Diminished lifespan and acute stress-induced death in DNA-PKcs-deficient mice with limiting telomeres.

An adequate and appropriate response to physiological and pathophysiological stresses is critical for long-term homeostasis and viability of the aging organism. Previous work has pointed to the immune system, telomeres and DNA repair pathways as important and distinct determinants of a normal healthy lifespan. In this study, we explored the genetic interactions of telomeres and DNA-PKcs, a protein involved in non-homologous end-joining (NHEJ) and immune responses, in the context of a key aspect of aging and lifespan--the capacity to mount an acute and appropriate immune-mediated stress response. We observed that the combination of DNA-PKcs deficiency and telomere dysfunction resulted in a shortened lifespan that was reduced further following viral infection or experimental activation of the innate immune response. Analysis of the innate immune response in the DNA-PKcs-deficient mice with short dysfunctional telomeres revealed high basal serum levels of tumor necrosis factor alpha (TNFalpha) and hyper-active cytokine responses upon challenge with polyinosinic-polycytidylic acid (poly-IC). We further show that serum cytokine levels become elevated in telomere dysfunctional mice as a function of age. These results raise speculation that these genetic factors may contribute to misdirected immune responses of the aged under conditions of acute and chronic stress.

The Fourth National Institutes of Health Symposium on the Functional Genomics of Critical Injury: Surviving stress from organ systems to molecules.

Recent strides in computational biology and high-throughput technologies have generated considerable interest in understanding complex biological systems. The application of these technologies to critical illness and injury offers the potential to define adaptive and maladaptive programs of gene expression induced by infection, shock, trauma, or other inflammatory triggers, and to detect biomarkers and genetic polymorphisms linked to these responses and outcome. A systems biology approach is timely because despite substantial effort, treatment approaches directed at a single mediator or inflammatory pathway have met with little success in altering outcomes of critically ill or injured patients. Highlights from the Fourth National Institute of Health Functional Genomics of Critical Illness and Injury Symposium are described herein, in addition to deliverables for the field identified during panel discussions. Next steps for the community and suggestions for future research are presented.

Physiological responses of over-wintering common carp (Cyprinus carpio) to disturbance by Eurasian otter (Lutra lutra).

Using a tame animal, the impact of otter (Lutra lutra) disturbance on over-wintering carp (Cyprinus carpio) was monitored in two experiments, 133 and 140 days, respectively, over two consecutive winters (November-April). The level of stress in over-wintering carp exposed to various intensities of disturbance by otters was quantified using biological indicators of stress (cortisol, cortisone, indices of nitrogen, carbohydrate, lipid and mineral metabolism and activity of basic blood plasma enzymes) taken from blood plasma of stocked carp at the end of the winter seasons (when the photoperiod was 12 light:12 dark, respectively, 13L:10D). Moreover, condition (Fulton's coefficient of condition and fat content in muscles) and mortality rate of that carp were measured after over-wintering and also after the subsequent vegetation period. The analysis of blood and tissue samples of experimental fish showed changes in nitrogen, carbohydrate and mineral metabolism as well as levels of hormones and fat reserves. Higher response to stress in metabolism of carp with lower intensity of disturbance by otter suggests that high level of disturbance can lead to metabolic adaptation of carp to stress. The effect of stress on the mortality rate of carp during the over-wintering is not clear. Nevertheless, the negative effect of stress on survival, condition and growth rate of carp in the subsequent vegetation period was not observed.

Warm weather transport of broiler chickens in Manitoba. I. Farm management factors associated with death loss in transit to slaughter.

This observational study was conducted to identify flock of origin level factors associated with mortality during transport to slaughter of 1 090 733 Manitoba broiler chickens in spring and early summer. The death loss in transit was 0.346% (3778 birds). Death loss on the farm of origin during the growing phase of production and bird body weight at slaughter were associated with increased mortality in-transit. Death loss during production significantly exceeded, while crowding of growing birds was significantly less than, European proposed animal welfare standards.

Is incomplete recovery from work a risk marker of cardiovascular death? Prospective evidence from industrial employees.

OBJECTIVE: A chronic lack of recovery from work during leisure time is hypothesized to indicate a health risk among employees. We examined whether incomplete recovery from work predicted cardiovascular mortality. METHODS: This prospective cohort study involved 788 industrial employees (534 men, 254 women, mean age 37.3, SD = 12.0) who were initially free from cardiovascular diseases. The baseline examination in 1973 determined cases of cardiovascular disease, cardiovascular risk factors, and the extent of recovery from work. Data on mortality in 1973 to 2000 were derived from the national mortality register. RESULTS: Sixty-seven cardiovascular deaths and 102 deaths from noncardiovascular causes occurred during the mean follow-up of 25.6 years. Employees who seldom recovered from work during free weekends had an elevated risk of cardiovascular death (p = .007) but not of other mortality (p = .82). The association between incomplete recovery and cardiovascular death remained after adjustment for age, sex, and 16 conventional risk factors, including occupational background, cholesterol, systolic pressure, body mass index, smoking, alcohol consumption, physical inactivity, depressive symptoms, fatigue, lack of energy, and job stress. The association was not explained by deaths that occurred close to the assessment of recovery from work. CONCLUSIONS: This study suggests that incomplete recovery from work is an aspect of the overall risk profile of cardiovascular disease mortality among employees.

Effects of travel distance and the season of the year on death rates of broilers transported to poultry processing plants.

Death losses among broilers transported to processing plants are caused by poor welfare. The number of birds dying during transport and in processing plants shortly after arrival there may serve as an indicator of the quality of welfare during loading and transport. In the Czech Republic, shipments of broilers to processing plants were monitored from 1997 to 2004. It was found that the mortality of broilers during transport was 0.247%, but it varied according to the transport distance to the processing plant from 0.146% (50 km maximum) to 0.862% (>300 km). The broiler mortality in transit was also influenced by the season of the year. The highest mortality was found in summer months, especially in June, July, and August, and in winter months, especially in December, January, and February. A comparison between period 1 (1997 to 2000) and period 2 (2001 to 2004) showed a long-term adverse trend in the number of broilers dying during transport to processing plants for all of the distances monitored (except transport distances <50 km), because the overall number of dead birds on arrival to processing plants increased from 0.224 to 0.265% (index of 1.18). This difference is statistically significant (P = 0.000). The stress caused to broilers by transport to processing plants is reflected in higher transport-related mortality of the birds. Long-term trends point to an increase in death losses of broilers. Longer transport distances and transportation in summer and winter months have led to an increase in death losses among broilers transported to processing plants.

Population-based analysis of the effect of the Northridge Earthquake on cardiac death in Los Angeles County, California.

OBJECTIVES: We sought to determine whether a natural disaster affected total cardiovascular mortality and coronary mortality in an entire population. BACKGROUND: The effect of the January 17, 1994 Northridge Earthquake (NEQ) on all deaths and causes of deaths within the entire population of Los Angeles County is unknown. The purposes of our study were to analyze all deaths in this entire population before, during and after the NEQ and to determine whether the NEQ temporally and spatially altered death due to cardiovascular disease. METHODS: We analyzed all death certificate data (n = 19,617) from Los Angeles County during January of 1992, 1993 (control periods) and 1994, using International Classification of Diseases, 9th Revision codes for ischemic heart disease (IHD) and atherosclerotic cardiovascular disease (ASCVD), as well as other causes of death. RESULTS: There was an average of 73 deaths per day due to IHD and ASCVD during January 1 to 16, 1994; this increased to 125 on the day of the NEQ, and then decreased to 57 deaths per day from January 18 to 31 (p < 0.00001, before NEQ vs. day of NEQ; after NEQ vs. day of NEQ; and before NEQ vs. after NEQ). The NEQ was associated with an increase in deaths due to myocardial infarction and trauma but not cardiomyopathy, hypertensive heart disease, valvular heart disease, cerebrovascular disease or noncardiovascular causes. Based on plots of daily deaths due to IHD and ASCVD, the decrease in deaths during the 14 days after the NEQ (-144) overcompensated for the increase on the day of the NEQ (+55). Geographic analysis revealed a redistribution of deaths due to IHD and ASCVD toward the epicenter on the day of the NEQ. CONCLUSIONS: When an entire population simultaneously experiences a major environmental stress, there is an increase in death due to coronary artery disease (but not other cardiac causes), followed by a decrease that overcompensates for the excess of death. The overcompensation may represent a residual population that is more resistant to stress or a possible preconditioning effect of the stress, or both. This study supports the concept that cardiovascular events within an entire population can be triggered by a shared stress.

Changing patterns of gastrointestinal bleeding.

This study, a retrospective analysis of 351 patients with acute gastrointestinal (GI) hemorrhage, was undertaken to define patterns of disease and age-related operative and mortality rates and to determine changes over time related to changes in management. One third (116 patients) of the admissions had bleeding esophageal varices. Upper GI hemorrhage accounted for 85% (N = 200) and lower GI hemorrhage for 15% (N = 35). Emergency surgical intervention was required in 90 patients (38%), 40% of the upper and 29% of the lower GI hemorrhage patients. Benign ulcer disease accounted for 86% of the cases requiring emergency surgery and was treated with vagotomy and drainage and/or oversewing. Lower GI bleeding is seen in older patients; it has a lower operative intervention rate and a higher mortality. Stress bleeding as a surgical lesion has disappeared since 1979. A more assertive policy for surgical intervention has decreased operative mortality for all age groups. Bleeding duodenal ulcers are decreasing in incidence while gastric lesions appear to be increasing. These population-specific patterns, different from earlier periods, may have implications for training and patient management decisions.

Methamphetamine mortality to emotional stimuli administered in the form of affective communication.

Methamphetamine induced mortality in physically stressed and non-physically stressed mice was investigated by employing a communication box in which shocked mice communicated their distress to unshocked mice in neighboring boxes. Intraperitoneal administration of methamphetamine 30 mg/kg caused greater mortality in both the shocked "sender" mice and the unshocked "responder" mice than in control when maintained at 27 +/- 1 degree C. Forty-eight hours after injection, the "sender", "responder" and control mice showed mortality of 80, 60 and 10%, respectively. This result indicates that the mortality of methamphetamine may be potentiated not only by physical stress but also by non-physical stress.

Body temperature and wheel running predict survival times in rats exposed to activity-stress.

The relationship between restricted feeding, core body temperature (Tb), wheel running, survival, and gastric erosion formation was examined in female rats exposed to activity-stress. Core body temperature and gross motor activity were telemetrically monitored in four groups of rats that had free access to running wheels and in one group that was not allowed to run on the wheels. Twenty-four hours prior to the onset of hypothermia and predicted mortality, different groups were left undisturbed, warmed with a heat lamp, denied access to running wheels, or euthanized. Length of survival in wheel-running rats varied from 2 to 12 days. During the first day of food deprivation, premorbid changes in the variability of Tb during the diurnal period and the mean number of wheel revolutions during the nocturnal period were strongly predictive of length of survival. Warming rats with a heat lamp or preventing rats from ever running on the wheel increased the length of survival and attenuated gastric erosion formation. Only rats that were warmed had a greater likelihood of survival. Gastric pathology was also reduced in rats that were euthanized prior to becoming moribund. Rats that were left undisturbed or locked from the running wheel over the last 24 h of testing became moribund and had extensive gastric mucosal damage. These results indicate that thermoregulatory disturbances induced by restricted feeding and not wheel running alone are critical in determining survival and the degree of gastric mucosal injury in rats exposed to activity-stress. Results further suggest that predisposing factors may put some rats at risk for the development of activity-stress-induced mortality.

Stress, severity of illness, and outcome in ventilated preterm infants.

AIM: To determine physiological and hormonal stress responses in ventilated preterm infants. METHODS: Physiological and hormonal stress responses were studied in 47 ventilated preterm infants who were judged clinically to require sedation. The correlation between the stress response and severity of illness was examined, and responses were compared between infants with different clinical outcomes. RESULTS: Stress hormone concentrations were significantly correlated with severity of illness, assessed using the arterial: alveolar oxygen partial pressure ratio. Noradrenaline showed the strongest correlation, with an exponential pattern of increased secretion. Catecholamine concentrations before sedation were significantly higher among infants who subsequently died (n = 15, at a median age of 6 days) than among survivors: median noradrenaline 4.31 vs 2.16 nmol/l, median adrenaline 0.69 vs 0.31 nmol/l. The observed fall in noradrenaline with sedation was lower among those who died than survivors (median fall 2% vs 40%). CONCLUSION: Preterm infants are capable of hormonal stress responses appropriate for the severity of their illness. Extreme catecholamine responses, in the sickest infants, are associated with the worst outcome.

Activity stress effects on voluntary ethanol consumption, mortality and ulcer development in rats.

The present study was designed to investigate the relationship between activity stress, alcohol consumption and ulcer proliferation. Ethanol consuming rats were initially divided into low, medium or high ethanol preferring groups on the basis of daily ethanol intake (g/kg/day). Following a habituation period in activity cages, animals were fed for 1 hr per day. Access to both water and ethanol remained ad lib. Yoked control home cage animals were fed the same amount of food consumed by their wheel-housed partners. This procedure continued until wheel-housed animals died, at which time they and their yoked home cage control partners were examined for ulcers. Results indicated that in contrast to the yoked controls, only the high ethanol-preferring rats reduced their ethanol consumption. Although no differences were apparent in ulcer frequency (mean number of ulcers per rat) or severity (mean cumulative ulcer length in millimeters), animals exposed to ethanol had a lower ulcer incidence (number of rats per group developing ulcers) and mortality rate than non-ethanol exposed animals.

Alprazolam but not diazepam protects hamsters with heart disease from the medical consequences of stress.

We have previously shown that subjecting cardiomyopathic hamsters in the lesion-developing period of their heart disease to cold-immobilization stress had lethal consequences which could be blocked by alprazolam treatment. This experiment replicated that finding and also examined the efficacy of diazepam in this paradigm. In contrast to alprazolam, diazepam did not prevent the cardiomyopathic subjects from succumbing to the stressor. Thus, the effect of alprazolam in reducing stress-induced mortality did not reflect a generic benzodiazepine action.

Effect of cold stress on rapeseed oil fed rats.

No mortality was observed in 6 week old male Sprague-Dawley rats subjected to cold at 4 C for 3 weeks and fed either a control diet (Chow) or a semisynthetic diet containing 20% by wt rapeseed oil high in erucic acid (23.6%). All rats fed the Chow diet and 17 of 20 rats fed the rapeseed oil-containing diet survived 4 weeks in the same environment. Three rats on the latter diet died of self-mutilation. Marked myocardial lipidosis as well as a large acumulation of 20:1 and 22:1 was observed in the hearts of rats fed the rapeseed oil-containing diet. Five of 20 rats on the Chow diet and 2 of 20 rats on the rapeseed oil-containing diet had focal necrotic areas in the myocardium.

Effects of prenatal exposure to a mild chronic variable stress on body weight, preweaning mortality and rat behavior.

Early stimulation has been shown to produce long-lasting effects in many species. Prenatal exposure to some strong stressors may affect development of the nervous system leading to behavioral impairment in adult life. The purpose of the present work was to study the postnatal harmful effects of exposure to variable mild stresses in rats during pregnancy. Female Holtzman rats were submitted daily to one session of a chronic variable stress (CVS) during pregnancy (prenatal stress; PS group). Control pregnant rats (C group) were undisturbed. The pups of PS and C dams were weighed and separated into two groups 48 h after delivery. One group was maintained with their own dams (PS group, N = 70; C group, N = 36) while the other PS pups were cross-fostered with C dams (PSF group, N = 47) and the other C pups were cross-fostered with PS dams (CF group, N = 58). Pups were undisturbed until weaning (postnatal day 28). The male offspring underwent motor activity tests (day 28), enriched environment tests (day 37) and social interaction tests (day 42) in an animal activity monitor. Body weight was recorded on days 2, 28 and 60. The PS pups showed lower birth weight than C pups (Duncan's test, P<0.05). The PS pups suckling with their stressed mothers displayed greater preweaning mortality (C: 23%, PS: 60%; chi2 test, P<0.05) and lower body weight than controls at days 28 and 60 (Duncan's test, P<0.05 and P<0.01, respectively). The PS, PSF and CF groups showed lower motor activity scores than controls when tested at day 28 (Duncan's test, P<0.01 for PS group and P<0.05 for CF and PSF groups). In the enriched environment test performed on day 37, between-group differences in total motor activity were not detected; however, the PS, CF and PSF groups displayed less exploration time than controls (Duncan's test, P<0.05). Only the PS group showed impaired motor activity and impaired social behavior at day 42 (Duncan's test, P<0.05). In fact, CVS treatment during gestation plus suckling with a previously stressed mother caused long-lasting physical and behavioral changes in rats. Cross-fostering PS-exposed pups to a dam which was not submitted to stress counteracted most of the harmful effects of the treatment. It is probable that prenatal stress plus suckling from a previously stressed mother can induce long-lasting changes in the neurotransmitter systems involved in emotional regulation. Further experiments using neurochemical and pharmacological approaches would be interesting in this model.

Detection of hormesis effect in longevity: simulation approach for heterogeneous population.

Manifestation of hormesis in longevity was modelled by modification of the mortality rate during and after the period of a stress factor action. In heterogeneous population this can lead to observation of unchanged mortality during action of the stress and decrease in mortality after stress period. Stochastic simulations were made to investigate the possibility of detecting the hormesis effect on the basis of the stress-control longitudinal data. The goal of the stochastic simulation was to investigate the role in the hormesis detection of control and stressed group size, of population heterogeneity variance value, of stress and hormesis attributable risks as well as the role of a prior information about the survival in the control group. It was demonstrated that if the attributable risks for stress and hormesis effects are approximately equal, then in both 'high' and 'low' heterogeneous populations the hormesis phenomenon is detected with probability higher than 75% even in relatively 'small' groups of 50 subjects. In case of 'weak' effect the hormesis phenomenon is not detected in a 'highly heterogeneous' population even in a group composed of 1000 subjects. In a 'low heterogeneous' population the hormesis phenomenon is detected with probability higher than 70% when the group size is not less than 200 subjects. Information about the survival in control group did not play a critical role in all experiments and exact survival curve may be replaced by the traditional Kaplan-Meier estimate.

Relationship of metabolic indexes to postoperative mortality in surgical infants.

Acute injury is known to evoke a metabolic stress response, characterized by cytokine release and reprioritization of hepatic protein synthesis to increase acute phase proteins at the expense of visceral proteins. The impact of these evolving, stress-induced, perioperative metabolic changes on clinical outcome in surgical infants has not yet been determined. The cytokine (tumor necrosis factor [TNF]), acute phase protein (C-reactive protein [CRP]), and visceral protein (prealbumin [PA]) responses to acute metabolic stress were evaluated in 41 infants (average age, 47 days) preoperatively and on postoperative days 1 through 7 (POD 1 to 7) following major surgery. Infants were retrospectively grouped according to whether they survived (group 1) or died within 30 days of surgery (group 2). Peak CRP values in the postoperative period were also included for both groups. Peak CRP levels (14.9 +/- 5.5 v 8.1 +/- 5.7 mg/dL) were significantly increased (P = .0056) and preoperative prealbumin levels (6.0 +/- 2.7 v 11.0 +/- 5.2 mg/dL) were significantly decreased (P = .0005) in group 2 (nonsurvivors) compared with group 1 (survivors). Though serum TNF levels were substantially increased in nonsurvivors compared with survivors, both preoperatively (16.5 +/- 35.2 v 0.6 +/- 2.6 pg/mL) and on POD 1 (3.6 +/- 6.8 v 0.6 +/- 2.7 pg/mL), these values did not reach statistical significance (P > .05). The most significant difference (P = .0001) was observed in persistently depressed late (POD 4 to 7) prealbumin levels in nonsurvivors relative to survivors (5.3 +/- 3.1 v 10.5 +/- 4.3 mg/dL), suggesting an increased risk of poor outcome if acute metabolic stress had not abated by this time.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant porcine somatotropin for sows during late gestation and throughout lactation.

Two experiments were conducted to evaluate whether administration of recombinant porcine somatotropin (pST) to sows (Hampshire-Yorkshire) enhanced lactational performance. In Exp. 1, sows (n = 84) were fed a corn-soybean meal diet (17.8% CP), or a similar diet with 8% added fat, from d 108 of gestation to d 28 of lactation. Half of the sows fed each diet were injected with 6 mg/d of pST from d 108 of gestation to d 24 of lactation. Diets were fed at 2.27 kg/d from d 108 of gestation until farrowing and then were self-fed during lactation. By d 3 of lactation, litter size was standardized at 8 to 10 pigs per litter. Treating sows with pST resulted in a 10-fold increase (P less than .001) in serum somatotropin at 4 h postinjection. Serum glucose was increased (P less than .01) and serum triglycerides, creatinine, and urea N were decreased (P less than .01) by pST. During the summer, apparent heat stress occurred in pST-treated sows, resulting in 14 deaths. Most (10) of the deaths occurred just before, during, or shortly after farrowing. Fewer (P less than .08) deaths occurred when pST-treated sows were fed the diet with added fat. Sows treated with pST consumed less feed (P less than .10) and lost more backfat (P less than .10) during lactation than controls. Increasing the dietary fat did not prevent these changes. Weaning weights of pigs and milk yield of sows (estimated by deuterium oxide dilution) were not affected by pST treatment. In Exp. 2, sows (n = 42) were injected weekly with 0 or 70 mg of pST on d 3, 10, 17, and 24 of lactation. Litters were standardized by d 3 at 8 to 10 pigs, and sows were fed the same control (low fat) diet as in Exp. 1. Sows treated with pST consumed less feed and lost more weight and backfat during lactation than untreated sows. Litter size, average pig weaning weights, and milk yield were not influenced by pST treatment. These data indicate that a 6-mg daily injection of pST from 6 d prepartum to d 24 of lactation or a 70-mg weekly injection of pST from 3 d postpartum to d 24 of lactation does not increase milk production in lactating sows.

Effects of stress due to deprivation and transport in different genotypes of house mouse.

The importance of various stress factors involved in boxing and transit of wild and laboratory mice on a 28 hour journey was studied. Transference from laboratory cage to transit box alone caused weight loss; under the best conditions the laboratory mice lost 5% of their initial weight and wild ones 8%. Deprivation of food resulted in absolute loss of weight; from this death ensued when 20% of initial weight was lost: the smaller wild mice died sooner than the larger laboratory ones. Water deprivation resulted in retarding recovery of weight lost; wild mice took longer to recover than laboratory ones. It also caused weight loss and, in conjunction with deprivation of food, poor condition and death. Transit itself affected percentage weight loss and wheat consumption; wild mice were affected differently from laboratory mice in both respects. Genotype is seen to be important not only in controlling initial weight and activity level, but also--and independently of weight--the total food requirement. In the light of these findings current literature giving guidance on shipment of small mammals is shown to be inadequate, and certain recommendations are given.

Small mammal survival and trapability in mark-recapture monitoring programs for hantavirus.

Following the 1993 hantavirus pulmonary syndrome (HPS) epidemic in the south-western United States, mammalogists and epidemiologists instituted long-term studies to monitor population density and prevalence of infection in rodents which constitute the reservoir for Sin Nombre virus (SNV). In this study, field techniques used in sampling small mammals for SNV infection were evaluated to determine if trapping and handling protocols were having significant effects on future trapability or mortality of animals. We compared rodent mark-recapture control plots, on which all rodents were simply measured, marked, and released on site, with experimental plots on which all animals were anesthetized with methoxyflurane, sampled for blood and saliva, measured, marked, and released. Blood samples were obtained from anesthetized animals on the experimental plots via a retro-orbital sinus puncture using a heparinized capillary tube. Dacron tipped oral swabs were used to collect buccal cells and saliva from the rodent's oral cavity. Field data were collected monthly from August 1994 to August 1996 at two sites in New Mexico (USA). Analyses were based on 3,661 captures of 1,513 individuals representing 21 species from three rodent families (Rodentia: Muridae, Heteromyidae, Sciuridae) and two species of rabbits (Lagomorpha: Leporidae). Overall, for most murid rodents (including five Peromyscus spp., Neotoma albigula, and Onychomys leucogaster) and one rabbit species (Sylvilagus floridanus), the handling/bleeding procedures had no significant effects on recapture rates or mortality. In contrast, several species of heteromyids (Dipodomys ordii and Perognathus flavus), one murid (Reithrodontomys megalotis) and one leporid (S. auduboni) suffered higher mortality rates, and heteromyid kangaroo rats (D. ordii and D. merriami) exhibited lower trapability as a result of the anesthesia and sampling procedures. In view of the overall non-significant influence of the sampling procedures on murid rodents, the anesthesia and blood/saliva sampling protocols described herein appear to be appropriate for hantavirus research, and may serve as a model for environmental monitoring of other zoonotic agents and their reservoirs.