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PubMed1988

Energy balance in adrenalectomized ob/ob mice: effects of dietary starch and glucose.

Effects of different carbohydrate types on energy balance, fatty acid synthesis, and plasma insulin concentrations in adrenalectomized ob/ob mice were investigated. Obese (ob/ob) and lean mice adrenalectomized at 4 wk of age received one of four high-carbohydrate powdered diets for 3 wk: stock, glucose, starch, or starch plus wheat bran. Adrenalectomy reduced energy intake of ob/ob mice equally independent of diet type, whereas energetic efficiency, in vivo rates of fatty acid synthesis in liver and white adipose tissue, and plasma insulin concentrations were substantially reduced to approach values in lean mice in all adrenalectomized ob/ob mice except those fed glucose. The ability of adrenalectomy to normalize energy balance in ob/ob mice depends on factors other than the reduced circulating concentration of glucocorticoids alone. Diet composition is a crucial factor, and striking differences exist between semipurified diets containing a simple sugar (glucose) and those containing a complex carbohydrate (starch), with no additional effect of dietary fiber (wheat bran).

Adipose Tissue↗

PubMed2000

Walking with labor epidural analgesia: the impact of bupivacaine concentration and a lidocaine-epinephrine test dose.

BACKGROUND: Regional analgesia techniques for labor that permit ambulation are popular among parturients. This study evaluated the influence of bupivacaine bolus concentration and a 3-ml 1.5% lidocaine-epinephrine test dose, on analgesic effectiveness and the ability to walk after block placement. METHODS: Using a randomized double-blind study design, epidural analgesia was initiated in 60 parturients undergoing labor as follows: Group TD/B.0625 received a 3-ml lidocaine-epinephrine test dose + 12 ml bupivacaine, 0.0625%; group TD/B.125 received a 3-ml test dose + 12 ml bupivacaine, 0.125%; group B.0625 received 15 ml bupivacaine, 0.0625% (no test dose); and group B.125 received 15 ml bupivacaine, 0.125% (no test dose). Initial boluses in all groups contained 10 microg sufentanil. Bupivacaine, 0.0625%, with 0.33 microg/ml sufentanil was infused throughout labor at 13.5-15 ml/h. Analgesia balance, proprioception, motor block, and patient ability to stand and walk were evaluated at various intervals. RESULTS: A bolus of 0.125% bupivacaine containing sufentanil, without a previous test dose, proved to be optimal with respect to analgesia and early ambulation. When a test dose was given before bupivacaine, 0.125%, fewer women walked within 1 h of block placement. Bupivacaine, 0.0625%, with sufentanil, with or without a test dose, provided inadequate analgesia, necessitating additional bupivacaine, which impaired the ability to walk. A high percentage of women in all groups (73-93%) walked at some stage during labor. CONCLUSIONS: Omitting a lidocaine-epinephrine test dose and using 0.125% bupivacaine for the initial bolus should permit ambulation in the early postblock period for most parturients who elect this option.

Adult↗

PubMed2001

Mutation of the ptsG gene results in increased production of succinate in fermentation of glucose by Escherichia coli.

Escherichia coli NZN111 is blocked in the ability to grow fermentatively on glucose but gave rise spontaneously to a mutant that had this ability. The mutant carries out a balanced fermentation of glucose to give approximately 1 mol of succinate, 0. 5 mol of acetate, and 0.5 mol of ethanol per mol of glucose. The causative mutation was mapped to the ptsG gene, which encodes the membrane-bound, glucose-specific permease of the phosphotransferase system, protein EIICB(glc). Replacement of the chromosomal ptsG gene with an insertionally inactivated form also restored growth on glucose and resulted in the same distribution of fermentation products. The physiological characteristics of the spontaneous and null mutants were consistent with loss of function of the ptsG gene product; the mutants possessed greatly reduced glucose phosphotransferase activity and lacked normal glucose repression. Introduction of the null mutant into strains not blocked in the ability to ferment glucose also increased succinate production in those strains. This phenomenon was widespread, occurring in different lineages of E. coli, including E. coli B.

Alleles↗

PubMed2005

Loss of signal transducer and activator of transduction 4 or 6 signaling contributes to immune cell morbidity and mortality in sepsis.

OBJECTIVE: The role of signal transducer and activator of transduction (STAT) 4 vs. 6 has been assessed thus far only in a model of high mortality strongly driven by proinflammation alone. Their role in a low-mortality (LD25) model of sepsis remains unclear. DESIGN AND SETTING: Prospective controlled animal study in a research laboratory. SUBJECTS: STAT4 and STAT6 knockout mice. INTERVENTIONS: We induced sepsis by cecal ligation and puncture (CLP) or sham CLP in three groups of mice: (a) STAT4-/-, (b) STAT6-/-, (c) BALB/c. Splenic T cells or macrophages were then harvested 24 h after CLP, and their ability to produce cytokines was assessed. RESULTS: Following CLP T-cells from BALB/c mice were suppressed in the ability to release the Th1 cytokines interleukin (IL) 2 and interferon gamma. The release of Th2 cytokine IL-10 was increased. The Th1 response of STAT4-deficient animals was not only markedly lower in shams but was further suppressed by CLP. The Th2 cytokine response was elevated even more than that of the septic BALB/c. This was associated with lower survival than in the BALB/c. STAT6 deficiency resulted in a stronger Th1 response and a suppressed Th2 response to CLP. A similar difference between IL-12 and IL-10 release was seen in macrophages from these mice. Interestingly, while this resulted in improved survival, compared to STAT4-/- mice, the STAT6-/- animals still had a higher mortality than the BALB/c. CONCLUSIONS: These data suggest that contributions from both STAT4 driven processes as well as STAT6 responses are needed in a balanced fashion to maximize the animals' ability to survive septic challenge.

Animals↗

PubMed2005

Metabolic profile of XK469 (2(R)-[4-(7-chloro-2-quinoxalinyl)oxyphenoxy]-propionic acid; NSC698215) in patients and in vitro: low potential for active or toxic metabolites or for drug-drug interactions.

As part of an ongoing phase 1 study, we studied the excretion of XK469 and its metabolism in patients and in vitro. Five primary metabolites were identified by HPLC/MS/MS. An oxidized product formed by cytosolic aldehyde oxidase was the predominant species both in urine and human hepatocytes in vitro. Conjugates of XK469 with glycine, taurine, and glucuronic acid, as well as the microsomal product, 4-oxo-XK469, were also found in urine and in vitro, but none were major contributors to the mass balance for XK469 elimination. Based upon the relative concentrations circulating in plasma, systemic exposure to parent drug was 100-fold higher than for the metabolites. Thus, both toxicity and efficacy of XK469 are most likely to be produced by the parent molecule, rather than the metabolites. Urinary recovery of parent drug was low (2% of dose in 24 h), partly because of the long half-life of XK469 (approximately 3 days). In addition, the metabolite profile in urine indicates that only 25% of the XK469-derived material was unchanged drug. Thus, urinary excretion was not a major factor in XK469 elimination. Variations in systemic exposure to XK469 will be strongly influenced by factors that alter the activity of aldehyde oxidase, including pharmacogenetics, enzyme inhibition, and enzyme induction, but no specific modifiers have been reported. The multiday half-life of XK469 hampered our ability to obtain a complete mass balance, and the possibility exists that other routes, such as biliary excretion, may also play a substantial role in XK469 disposition.

Half-Life↗

PubMed1995

Physical determinants of independence in mature women.

The purpose of this study was to determine the relationship in mature women between muscle strength and whole body oxidative capacity and the ability to perform activities of daily living (ADL). Sixty-one women (mean age 69 years) without major disease or disability were recruited from either a community exercise center or a personal care facility. Physiological measurements consisted of peak oxygen consumption on a cycle ergometer (VO2peak) and one repetition maximum strength of nine muscle groups (1-RM). Ability to perform ADL was measured with a balance and gait test, "Bag Carrying Test", and ADL questionnaires. Significant correlations were found with VO2peak and calf muscle strength and ability to perform ADL, with weaker or no correlations for other muscle groups. For some relationships, it was possible to identify the minimum level of physiological functioning associated with successful performance of independence tasks. In summary, physiological capacities, particularly VO2peak and strength of the calf muscles, predicted ability to perform activities needed for functional independence in healthy mature women.

Activities of Daily Living↗

PubMed2005

Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke.

The restoration of energy balance during ischemia is critical to cellular survival; however, relatively little is known concerning the regulation of neuronal metabolic pathways in response to central nervous system ischemia. AMP-activated protein kinase (AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion in vivo and oxygen-glucose deprivation in vitro, to delineate changes in AMPK activity incurred from a metabolic stress. AMPK is highly expressed in cortical and hippocampal neurons under both normal and ischemic conditions. AMPK activity, as assessed by phosphorylation status, is increased following both middle cerebral artery occlusion and oxygen-glucose deprivation. Pharmacological inhibition of AMPK by either C75, a known modulator of neuronal ATP levels, or compound C reduced stroke damage. In contrast, activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside exacerbated damage. Mice deficient in neuronal nitric-oxide synthase demonstrated a decrease in both stroke damage and AMPK activation compared with wild type, suggesting a possible interaction between NO and AMPK activation in stroke. These data demonstrate a role for AMPK in the response of neurons during metabolic stress and suggest that in ischemia the activation of AMPK is deleterious. The ability to manipulate pharmacologically neuronal energy balance during ischemia represents an innovative approach to neuroprotection.

4-Butyrolactone↗

PubMed1989

Effect of inhibition of DNA synthesis on recovery of X-irradiated L5178Y-S cells. I. Aphidicolin.

Irradiated L51 78Y-S cells (LY-S) were characterized by an exponential survival curve and the potentiation effect of split--dose irradiation. Previously we showed [13] that in LY-S cells the reduction of DNA replicative synthesis rate affected the balance between the fixation and repair of sublethal damage (SLD) and of potentially lethal damage (PLD) in favor of repair. We report here that a block of DNA synthesis by aphidicolin (APC), an inhibitor of DNA polymerase alpha, was sufficient to protect LY-S cells from fixation of PLD and SLD induced by X-rays. Treatment with APC 0.5 micrograms/ml for 2 h, efficiently inhibited DNA replication (95%) with minimal effect on survival. Inhibition of DNA synthesis by combined irradiation and APC was not significantly different from APC treatment alone. The level of protection by APC was dependent on the length of time between irradiation and APC application. An opposite effect was observed when the drug treatment had proceeded irradiation: The killing effect of X-ray increased. The effect of aphidicolin treatment remained even after removal of APC and was dependent on the drug concentration and time between drug removal and irradiation. These results are interpreted as indicating that X-ray damage was fixed in LY-S cells, because of their lack of ability to maintain the nucleotide pool balance, and that fixation took place during progression through the cell cycle.

Animals↗

PubMed2005

The vestibular control of balance after stroke.

OBJECTIVES: To examine vestibular control of balance in those who recovered the ability to stand after middle cerebral artery (MCA) stroke. METHODS: Sixteen patients with MCA stroke were compared with 10 age matched controls. Two additional patients were studied with isolated corticospinal tract lesions, one each at the level of the pons and medulla. Vestibular evoked postural responses were obtained using galvanic vestibular stimulation (GVS) while patients stood with their eyes closed and head facing forwards, equally loading both legs. The GVS response was characterised by measuring the amplitude of the stimulus evoked lateral forces acting through each leg and the lateral displacement of the axial skeleton. RESULTS: Lateral displacement and net lateral force following GVS were significantly larger after stroke. Unlike controls, the lateral forces in the stroke group were asymmetrical, being enhanced on the side of the non-paretic limb and small on the side of the paretic limb. The degree of GVS evoked asymmetry correlated with corticospinal damage assessed using transcranial magnetic stimulation. A similar asymmetrical response was seen in the patient with the pontine lesion but not the patient with the medullary lesion. CONCLUSIONS: MCA stroke may disrupt corticobulbar projections to brainstem output pathways involved in vestibular control of balance. These projections are either collaterals of the corticospinal tract or lie close to that tract and terminate in the pons/upper medulla. This hypothesis accounts for the association between corticospinal tract damage and GVS response asymmetry, and the lack of GVS evoked asymmetry with corticospinal lesions below the rostral medulla.

Adult↗

PubMed1989

Effect of a high protein intake on acid-base balance in adult rats.

Adult rats are able to maintain Ca balance under protein loads that produce Ca loss in adult humans. This species difference was investigated by determining the relationship between protein intake, endogenous acid production (EAP), net acid excretion (NAE), and urinary Ca in adult rats for comparison with a similar study on adult humans. Diets containing 10, 30, and 50% casein were fed in conjunction with proportionate increments in the sulfur amino acid (SAA) methionine (0.6, 1.8, and 3.0%). Urine volume, Ca, sulfate, organic anions, TA (titratable acidity as acid phosphates), and ammonium increased progressively with increases in protein intake, and pH decreased. When protein intake was increased at a constant level of SAA, no increase in urinary Ca, sulfate, and TA or decrease in pH was observed. Both SAA and non-SAA enhanced ammonium excretion but only non-SAA enhanced organic anion excretion, an indicator of incomplete oxidation of organic acids. SAA were responsible for 89 and 91% of the increase in EAP and Ca excretion, respectively, caused by increasing protein intake from 10-30% of the diet. In a comparison experiment, human adults on a high protein intake exhibited a much smaller increase in acid excretion as ammonium, a greater increase as TA, no change in organic anion excretion, and no increase in EAP from non-SAA. The importance of these species differences in acid-base response to a high protein intake in the greater ability of rats to maintain Ca balance on high protein intakes is unclear; however, the smaller fraction of endogenous Ca excreted in the urine of rats is probably an important factor.

Acid-Base Imbalance↗

PubMed1990

Growth hormone and pulmonary disease. Metabolic effects in patients receiving parenteral nutrition.

Six severely malnourished patients with chronic obstructive pulmonary disease were maintained for 3 days with infusions of 5% dextrose in water followed by 12 days of eucaloric total parenteral nutrition. On days 8 through 11, they received 30 micrograms/d of growth hormone and twice this amount on days 11 through 15. Growth hormone had no significant effects on the plasma concentration of glucose, cortisol, or glucagon but caused a 50% increase in insulin and a 250% increase in somatomedin C concentrations. A positive nitrogen balance of 2 g/d due to growth hormone was probably mediated by insulin. Growth hormone-induced increases in energy expenditure and fat oxidation and decrease in glucose oxidation cannot be accounted for by insulin. The ability of growth hormone to improve nitrogen balance may be particularly important for malnourished patients with chronic obstructive pulmonary disease who, because of their pulmonary insufficiency, are intolerant of excess nutrients.

Aged↗

PubMed2002

Adenosine type 1 receptor antagonists in fluid retaining disorders.

Adenosine is a vasoactive hormone whose action is mediated through at least four receptors. The most prevalent receptors are type 1, which promote vasoconstriction, and type 2, comprised of 2 subtypes (a,b) that promote vasodilation. In the kidney, type 1 receptors located on preglomerular vessels and in the tubule are involved in the regulation of glomerular filtration. Whole body fluid balance is strongly dependent on the ability of the kidney to maintain stable glomerular filtration. Several antagonists to adenosine type 1 receptors have been developed. These agents generate excess fluid (diuresis) and sodium (natriuresis) excretion in control animals and animal models of fluid retention, as well as in normal and oedematous humans. In both animals and humans, these effects are generally achieved without major changes in glomerular filtration. Animal studies have confirmed the location of adenosine type 1 receptors in relevant tissue sites in the kidney. More highly selective antagonists for adenosine type 1 receptors are regularly developed, improving their use in fluid retaining disorders. Clinical trials with these agents have commenced for the treatment of hypertension, renal failure and congestive heart failure, all disorders that include varying levels of fluid retention. The clinical trial results have been mixed. The early results with congestive heart failure suggest great promise for these agents, whereas trials in hypertension and renal failure have been equivocal.

Animals↗

PubMed2001

Levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from blood of women scheduled for breast biopsy.

Systemic oxidative stress is thought to contribute to risk of various cancers, including breast cancer. DNA repair ability also has been associated with breast cancer risk. In this work, we examined levels of oxidative DNA damage as an indication of breast cancer risk in women because oxidative DNA damage levels should reflect the net balance of oxidative stress and DNA repair ability. Levels of 5-hydroxymethyl-2'-deoxyuridine, one form of oxidative DNA damage, were measured in DNA from blood of women scheduled for breast biopsy. The blood samples analyzed included women whose biopsy results indicated invasive breast cancer, high-risk lesions (atypical hyperplasia or carcinoma in situ), or benign lesions. Mean levels of 5-hydroxymethyl-2'-deoxyuridine were significantly higher in blood of women who had high risk or invasive breast lesions versus women with benign lesions. If atypical hyperplasia or carcinoma in situ are precursor lesions for breast cancer, then these results suggest that oxidative DNA damage may be involved in the cancer process before invasive cancer develops.

Biomarkers, Tumor↗

PubMed1996

L-cystine-di-beta-naphthylamidase activity in plasma of the snake Bothrops jararaca after chronic challenges of water balance.

Plasma protein, osmolality and L-cystine-di-beta-naphthylamidase activity were measured in Bothrops jararaca snakes submitted to normal hydration, water deprivation, water loading, salt loading or argvasotocin injections. Protein and osmolality were similar for male and female snakes in all treatments. Protein content was similar in all treatments, indicating the ability of the animals to maintain fluid balance between the vascular and extravascular compartment under osmotic challenges. Osmolality was increased in water-deprived and salt-loaded and was decreased in water-loaded animals compared with normally hydrated or argvasotocin-injected snakes. Enzymatic activity differed between males and females and was higher in salt-loaded females and in arg-vasotocin-injected females and males than in water-loaded snakes. A positive linear regression between osmolality and L-cystine-di-beta-naphthylamidase was obtained for female snakes (correlation coefficient = 0.6162, P < 0.01). The data show a role of arg-vasotocin in the consistent relationship between water balance and this sex-related aminopeptidase activity.

Aminopeptidases↗

PubMed1989

Potential renal solute load of infant formulas.

The potential renal solute load (PRSL) of infant feedings is the sum of dietary nitrogen (expressed as mmol of urea, i.e., mg nitrogen divided by 28), sodium, potassium, chloride and phosphorus. The PRSL determines the renal solute load, and, therefore, the osmolar concentration of the urine. When water intake is reduced and/or water losses are increased, the renal concentrating ability may be exceeded, and negative water balance (dehydration) may ensue. Under these circumstances, feedings providing high PRSL lead more rapidly to dehydration than do feedings providing lower PRSL. On the basis of simulated clinical situations and epidemiologic data, it is concluded that conventional infant formulas (PRSL 135-177 mosmol/l, or 20-26 mosmol/100 kcal) provide a satisfactory margin of safety. A feeding providing the upper limits for concentrations of protein and electrolytes specified by the Food and Drug Administration rule does not afford a satisfactory margin of safety. It is recommended that the upper limit for protein content of infant formulas be decreased from 4.5 g/100 kcal to 3.2 g/100 kcal and that an upper limit for phosphorus concentration of infant formulas be set at 93 mg/100 kcal. Maximum PRSL will then be 221 mosmol/l (33 mosmol/100 kcal).

Electrolytes↗

PubMed1977

The artificial heart. Progress and promise.

A multidisciplinary group has designed, fabricated, and evaluated an artificial heart. The heart consists of two smooth-surfaced sac-type pumps, two pneumatic power units, and an electronic control system. The artificial heart has been employed in 22 calves. A variety of problems have been encountered and overcome and a significant improvement in pump design has been made. As a result, a gradual increase in survival times has occurred. The last two calves in which the heart was tested lived for 60 and 42 days respectively. These animals ate well and gained weight. The ability of the control system to balance the output of the two pumps over long periods of time and to automatically increase cardiac output with treadmill exercise has been confirmed. No insurmountable problems in the development of the artificial heart have been identified. The date that an artificial heart will be available for clinical use depends on the availability of funds and on the tenacity of the investigators.

Animals↗

PubMed2006

Supramolecular self-organization of "Janus-like" diblock codendrimers: synthesis, thermal behavior, and phase structure modeling.

We report on the design and synthesis of three series of segmented amphiphilic block codendrimers, and on their self-organizing behavior in liquid-crystalline mesophases. Connecting two prefunctionalized monodendrons, each differing in their chemical constitution and generation number, yielded these diblock supermolecules. One wedge of the codendrimer was made hydrophobic, and is based on a branched poly(benzyl ether) monodendron functionalized at the periphery by lipophilic aliphatic fragments (also known as Percec dendrons). The other segment was made hydrophilic by the grafting of hydroxyl-containing moieties onto the focal functions of the former dendrons. Both types of dendrons were prepared independently by convergent methods and then joined in the ultimate stage of the synthetic procedure by cross-coupling reactions. In this way, the proportion of the dendritic blocks was varied independently to allow control of the hydrophilic/hydrophobic balance (HHB), the hydrogen-bonding ability, and consequently the capacity to tune the mesomorphic properties of the resulting "superamphiphiles" was anticipated. Essentially all the dendritic compounds display a thermotropic mesomorphism directly at or near room temperature as determined by using X-ray diffraction, polarized optical microscopy, and differential scanning calorimetry. The nature and the supramolecular organization of the mesophases, namely columnar and cubic phases, are correlated to the size of the respective block monodendrons and the chemical structures of the dendromesogens. The molecular organization within the cubic phases can be geometrically described and well understood by the space-filling polyhedron model.

Journal Article↗

PubMed1986

Differential effect of caffeine administration on calcium and vitamin D metabolism in young and adult rats.

Since coffee drinking may lead to a worsening of calcium balance in humans, we studied the serial changes of serum calcium, PTH, 1,25-dihydroxyvitamin D (1,25(OH)2D) and calcium balance in young and adult rats after daily administration of caffeine for 4 weeks. In the young rats, there was an increase in urinary calcium and endogenous fecal calcium excretion after four days of caffeine administration that persisted for the duration of the experiment. Serum calcium decreased on the fourth day of caffeine administration and then returned to control levels. In contrast, the serum PTH and 1,25(OH)2D remained unchanged initially, but increased after 2 weeks of caffeine administration. The intestinal absorption coefficient of calcium remained unchanged, instead of declining gradually as observed in the young control group. This finding suggests that the intestinal absorption of calcium was stimulated by the increase in 1,25(OH)2D production after chronic administration of caffeine. In the adult rat group, an increase in the urinary calcium and endogenous fecal calcium excretion and serum levels of PTH was found after caffeine administration. However, the serum 1,25(OH)2D levels and intestinal absorption coefficient of calcium remained the same as in the adult control group. A decrease in the net balance of calcium occurred as a result of increased calcium excretion. The current study, using an animal model, supports the suggestion that chronic administration of caffeine could lead to negative calcium balance when there is an impaired ability to increase the efficiency of calcium absorption. Such a situation exists in elderly human subjects, since they have a reduced capacity to synthesize 1,25(OH)2D.

Aging↗