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PubMed1999

Alterations in endogenous circadian rhythm of core temperature in senescent Fischer 344 rats.

We assessed whether alterations in endogenous circadian rhythm of core temperature (CRT) in aging rats are associated with chronological time or with a biological marker of senescence, i.e., spontaneous rapid body weight loss. CRT was measured in male Fischer 344 (F344) rats beginning at age 689 days and then continuously until death. Young rats were also monitored. The rats were housed under constant dim red light at 24-26 degrees C, and core temperature was recorded every 10 min via biotelemetry. The CRT amplitude of the body weight-stable (presenescent) old rats was significantly less than that of young rats at all analysis periods. At the onset of spontaneous rapid weight loss (senescence), all measures of endogenous CRT differed significantly from those in the presenescent period. The suprachiasmatic nucleus (a circadian pacemaker) of the senescent rats maintained its light responsiveness as determined by an increase in c-fos expression after a brief light exposure. These data demonstrate that some characteristics of the CRT are altered slowly with chronological aging, whereas others occur rapidly with the onset of senescence.

Aging↗
PubMed2003

Chronic centrifugation (hypergravity) disrupts the circadian system of the rat.

The present study was conducted to evaluate the response of rat deep body temperature (DBT) and gross locomotor activity (LMA) circadian rhythms to acute hypergravity onset and adaptation to chronic (14 day) hypergravity exposure over three gravity intensities (1.25, 1.5, and 2 G). Centrifugation of unanesthetized naive animals resulted in a dramatic acute decrease in DBT (-1.45, -2.40, and -3.09 degrees C for the 1.25, 1.5, and 2.0 G groups, respectively). LMA was suppressed for the duration of centrifugation (vs. control period); the percent decrease for each group on days 12-14, respectively, was 1.0 G, -15.2%, P = not significant; 1.25 G, -26.9%, P < 0.02; 1.5 G, -44.5%, P < 0.01; and 2.0 G, -63.1%, P < 0.002. The time required for DBT and LMA circadian rhythmic adaptation and stabilization to hypergravity onset increased from 1.25 to 2.0 G in all circadian metrics except daily means. Periodicity analysis detected the phenomenon of circadian rhythm splitting, which has not been reported previously in response to chronic hypergravity exposure. Our analysis documents the disruptive and dose-dependent effects of hypergravity on circadian rhythmicity and the time course of adaptation to 14-day chronic centrifugation exposure.

Adaptation, Physiological↗
PubMed1993

Changes in plasma copper and zinc during rat development.

The association of copper and zinc to plasma ligands was studied during the rat perinatal period. Analysis was carried out by means of column chromatography (Sephadex G-150) and atomic absorption spectrophotometry. Levels of copper were low at birth and showed a sharp increase after day 10. This increase was similar to that of ceruloplasmin activity as well as its association with copper. Zinc levels, instead, showed higher levels before birth and decreased slowly toward the adult values. Association of zinc to albumin and associated proteins showed a pattern similar to the decrease in plasma zinc levels.

Aging↗
PubMed1982

The pharmacokinetics of nomifensine. Comparison of pharmacokinetics and pharmacodynamics using computer pharmaco-EEG.

Pharmacokinetics and pharmacodynamics of nomifensine infusions as compared with oral preparations were investigated in a double-blind place-controlled crossover study in 10 healthy normal volunteers. They received randomized in weekly intervals 75 mg nomifensine and placebo intravenously as well as placebo, 75 and 150 mg nomifensine orally. Blood samples, quantitative EEG evaluations, psychometric tests, blood pressure, pulse rate and side effects were obtained and monitored at the hours 0, 1, 2, 4, 6 and 8. Nomifensine serum levels were determined by a radioimmunoassay; peak levels occurred within the first 2 h, the elimination half-life was around 2 h, both results indicating fast absorption and elimination. While the evaluation of the total nomifensine demonstrated almost identical bioavailability of the oral and intravenous form, free nomifensine levels after 75 mg i.v. were more similar to those after 150 mg than 75 mg p.o. Digital computer period analysis of the EEG confirmed nomifensine as a drug with a significant effect on the CNS as compared with placebo, showing in fact an antidepressant 'pharmaco-EEG profile' similar to desipramine. Evaluation of dose-effect curves demonstrated that 75 mg i.v. was the most effective drug, being closer to 150 than 75 mg p.o. The latter oral dosage could be discriminated from placebo only in certain variables at certain times. Concerning time-effect, nomifensine was most effective around the 6th hour post-drug, which was similar to the psychometric findings, thus showing a considerable delay compared to the peak serum concentration. Relating pharmacodynamic findings to pharmacokinetic results it became evident that free nomifensine may be of far greater importance for the drugs encephalotropic and psychotropic properties than the total unconjugated and conjugated nomifensine--thus justifying the development of a parenteral preparation. Finally, the relationship of blood levels and CNS effects was found to have a characteristic 'hysteresis loop' shape suggesting a delay of pharmacodynamic effects as opposed to the serum concentrations. This delay may be due to a slowly formed active metabolite, the drug acting on deep compartment receptors or both.

Adult↗
PubMedDate not supplied

Dietary fish oil increases conversion of very low density lipoprotein apoprotein B to low density lipoprotein.

Dietary fish oils, which are rich in omega-3 fatty acids, are known to produce a marked lowering of very low density lipoprotein (VLDL) triglyceride concentrations, but they have a less marked effect on low density lipoprotein (LDL) cholesterol. Our previous apolipoprotein (apo) B kinetic studies in miniature pigs demonstrated that conversion of VLDL apo B to LDL apo B accounted for 15% to 20% of total VLDL apo B catabolism. In addition, 75% to 80% of LDL apo B was derived independent of plasma VLDL or intermediate density lipoprotein (IDL) apo B catabolism. The present studies were carried out to determine if fish-oil diets influenced: 1) the conversion of VLDL to LDL, and 2) the pathways of LDL apo B synthesis. Autologous 125I-VLDL and 131I-LDL were injected into four pigs after both a corn-oil (30 g/day for 18 days) and a Maxepa (30 g/day for 18 days) dietary period. Analysis of apo B specific activity curves demonstrated that fish oil reduced the VLDL pool size by 38% (p less than 0.05) due to an increase in fractional catabolic rate (0.83 +/- 0.13 vs. 0.48 +/- 0.03 hr-1), as the synthesis rate was unaffected. However, the proportion of VLDL apo B converted to LDL increased significantly (56 +/- 7% vs. 17 +/- 3%, p less than 0.01) whereas the proportion cleared directly decreased (46 +/- 5% vs. 83 +/- 3%, p less than 0.005). Fish oil reduced total LDL apo B synthesis (0.6 +/- 0.1 vs. 1.1 +/- 0.2 mg/hr/kg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Intravenous fenoldopam versus sodium nitroprusside in patients with severe hypertension.

In an open-label study, we compared the efficacy and safety of intravenous infusion of fenoldopam mesylate with that of sodium nitroprusside in patients with severe hypertension or in hypertensive crisis. Both antihypertensive medications were infused at a maximal dose increment of 0.2 microgram/kg/min (fenoldopam) and 1 microgram/kg/min (nitroprusside), with a maximal infusion rate of 1.5 micrograms/kg/min fenoldopam mesylate or 8 micrograms/kg/min sodium nitroprusside. Once the desired reduction in diastolic blood pressure was achieved (less than 110 mm Hg if initial diastolic blood pressure was 120-149 mm Hg, or by at least 40 mm Hg if initial diastolic blood pressure was 150-190 mm Hg), the maximal infusion rate used was maintained for at least 1 hour, and then, the infusion was slowed gradually over 2 hours. After the infusion treatment, patients remained in the hospital for 2 days of follow-up. Both antihypertensive agents successfully controlled the blood pressure in all the patients by the end of the maintenance periods. Between the baseline and the end of the maintenance period, analysis of variance showed that the changes in the variables induced by fenoldopam mesylate did not differ significantly from those induced by sodium nitroprusside. The incidence of side effects listed were similar in both groups of patients. The detection of toxic levels of thiocyanate in two patients treated with nitroprusside, however, shows that fenoldopam might be preferable for the control of a hypertensive crisis or severe hypertension in patients with decreased renal function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1995

Improved survival of stroke patients during the 1980s. The Minnesota Stroke Survey.

BACKGROUND AND PURPOSE: The underlying reasons for the decline in stroke mortality in the United States are not well understood and have been the subject of ongoing debate. This study was undertaken to determine whether survival of hospitalized stroke patients has changed during the 1980s, thereby contributing to the decline in stroke mortality during that period. METHODS: For the years 1980, 1985, and 1990, we obtained listings of discharge diagnoses from hospitals in the Minneapolis-St Paul metropolitan area and identified all hospitalizations with a discharge diagnosis code of acute cerebrovascular disease according to the International Classification of Diseases, 9th Revision. A 50% random sample of men and women aged 30 to 74 years was selected in each survey for detailed medical record abstraction. Standardized sets of criteria for stroke were then used to validate acute stroke events throughout the 1980s. Each of the three period cohorts of hospitalized stroke patients (1980, 1985, and 1990) was followed for at least 2 years for all-cause mortality end point. RESULTS: A total of 1853 patients met minimal criteria for acute stroke: 564 patients in 1980, 598 patients in 1985, and 691 patients in 1990. Controlling for age, the odds of death within 2 years after stroke were approximately 40% lower in 1990 than in 1980. The relative odds of 2-year death in 1990 (versus 1980) were 0.65 (95% confidence interval, 0.47 to 0.89) and 0.60 (95% confidence interval, 0.42 to 0.85) for men and women, respectively. The improved survival was evident in the short term (28 days) as well as for stroke patients who survived that period. Analysis according to stroke subtype revealed that improved survival of ischemic stroke and specifically of stroke with no apparent cardioembolic source largely accounted for the overall trend. The prognosis of stroke patients who were admitted in a comatose state has not changed during that decade. CONCLUSIONS: Despite the absence of any clear major advances in acute stroke therapy, survival of stroke patients substantially improved during the 1980s. The underlying reasons for this unexpected yet remarkable trend remain uncertain but may include improved supportive and rehabilitative care of stroke victims as well as a change in the natural history of the disease.

Adult↗
PubMed2006

Neural processing of counting in evolved spiking and McCulloch-Pitts agents.

This article investigates the evolution of autonomous agents that perform a memory-dependent counting task. Two types of neurocontrollers are evolved: networks of McCulloch-Pitts neurons, and spiking integrate-and-fire networks. The results demonstrate the superiority of the spiky model in evolutionary success and network simplicity. The combination of spiking dynamics with incremental evolution leads to the successful evolution of agents counting over very long periods. Analysis of the evolved networks unravels the counting mechanism and demonstrates how the spiking dynamics are utilized. Using new measures of spikiness we find that even in agents with spiking dynamics, these are usually truly utilized only when they are really needed, that is, in the evolved subnetwork responsible for counting.

Animals↗
PubMed2003

Ocular hypertension in mice with a targeted type I collagen mutation.

PURPOSE: To evaluate intraocular pressure (IOP) in transgenic mice with a targeted mutation in the gene for the alpha1 subunit of collagen type I. METHODS: Homozygous B6; 129-Cola1(tm1Jae) mice and corresponding wild-type mice were anesthetized. A fluid-filled glass microneedle connected to a pressure transducer was then inserted through the cornea into the anterior chamber to measure IOP. All measurements were made between 11:30 AM and 1:30 PM. The IOP of seven Col1a1(r/r) and eight corresponding wild-type Col1a1(+/+) male mice was measured at 12, 18, 24, and 36 weeks after birth. The IOP of 5 to 24 additional Col1a1(r/r) mice was measured at 7, 12, 18, 24, and 36 weeks after birth. The structure of the anterior segment and the distribution of collagen I were assessed by immunohistochemistry. RESULTS: Mean IOP measurements of the control Col1a1(+/+) mice (IOP(c)) at 12 and 18 weeks after birth were relatively constant at 18.9 +/- 2.0 and 19.2 +/- 1.9 mm Hg, respectively. Mean IOP then decreased to 15.8 +/- 0.8 and 16.2 +/- 1.2 mm Hg at 24 and 36 weeks, respectively. In contrast, mean IOP measurements in the transgenic (Col1a1(r/r)) mice was 2.7 +/- 3.4 mm Hg higher at 12 weeks and increased to a maximum of 23.6 +/- 2.4 mm Hg at 24 weeks. The difference between mean IOP in these two groups gradually increased to a maximum of 4.8 mm Hg (30%) at 36 weeks and was significantly different from the control mice at both 24 and 36 weeks of age. No anterior segment abnormality was observed in Col1a1(r/r) mice and no difference between the anterior segment appearance of Col1a1(r/r) and Col1a1(+/+) mice was observed throughout the 36-week analysis period. However, collagen I immunoreactivity in sclera and associated structures was greater in Col1a1(r/r) mice than in Col1a1(+/+) mice. When the mean IOP measurements from the additional Col1a1(r/r) mice were included with these measurements, mean IOP at each age was 16.7 +/- 0.8, 21.8 +/- 3.9, 23.2 +/- 2.8, 23.5 +/- 2.4, and 22.1 +/- 3.6 mm Hg, respectively. Mean IOP in the Col1a1(r/r) mice was significantly higher than in the Col1a1(+/+) mice at 18, 24, and 36 weeks by 21%, 44%, and 36%, respectively (P < 0.05). CONCLUSIONS: These results demonstrate ocular hypertension in mice with a targeted type I collagen mutation and suggest there is an association between IOP regulation and fibrillar collagen turnover.

Animals↗
PubMed2000

Effects of gonadal steroids in women with a history of postpartum depression.

OBJECTIVE: Endocrine factors are purported to play a role in the etiology of postpartum depression, but direct evidence for this role is lacking. The authors investigated the possible role of changes in gonadal steroid levels in postpartum depression by simulating two hormonal conditions related to pregnancy and parturition in euthymic women with and without a history of postpartum depression. METHOD: The supraphysiologic gonadal steroid levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by inducing hypogonadism in euthymic women-eight with and eight without a history of postpartum depression-with the gonadotropin-releasing hormone agonist leuprolide acetate, adding back supraphysiologic doses of estradiol and progesterone for 8 weeks, and then withdrawing both steroids under double-blind conditions. Outcome measures were daily symptom self-ratings and standardized subjective and objective cross-sectional mood rating scales. RESULTS: Five of the eight women with a history of postpartum depression (62.5%) and none of the eight women in the comparison group developed significant mood symptoms during the withdrawal period. Analysis of variance with repeated measures of daily and cross-sectional ratings of mood showed significant phase-by-group effects. These effects reflected significant increases in depressive symptoms in women with a history of postpartum depression but not in the comparison group after hormone withdrawal (and during the end of the hormone replacement phase), compared with baseline. CONCLUSIONS: The data provide direct evidence in support of the involvement of the reproductive hormones estrogen and progesterone in the development of postpartum depression in a subgroup of women. Further, they suggest that women with a history of postpartum depression are differentially sensitive to mood-destabilizing effects of gonadal steroids.

Adult↗
PubMed2005

Diazepam tolerance effects on vestibular function testing, part II: vestibulo-ocular reflex parameters during rotational testing.

OBJECTIVES: The purpose of this prospective study was to determine whether clinical doses of diazepam (DZ; 10 mg/d) administered for 14 days result in tolerance as measured by the sinuosidal harmonic acceleration (SHA) rotational test. It has been shown that repeated dosing with DZ leads to accumulation and tolerance in outcome measures that assess memory, sedation, and psychomotor tasks. METHODS: In a double-blinded, repeated-measures design, 30 normal male subjects who ranged in age from 20 to 36 years were randomly assigned to a placebo group or a DZ group and participated in 6 SHA rotational sessions over a 2-week period. Analysis of drug-placebo differences in percent change from baseline was performed with a 1-way analysis of variance. RESULTS: Vestibulo-ocular reflex gain and phase frequencies at 0.01, 0.02, 0.04, and 0.08 Hz were significant (p < .05) for treatment group. No significant effect was observed for gain and phase frequency at 0.16 Hz--a finding that indicates selective effects on different central nervous system mechanisms. There was no statistical significance for time. CONCLUSIONS: Clinically, the DZ subjects' scores remained within the normal ranges for vestibulo-ocular phase and gain, suggesting that patients in whom drug cessation is problematic may not have to discontinue DZ before testing with the SHA rotational system.

Adult↗
PubMed2002

The new phosphodiesterase 4 inhibitor roflumilast is efficacious in exercise-induced asthma and leads to suppression of LPS-stimulated TNF-alpha ex vivo.

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Efficacy and tolerability of sustained-release clomipramine (Anafranil SR) in the treatment of phobias: a comparison with the conventional formulation of clomipramine (Anafranil).

This multicentre double-blind trial in general practice compared the efficacy and tolerability of the sustained-release formulation of clomipramine (Anafranil SR) with its conventional formulation (Anafranil) in the treatment of phobias. Patients were allocated at random to receive clomipramine 75 mg once daily as either the sustained-release or conventional formulation for 11 weeks following a 1-week dosage build-up period. Analysis of results from forty-six patients showed that the sustained release formulation of clomipramine 75 mg was as effective as the conventional formulation of clomipramine 75 mg in improving symptoms of phobia as assessed by a phobia inventory and global evaluation. Unwanted effects attributable to therapy were similar in both treatment groups but there were fewer withdrawals due to unwanted effects of the sustained release formulation of clomipramine 75 mg. It was concluded that the sustained-release formulation of clomipramine does offer advantages for patients requiring 75 mg clomipramine daily.

Adolescent↗
PubMed2005

Assessment of outcome over a 10-year period of patients admitted to a multidisciplinary adult intensive care unit with haematological and solid tumours.

The risk factors for time to mortality, censored at 30 days, of patients admitted to an adult teaching hospital ICU with haematological and solid malignancies were assessed in a retrospective cohort study. Patients, demographics and daily ICU patient data, from admission to day 8, were identified from a prospective computerized database and casenote review in consecutive admissions to ICU with haematological and solid tumours over a 10-year period (1989-99). The cohort, 108 ICU admissions in 89 patients was of mean age (+/-SD) 55+/-14 years; 43% were female. Patient diagnoses were leukaemia (35%), lymphoma (38%) and solid tumours (27%). Median time from hospital to ICU admission was five days (range 0-67). On ICU admission, 50% had septic shock and first day APACHE II score was 28+/-9. Forty-six per cent of patients were ventilated. ICU and 30-day mortality were 39% and 54% respectively. Multivariate Cox model predictors (P<0.05), using only ICU admission day data were: Charlson comorbidity index (CCI), time to ICU admission (days) and mechanical ventilation. For daily data (admission through day 8), predictors were: cohort effect (2nd vs 1st five-year period); CCI; time to ICU admission (days); APACHE II score and mechanical ventilation. Outcomes were considered appropriate for severity of illness and demonstrated improvement over time. Ventilation was an independent outcome determinant. Controlling for other factors, mortality has improved over time (1st vs 2nd five year period). Analysis restricted to admission data alone may be insensitive to particular covariate effects.

APACHE↗
PubMed2005

Health as expanding consciousness: seven women living with multiple sclerosis or rheumatoid arthritis.

The meaning of health as expanding consciousness is explored through stories of seven women who developed multiple sclerosis or rheumatoid arthritis during their lives. Using Newman's hermeneutic-dialectic approach, unstructured interviews were conducted over a 2-year period. Analysis and interpretation of narratives concerning person-environment interactions revealed turning points and separate choice points before four new ways of living including finding simple pleasures, being positive, gaining self-control, and self-differentiation, were found. Support for Newman's stages of expanding consciousness and more comprehensive descriptions of self-transcendence in space and time are presented. Implications for theory development and theory-guided practice are offered.

Adult↗
PubMed2002

Reading, writing, and having babies: a nurturing alternative school program.

This ethnographic study, a component of another study that examined the lived experiences of a small group of pregnant teenagers, focused on the social and learning environment of an alternative school program for pregnant and parenting female adolescents, aged 13 to 19. Field notes, participant observation, group discussion, and informal conversational data were gathered over a 16-week period. Analysis of the data revealed four major themes: nurture and positive regard, sisterhood and belonging, mentoring and sense of family, and proactive learning environment and academic pride. The girls who attended the program developed close relationships with their peers and teachers. Many of them experienced academic success for the first time and reported that pregnancy and impending motherhood motivated them to do better in school. Recommendations for a more comprehensive school-based approach to meeting the needs of pregnant and parenting teens are made, particularly after the babies are born.

Adaptation, Psychological↗
PubMed1976

An assessment of the therapeutic potential of azapropazone in rheumatoid arthritis.

A trial to compare the therapeutic potential of 1200 mg. azapropazone daily with 3.9 g. aspirin daily was carried out in 108 out-patients with rheumatoid arthritis over a 14-day period. Analysis of results from the 85 patients with completed assessment data (49 on azapropazone; 36 on aspirin) showed that azapropazone was better than aspirin from the point of view of pain relief, number of days patients were withdrawn prematurely from the trial, and patient satisfaction with treatment. The differences, however, were not statistically significant. The authors compare the results obtained in this trial with those obtained previously from trials with 13 other antirheumatic drugs using the same method.

Administration, Oral↗
PubMed1976

Patient tolerance of long-term diuretic/potassium supplement therapy.

Forty patients with congestive heart failure or hypertensive heart disease were given long-term maintenance treatment with a combined bumetanide/slow-release potassium supplement preparation ('Burinex K'). Stabilised doses ranged from 0.5 mg to 2 mg bumetanide with from 7.7 mmol to 30.8 mmol potassium. Patients took doses either at 9 a.m. or at 5 p.m. daily during a series of alternate 2 to 4-weekly treatment periods. Analysis of patient preference for morning or evening diuresis showed that the majority (72.5%), including all 18 patients who went out to work, preferred the evening regimen. Bumetanide proved to be a highly effective diuretic, irrespective of time of administration. Evening diuresis was associated with a statistically significant increase in the 24-hour excretion of sodium. Serial laboratory analyses showed no clinically significant changes in serum potassium or other parameters examined an in contrast to other diuretics bumetanide produced no significant hyperuricaemic effects.

Adult↗