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PubMed1999

Loss of cytoplasmic retention ability of mutant LKB1 found in Peutz-Jeghers syndrome patients.

LKB1 Serine/Threonine (ST) kinase (also called STK11) originally identified in our novel protein kinase search project has recently been recognized as a susceptibility gene of Peutz-Jeghers Syndrome (PJS; MIM 175200). PJS is a dominantly inherited human disorder which is characterized by gastrointestinal hamartomatous polyposis and mucocutaneous melanin pigmentation. Since PJS patients also show a predisposition to a wide spectrum of cancers, it is speculated that LKB1 has a tumor suppressor function. In the present study we have characterized the basic biochemical property of LKB1. In the analysis of mutant LKB1 identified in PJS patients, it was found that one of the mutants, SL26, does not lose its kinase function, but alters its subcellular distribution to accumulate in the nucleus only, whereas wild type LKB1 shows both nuclear and cytoplasmic localization. Domain mapping of the nuclear targeting signal of LKB1 assigned it to its amino terminal side. Furthermore, it was shown that LKB1 also has a cytoplasmic retention ability which is considered defective and pathogenic in the SL26 mutant. It is speculated that subcellular distribution of LKB1 is regulated in the balance of these two forces, importation into the nucleus and retention within the cytoplasm; and the cytoplasmic retention ability is necessary for LKB1 to fulfil its normal function.

AMP-Activated Protein Kinase Kinases↗
PubMed2000

Influence of topiramate in the regulation of energy balance.

Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from D-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague-Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated. Copyright1999 ASCRS and ESCRS

Adipose Tissue↗
PubMed2001

Screening evaluation of an ionized nanocrystalline silver dressing in chronic wound care.

The successful topical treatment of chronic wounds requires adequate debridement, bacterial balance, and moisture balance. An ionized nanocrystalline silver dressing was evaluated through an uncontrolled, prospective study of a case series of 29 patients with a variety of chronic nonhealing wounds. The four arms of the study included nine patients with foot ulcers, six patients with venous stasis ulcers, two patients with pressure ulcers, and 12 patients with miscellaneous wounds. All wounds were assessed for the usual signs of clinical infection, with most of these parameters being measured and recorded. Microbiologically, bacterial load was determined via quantitative biopsies and semi-quantitative swabs. In general, the results showed a marked clinical improvement for the majority of wounds treated with the dressing. Among improved parameters included decreased exudate and decreased purulence. The quantitative bacterial biopsies did not show any decrease in organism numbers, although the semi-quantitative swabs indicated a decrease in the wound surface bacterial loading. This was indicative of the dressing's ability to reduce surface bacteria and achieve an element of bacterial balance in the superficial dermal compartment. The proposed mechanism of action for this ionized nanocrystalline based dressing is through bacterial and moisture balance within the superficial wound space compartment.

Algorithms↗
PubMed2003

Sexual selection favors female-biased sex ratios: the balance between the opposing forces of sex-ratio selection and sexual selection.

In a verbal model, Trivers and Willard proposed that, whenever there is sexual selection among males, natural selection should favor mothers that produce sons when in good condition but daughters when in poor condition. The predictions of this model have been the subject of recent debate. We present an explicit population genetic model for the evolution of a maternal-effect gene that biases offspring sex ratio. We show that, like local mate competition, sexual selection favors female-biased sex ratios whenever maternal condition affects the reproductive competitive ability of sons. However, Fisherian sex-ratio selection, which favors a balanced sex ratio, is an opposing force. We show that the evolution of maternal sex-ratio biasing by these opposing selection forces requires a positive covariance across environments between the sex-ratio bias toward sons (b) and the mating success of sons (r). This covariance alone is not a sufficient condition for the evolution of maternal sex-ratio biasing; it must be sufficiently positive to outweigh the opposing sex-ratio selection. To identify the necessary and sufficient conditions, we partition total evolutionary change into three components: (1) maternal sex-ratio bias, (2) sexual selection on sons, and (3) sex-ratio selection. Because the magnitude of the first component asymmetrically affects the strength of the second, biasing broods toward females in a poor environment evolves faster than the same degree of bias toward males in a good environment. Consequently, female-biased sex ratios, rather than male-biased sex ratios, are more likely to evolve. We discuss our findings in the context of the primary sex-ratio biases observed in strongly sexually selected species and indicate how this perspective can assist the experimental study of sex ratio evolution.

Alleles↗
PubMed2003

Reducing fear of falling in seniors through education and activity programs: a randomized trial.

OBJECTIVES: To determine the relative effect of education and activity programs on fear of falling, balance, strength, and health status. DESIGN: A randomized intervention trial with two groups (education and activity); evaluators were blind to group allocation. SETTING: Motor performance laboratory at Queen's University. PARTICIPANTS: Thirty-eight community-dwelling seniors who reported a fear of falling and activity restriction but were free of neurological and mobility-limiting orthopedic conditions. INTERVENTIONS: Programs designed to reduce fear of falling were delivered weekly to groups of three to five seniors for 8 weeks, each session lasting 1 hour. The activity program included low-resistance exercises and weight-shifting activities. Education focused on identifying and reducing risk factors for falls. MEASUREMENTS: Balance confidence, activity level, limits of stability (LOS), isokinetic strength, and health status were measured twice preintervention (baseline), postintervention, and 6 weeks later. RESULTS: Both programs reduced fear of falling (P <.006) as ascertained from the balance confidence scores. Differential effects were observed in LOS (P <.05); activity improved balance, whereas education led to modest declines. Gains in perception of health status were limited to physical health for the activity group and mental health for the education group. Benefits were generally sustained at follow-up. CONCLUSION: Improved balance confidence is not intervention-specific, but associated changes in physical ability and health status are a function of the composition of the intervention program.

Accidental Falls↗
PubMed2001

Thiols in cellular redox signalling and control.

Reactive oxygen (ROS) and reactive nitrogen species (RNS) produced in vivo at levels that cannot be dealt with adequately by endogenous antioxidant systems can lead to the damage of lipids, proteins, carbohydrates and nucleic acids. Oxidative modification of these molecules by toxic levels of ROS and RNS represents an extreme event that can lead to deleterious consequences such as loss of function. More recently, however, interest has focused on the formation of these species at sub-toxic levels and their potential to act as biological signal molecules. Subtoxic ROS and RNS production can lead to alterations in cellular and extracellular redox state, and it is such alterations that have been shown to signal changes in cell functions. By the use of a variety of cell types it has been shown that numerous cellular processes including gene expression can be regulated by subtle changes in redox balance Examples of this include the activation of certain nuclear transcription factors, and the determination of cellular fate by apoptosis or necrosis. Cellular redox balance is, under normal circumstances, probably under genetic control and maintained by an array of enzymatic systems that ensure that overall reducing conditions prevail. Thiols, by virtue of their ability to be reversibly oxidised, are recognised as key components involved in the maintenance of redox balance. Additionally, increasing evidence suggests that thiol groups located on various molecules act as redox sensitive switches thereby providing a common trigger for a variety of ROS and RNS mediated signalling events. In this review we discuss a number of cellular processes in which ROS and RNS have been implicated in redox signalling mechanisms. Particular attention has been paid to the importance of thiols and thiol-containing molecules in these processes.

Albumins↗
PubMed1996

Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis.

BACKGROUND: Numerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin. METHODS AND RESULTS: In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg X kg-1 X d-1), L-163,082 (1 mg X kg-1 X d-1), or L-164,282 (1.5 mg X kg-1 X d-1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty. CONCLUSIONS: These findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2 antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Angiotensin II↗
PubMed1979

A mechanism for secretory IgA-mediated inhibition of the cell penetration and intracellular development of Eimeria tenella.

The ability of Eimeria tenella sporozoites to develop normally in cultured chick kidney cells was used as an indicator of the anticoccidial effects of sera and extracts of caecal contents or tissue. Pre-treatment of sporozoites with normal serum globulin enhanced the frequency of intracellular development but pre-treatment in balanced salt solution, without protein, damaged sporozoites so that most had lost the ability to differentiate, even when they were able to invade host cells. The same inhibitory effect was seen when sporozoites were incubated in extracts of caecal contents from non-immunized chickens, although parasitic development was unaffected when sporozoites were pretreated in similar extracts of mucosae. Extracts of immune caecal contents impaired both cell penetration and subsequent development. These results show that sporozoites can lose the ability to differentiate before the ability to penetrate cells and provide evidence of a possible synergism between non-specific factors and secretory antibodies in anticoccidial immunity.

Animals↗
PubMed1974

The uptake of lead by children in differing environments.

Balance studies have been performed for lead upon eight healthy children in three different home environments and upon eight children with inborn errors of metabolism in hospital (consuming two different types of synthetic diet). The balances were for 3 days and involved the use of metal-free diapers where indicated. The concentration of lead in all the samples was determined by atomic absorption spectroscopy after suitable sample preparation. In addition, the total population of children under the age of 16 living in a working class area exposed to undue amounts of lead was examined in an attempt to determine whether their mental development had been affected. Blood lead levels, general intelligence, reading ability, and rate of behavior disorder were measured. The results of the balances showed that the mean daily intake of lead in both groups of children was lower than previously recorded figures, being lowest of all in the breastfed infant. The healthy group absorbed a mean value of 53% and retained 18% of the dietary intake and there was no relationship to age or month of the year of study. The children with inborn errors showed a significantly lower percentage absorption of lead. The preliminary results of the population survey showed that distance from the polluting lead source was related to blood lead level, but no relationship could be found between blood lead level and any measure of mental function.

Breast Feeding↗
PubMed1980

Maintenance of ambulation in Duchenne muscular dystrophy. The role of the orthopedic surgeon.

As the processes of pseudohypertrophic muscular dystrophy advance, contractures about joints in the lower extremities progress until an unstable base of support secondary to equinovarus and weakened pelvic balance produced by hip flexion prohibit ambulation. Properly timed surgery and bracing have helped some patients to extend significantly their ability to ambulate. Because severe weakness can result from prolonged restraint, operative procedures must permit immediate mobilization without fear of excessive pain or wound dehiscence. The primary aims of surgery are to maintain standing balance and prolong independent ambulation. Conditions requiring surgical correction are lower extremity flexion contracture, metatarsus adductus, and rigid forefoot equinocavovarus. Techniques designed to improve these deformities and permit early postoperative mobilization include subcutaneous release of contracted tendons and percutaneous removal of cancellous bone with corrective manipulation of the feet. Postoperative plastic bracing enhances balance through mild knee flexion and ischial seating. Maintenance of the upright posture extends the ability of these patients to attend to their tasks of daily living. In addition, these techniques offer a method of prolonging ambulation in the patient with pseudohypertrophic muscular dystrophy. In so doing, confinement to a wheelchair with its inevitable downhill course may be significantly postponed.

Braces↗
PubMed1996

Effects of age on rapid ankle torque development.

BACKGROUND: When balance is disturbed, often only fractions of a second are available in which to make the initial responses needed for its restoration. Abilities to develop joint torques rapidly may be critical to such responses. We undertook this study to quantify age effects among healthy adults in abilities to develop ankle joint torques rapidly. METHODS: Ankle dorsiflexion (DF) and plantarflexion (PF) torque development during rapid isometric and during isokinetic (30, 60, 120, 180, and 240 deg/sec) exertions was assessed in 24 healthy young (mean age 23 years) and 24 healthy old adults (mean age 72 years). The effects of age, gender, and torque direction on the times needed to reach given torque magnitudes, maximum rates of isometric torque development (MRTD), and maximum isokinetic torques were examined. RESULTS: The old adults required substantially more time to reach given torque magnitudes than the young adults. For example, the young and old females needed approximately 236 and 337 msec to develop 15 Nm of DF torque, of which 141 and 164 msec were reaction times. Isometric MRTD were 25 to 36% lower in the old than in the young adults. The age declines in isometric torque development time were associated with losses in maximum isometric strength. Maximum isokinetic torques developed by the old were 20 to 40% lower than those of young adults. The percent losses in isokinetic torques with age were independent of joint angular velocity for PF, but increased with velocity for DF. CONCLUSIONS: We found substantial age declines in abilities of healthy old adults to rapidly develop ankle joint torques. The capacities of even healthy old adults to recover balance or to carry out other time-critical actions that require moderate-to-substantial strengths may be considerably degraded by these declines.

Adult↗
PubMed2002

Mitochondrial respiratory control is lost during growth factor deprivation.

The ability of cells to maintain a bioenergetically favorable ATP/ADP ratio confers a tight balance between cellular events that consume ATP and the rate of ATP production. However, after growth factor withdrawal, the cellular ATP/ADP ratio declines. To investigate these changes, mitochondria from growth factor-deprived cells isolated before the onset of apoptosis were characterized in vitro. Mitochondria from growth factor-deprived cells have lost their ability to undergo matrix condensation in response to ADP, which is accompanied by a failure to perform ADP-coupled respiration. At the time of analysis, mitochondria from growth factor-deprived cells were not depleted of cytochrome c and cytochrome c-dependent respiration was unaffected, demonstrating that the inhibition of the respiratory rate is not due to loss of cytochrome c. Agents that disrupt the mitochondrial outer membrane, such as digitonin, or maintain outer membrane exchange of adenine nucleotide, such as Bcl-x(L), restored ADP-dependent control of mitochondrial respiration. Together, these data suggest that the regulation of mitochondrial outer membrane permeability contributes to respiratory control.

Adenosine Diphosphate↗
PubMed1983

Water balance in Monodelphis domestica (Didelphidae) from the semiarid Caatinga of Brazil.

1. Water conservation and energy metabolism in a semiarid-area, neotropical marsupial (Monodelphis domestica) were studied in the laboratory. 2. The rate of energy consumption in this species is low, corresponding with results reported for Australian and other neotropical marsupials. 3. Evaporative water loss rate is low and comparable to that of several desert small rodents, when body size differences are taken into account; however, the ratio of metabolic water production-to-evaporative water loss is lower than in the rodents. 4. Urine osmotic, urea, and chloride concentrations in water-stressed animals are within the range of values reported for some arid-area granivorous rodents, for insectivorous/carnivorous Australian marsupials, and for a North American insectivorous desert rodent. 5. Water-balance computations indicate that this species should be able to maintain water balance at 25 degrees C on a high-protein diet with a water content of about 60% without access to drinking water; this water requirement is comparable to that of ecologically similar marsupials and placentas in arid areas of other continents.

Animals↗
PubMed2002

Activated ras regulates the proliferation/apoptosis balance and early survival of developing micrometastases.

Mutant, activated ras oncogenes are found in many human cancers. Experimental studies have shown that Ras enhances metastatic ability in several cell types. However, the biological mechanisms by which Ras contributes to metastasis remain poorly understood. Our goal was to determine which steps in the formation of macroscopic metastases were affected by Ras. Green fluorescent protein-transfected NIH 3T3 and T24 H-ras-transformed (PAP2) fibroblasts were injected via mesenteric vein to target mouse liver. The proportion of cells that survived at each step of the metastatic process (at 60 min to 14 days after injection) were quantified. We found that Ras did not enhance the ability of cells to extravasate from liver sinusoids or to survive as solitary undivided cells in liver tissue. Furthermore, we found that a subset of cells from both cell lines initiated growth to form micrometastases by day 3. Only micrometastases formed by ras-transformed cells, however, persisted to form macroscopic metastases by day 14, whereas most NIH 3T3 micrometastases disappeared. We investigated this difference in maintenance of developing metastases by quantifying apoptosis and proliferation within the micrometastases. PAP2 metastases had a significantly higher proportion of proliferating cells as compared with apoptosing cells, whereas NIH 3T3 metastases had low proliferation and high apoptosis levels. Whereas the ability of Ras to induce vascular endothelial growth factor has suggested one way that Ras might affect metastatic ability (through induction of angiogenesis), our study provides in vivo evidence for a direct role for Ras in maintenance of metastatic growth via a shift in proliferation/apoptosis balance to favor metastatic growth.

3T3 Cells↗
PubMed1995

Dietary alpha-linolenate/linoleate balance influences learning and memory in the senescence-accelerated mouse (SAM).

The senescence-accelerated mouse (SAMP8) is a model of age-related deterioration of memory and learning ability. A semipurified diet supplemented either with safflower oil (rich in linoleate) or with perilla oil (rich in alpha-linolenate) was fed to SAMP8 mouse dams and their pups. The offspring (males from several mothers) at 28 weeks of age were used for behavioral tests. The proportions of n-3 and n-6 highly unsaturated fatty acids in brain phospholipids reflected the n-3/n-6 balance of the diets. The learning and memory abilities of the two dietary groups were tested with the Sidman active avoidance task and the light and dark discrimination learning test. The group given perilla oil showed much greater improvement in learning in the Sidman active avoidance task than did the group fed safflower oil. In the light and dark discrimination learning test, the total number of responses to positive and negative stimuli was lower in those fed perilla oil, and their responses to positive stimuli were higher than to negative stimuli after the 10th session. Consequently, the correct response ratios of discrimination were higher in the perilla oil group than in the safflower oil group. In the open field test, the total amount of locomotor activity during 5 min was lower in the perilla oil group at 7 months of age than in the group fed safflower oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMedDate not supplied

Parenteral nutrition in cancer patients receiving chemotherapy: effects on toxicity and nutritional status.

The role of total parenteral nutrition (TPN) in reducing toxicity related to cancer chemotherapy (CT) is presently a controversial issue. To evaluate the effectiveness of TPN in reducing CT-associated toxicity and correcting and preventing CT-related impairments of nutritional status, a prospective crossover controlled study was performed in 43 cancer patients (19 normally nourished and 24 malnourished) randomly divided into two groups (A and B). Group A patients received TPN concomitantly with the first course of chemotherapy, and the second course was administered 21 to 28 days later without TPN support; group B patients were treated in the opposite sequence. The rates of myelotoxicities and gastrointestinal toxicities after CT courses with or without TPN were essentially similar in normally nourished and malnourished patients. No changes in nutritional indexes were detected in normally nourished subjects after each course. Conversely, in undernourished subjects, prealbumin, retinol-binding protein, and nitrogen balance increased in CT+TPN courses (p < .02). In CT-only courses, undernourished subjects showed a decrease in prealbumin and nitrogen balance. Significant changes of nitrogen balance in CT vs CT+TPN courses were detected in malnourished subjects. TPN appears to be unable to reduce CT-associated toxicity. CT administration does not result in any impairment of the nutritional status in normally nourished cancer patients. From our study, it appears that TPN should be limited to severely malnourished neoplastic patients undergoing CT, because of its ability to prevent further impairment of nutritional status and to improve the nitrogen balance and the levels of fast-turnover visceral proteins.

Adult↗
PubMed2003

Rethinking positive and negative aspects of alcohol use: suggestions from a comparison of alcohol expectancies and decisional balance.

OBJECTIVE: Few studies have compared similar alcohol-related constructs such as alcohol expectancies and decisional balance: two conceptualizations of the positive and negative aspects of alcohol. The purpose of this study was to compare these constructs and to examine their ability to predict alcohol use and problems. METHOD: A sample of 406 college students recruited from Psychology courses at a mid-sized Northeastern University completed a questionnaire that included measures of alcohol expectancies, decisional balance, drinking indices and drinking problems. Of these students, N = 389 (73% female) were drinkers and were included in analyses. RESULTS: Positive expectancies (PE) and the pros were more related to one another than were negative expectancies (NE) and the cons. The 8-item pros scale outperformed 20 items measuring PE in the prediction of alcohol problems and performed equally well in the prediction of alcohol indices. The negative relationship of cons to alcohol indices, something not found with NE, suggested that the cons scale may include components important to the measurement of negative aspects of alcohol. CONCLUSIONS: Although expectancies, particularly PE, have been a common choice for use by researchers, these data suggest that decisional balance scales may be a better choice because their predictive ability is equal to or better than that of expectancies, and their response burden on participants is lower. Instruments that aim to measure the negative aspects of alcohol use should include severe and distal items to better capture this negative attitudinal domain.

Adult↗