24, p < 0.05). Serum glucose concentrations and incidence of glycosuria among the five groups were not significantly different. CONCLUSIONS: Endotoxin significantly reduces nitrogen balance compared to controls fed PN. Octreotide does not significantly improve nitrogen retention or glucose homeostasis in endotoxemic parenterally fed rats.

Animals↗
PubMed2000

The interaction between dietary fructose and magnesium adversely affects macromineral homeostasis in men.

OBJECTIVE: Studies with rats have found that an interaction between fructose and magnesium affects macromineral metabolism; high dietary fructose significantly increased kidney calcification in both male and female rats, particularly when dietary magnesium was low. This study tests the hypothesis that an interaction between dietary fructose and magnesium adversely affects macromineral homeostasis in men. METHODS: Eleven men aged 22 to 40 years were fed a mixed, Western diet for four 42-day dietary periods in which dietary magnesium was either approximately 170 or 370 mg/day and dietary fructose was either 4% or 20% of energy. A decaffeinated beverage containing high fructose corn syrup replaced cornstarch, bread and rice in the low fructose diet to give the high fructose diet. RESULTS: High dietary fructose significantly (p<0.01) increased magnesium balance during both low and high dietary magnesium intakes. Ultrafilterable and ionized serum magnesium also apparently were related to magnesium and fructose intakes; they were higher when fructose was fed and when Mg intakes were high. High fructose depressed calcium balance: the effect tended to be more marked when dietary Mg was low. High dietary fructose also significantly (p<0.005) decreased phosphorous balance. Urinary phosphorous losses were significantly (p<0.001) higher when high dietary fructose was fed. High dietary fructose also increased the concentration of serum alkaline phosphatase (p<0.005). CONCLUSION: These findings indicate that dietary fructose adversely affects macromineral homeostasis in humans and suggest further studies to see if a high fructose diet coupled with low dietary magnesium and marginal calcium leads to bone loss.

Adult↗
PubMed1998

Potassium homeostasis: ontogenic aspects.

Potassium is the most abundant intracellular cation and plays an important role in a variety of cell functions. Potassium regulation and homeostasis during infancy are, owing to growth and development, different from in later life: infants need to retain more K+ than adults, to avoid growth retardation. Since the K+ requirements are different in infants and in adults, the mechanisms regulating K+ homeostasis also need to be different. This paper includes a review of the literature concerning the regulation of internal and external K+ balances during ontogeny. We examined the role of gastrointestinal tract, kidney and some tissue stores in K+ excretion and distribution during development. We conclude that positive K+ balance in infancy is characterized by higher K+ absorption in gut, lower K+ secretion/excretion in kidney and immaturity of the mechanisms regulating intra/extracellular K+ distribution. Several factors contribute to maintain the positive K+ balance. They include higher expression of absorptive transporters in colon and probably in kidney, lower expression of secretive transporters in colon and kidney, lower renal K+ excretion following K+ loading, immaturity of hepato-renal K+ reflex mechanism, immaturity of tissue K+ binding/releasing capacity and immaturity of the neuro-hormonal control of K+ transport in several organs.

Absorption↗
PubMed1998

Antihypertensive treatment with candesartan cilexetil does not affect glucose homeostasis or serum lipid profile in patients with mild hypertension and type II diabetes.

This multicentre, randomized, controlled clinical trial assessed the effects of candesartan cilexetil (cand.cil.), a novel angiotensin II antagonist selective for the AT1 receptor with long-lasting antihypertensive activity, compared to placebo on glucose homeostasis and serum lipid profile in mild hypertensives with type II diabetes. A total of 161 men and women, 30-75 years old, with mild hypertension (sitting diastolic blood pressure 90-100 mmHg) and type II diabetes (HbA1c 5.5-9.0%), both measured after a 4-week placebo run-in period, were randomized to double-blind treatment with cand.cil. 8 mg o.i.d. (n = 83) or placebo (n = 78). Dose was increased to 16 mg o.i.d. if diastolic blood pressure remained >90 mmHg. At randomization and after 12 weeks of treatment HbA1c (primary effect variable), blood glucose and the serum lipid profile (including total cholesterol, HDL and LDL cholesterol, triglycerides) were assessed. The statistical analysis of the differences between treatments was based on changes from randomization to the end of the study. Cand.cil. had no significant effect on HbA1c, blood glucose and serum lipids compared to placebo. The median HbA1c both at baseline and after 12 weeks was 7.1% in patients on cand.cil., and 7.2% and 7.1% in patients on placebo. The 95% confidence interval for the median difference in change between the groups was narrow (-0.25; 0.16), including zero, which excluded any clinically important difference. The same held true for blood glucose (-1.10; 0.20), total cholesterol (-0.40; 0.20) and the other lipid parameters. More than 60% of the patients reached a diastolic blood pressure <90 mmHg; adverse events and withdrawals were similar in both groups. Thus, in patients with mild hypertension and type II diabetes, cand.cil. 8-16 mg o.i.d. for 12 weeks does not affect glucose homeostasis and serum lipids. Blood pressure was controlled in most patients, and cand.cil. was well tolerated.

Adult↗
PubMed2000

Contribution of circadian physiology and sleep homeostasis to age-related changes in human sleep.

The circadian pacemaker and sleep homeostasis play pivotal roles in vigilance state control. It has been hypothesized that age-related changes in the human circadian pacemaker, as well as sleep homeostatic mechanisms, contribute to the hallmarks of age-related changes in sleep, that is, earlier wake time and reduced sleep consolidation. Assessments of circadian parameters in healthy young (approximately 20-30 years old) and older people (approximately 65-75 years old)--in the absence of the confounding effects of sleep, changes in posture, and light exposure--have demonstrated that an earlier wake time in older people is accompanied by about a 1 h advance of the rhythms of core body temperature and melatonin. In addition, older people wake up at an earlier circadian phase of the body temperature and plasma melatonin rhythm. The amplitude of the endogenous circadian component of the core body temperature rhythm assessed during constant routine and forced desynchrony protocols is reduced by 20-30% in older people. Recent assessments of the intrinsic period of the human circadian pacemaker in the absence of the confounding effects of light revealed no age-related reduction of this parameter in both sighted and blind individuals. Wake maintenance and sleep initiation are not markedly affected by age except that sleep latencies are longer in older people when sleep initiation is attempted in the early morning. In contrast, major age-related reductions in the consolidation and duration of sleep occur at all circadian phases. Sleep of older people is particularly disrupted when scheduled on the rising limb of the temperature rhythm, indicating that the sleep of older people is more susceptible to arousal signals generated by the circadian pacemaker. Sleep-homeostatic mechanisms, as assayed by the sleep-deprivation-induced increase of EEG slow-wave activity (SWA), are operative in older people, although during both baseline sleep and recovery sleep SWA in older people remains at lower levels. The internal circadian phase advance of awakening, as well as the age-related reduction in sleep consolidation, appears related to an age-related reduction in the promotion of sleep by the circadian pacemaker during the biological night in combination with a reduced homeostatic pressure for sleep. Early morning light exposure associated with this advance of awakening in older people could reinforce the advanced circadian phase. Quantification of the interaction between sleep homeostasis and circadian rhythmicity contributes to understanding age-related changes in sleep timing and quality.

Adult↗