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Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection.

Patients suffering from serious bacterial infection present to the hospital after early inflammatory events, such as release of tumor necrosis factor (TNF), have been initiated. The role of other cytokines, such as interleukin-8 (IL-8), a neutrophil chemoattractant and activator, in the pathophysiology of human sepsis is not well characterized, and there are only limited data on IL-6. We studied serial concentrations of TNF, IL-6 (involved in the acute-phase response), and IL-8 in plasma and leukocyte levels of mRNA for these cytokines in patients with localized and septicemic Pseudomonas pseudomallei infection on admission to the hospital and during a prolonged recovery phase (up to 30 days). Of 18 patients, 8 had detectable plasma IL-8 and all had raised plasma IL-6 concentrations. In patients who died median initial concentration of IL-8 (167 pg/ml; range, 97 to 362 pg/ml) and IL-6 (4,800 pg/ml; range, 60 to 9,245 pg/ml) in plasma were higher than those in survivors (P less than 0.008 and P = 0.007, respectively). Septic patients who survived and patients with localized disease had similar cytokine levels. Plasma IL-8 and IL-6 concentrations were elevated throughout the inpatient period of recovery. Circulating leukocytes contained mRNA for IL-8 but not for IL-6 and TNF, and they may secrete IL-8. An elevated plasma IL-6 concentration (greater than 1,000 pg/ml) had 75% mortality) was the best predictor of mortality in P. pseudomallei sepsis. Fifty percent of patients with detectable plasma IL-8 concentrations died. In contrast, plasma TNF bioactivity did not relate to outcome; 75% of patients who did never had detectable plasma TNF activity.

Adult↗

The effect of ethanol on metabolic, hemodynamic and electrical responses to cortical spreading depression.

Alcohol induces a decrease in cerebral blood flow (CBF) and metabolic rate, mitochondrial damage and other impairments in brain function and structure. Cortical spreading depression (CSD) is a phenomenon causing changes in ion homeostasis and raises energy demand, mitochondrial activity and CBF. It is of great interest to study the effect of ethanol on brain response under a challenge of increasing oxygen demand by inducing CSD. A special multisite assembly (MSA) was constructed to evaluate metabolic (mitochondrial NADH), hemodynamic (reflectance) and electrical (DC potential) activities from four parasagittally adjacently arranged areas of the cerebral cortex, continuously and simultaneously in vivo. Three CSD cycles were initiated every 30 min before and after ethanol or saline infusion over 4.5 h. During CSD amplitude changes of reflectance, NADH and DC potential as well as propagation rates and wave frequency were calculated. After ethanol infusion CSD showed a decrease in the negative shift of the DC potential, and alterations in the biphasic responses in reflectance, which may indicate alteration in blood volume: unclear responses in the initial vasoconstriction phase and a significant increase in the subsequent vasodilatation phase. The reduction in the amplitude of the NADH oxidation cycle may depict a decrease in energy production, which could also be indicated by a decline in wave frequency (prolonging the recovery phase of the CSD). The decrease in propagation rate indicates a decline in tissue excitability and in the CSD initiation mechanism induced by ethanol treatment.

Alcohol-Induced Disorders, Nervous System↗

Safe mobilization of normal progenitors in advanced chronic myeloid leukemia with intensive chemotherapy and granulocyte-colony stimulating factor.

Twenty-one patients with advanced chronic myeloid leukemia (late chronic phase (n = 8), accelerated phase (n = 11) and blast crisis (n = 2)) were treated with idarubicin, cytarabine, and etoposide followed by G-CSF and subsequent collection of peripheral blood progenitor cells in the early recovery phase. Treatment was reasonably well tolerated with no deaths or intensive care admissions. Despite the advanced phase of disease and heavy pretreatment with cytotoxics and interferon-alfa, 11 of 21 patients (52%) achieved a cytogenetic response. Of the nine major cytogenetic responses (complete (n = 3) and partial (n = 6)), seven achieved adequate progenitor collections for consideration for autologous transplantation. The only predictor of response was disease duration (P = 0.02). With a median follow-up of 1171 days from treatment it appears unlikely that G-CSF contributed to disease progression. Survival post-IcE was predicted by disease stage (P = 0.0001). Intensive chemotherapy followed by G-CSF allowed adequate yields of predominantly Philadelphia chromosome negative progenitor cells to be obtained from one-third of patients with advanced CML.

Adult↗

Lower extremity general muscle moment patterns in healthy individuals during recumbent cycling.

OBJECTIVE: The purpose of this study was to compare lower extremity generalized muscle moments across two workloads during recumbent bicycling in younger and older healthy adults. DESIGN: The study design was a comparative investigation of cycling patterns. BACKGROUND: Biomechanical data regarding muscle activation, kinematic, and kinetic patterns have been presented for upright cycling, but only a few studies have evaluated biomechanical patterns during the alternative configuration of recumbent cycling. METHODS: Twenty-four healthy adults, classified by age into two different groups, under 35 and over 50 years of age, rode a recumbent bicycle at a constant cadence (60-65 rpm) and at two different resistances (0.5 and 1.0 kg m) while kinematic and kinetic data were recorded. General muscle moments were calculated using joint kinematic and kinetic data via inverse dynamic equations. RESULTS: The ankle general muscle moment remained plantar flexor throughout the pedaling cycle; the knee general muscle moment remained flexor throughout the cycle, except during the power phase of the higher workload where an extensor general muscle moment was observed; and the hip general muscle moment was extensor with a transient flexor general muscle moment period during the recovery phase. Increased workload led to increases in ankle plantar flexor and knee extensor general muscle moment magnitudes, but no changes at the hip. Age had no effect on general muscle moment magnitudes or patterns. CONCLUSIONS: Configurational differences between the upright and recumbent bicycle do not affect patterns, but the total output requirements do affect the magnitudes of the general muscle moments. RELEVANCE: Based on previous studies, the recumbent bicycle appears to be a safe rehabilitation tool for post-cerebrovascular accident and cardiorespiratory patients, but in order to more properly and efficiently use the recumbent bicycle as a rehabilitation tool, normative biomechanical data are necessary. The current study is the first such investigation to report normative data of lower extremity general muscle moment patterns during recumbent cycling. Effects of age and workload were also demonstrated.

Adult↗

Calcium buffering and protection from excitotoxic cell death by exogenous calbindin-D28k in HEK 293 cells.

Calbindin-D28k (CaBP) is a calcium-binding protein found in specific neuronal populations in the mammalian brain that, as a result of its proposed calcium-buffering action, may protect neurons against potentially harmful increases in intracellular calcium. We have stably transfected HEK 293 cells with recombinant human CaBP in order to determine the influence of this protein upon transient increases in intracellular ionic calcium concentration ([Ca(2+)](i)) induced either by transient transfection of the NR1 and NR2A subunits of the N-methyl-D-aspartate (NMDA) receptor and brief exposure to glutamate, photolysis of the caged calcium compound NP-EGTA, or exposure to the Ca(2+)]-ionophore 4-Br-A23187. The presence of CaBP did not significantly reduce the peak [Ca(2+)](i)stimulated by glutamate activation of NMDA receptors but significantly prolonged the recovery to baseline values. Flash photolysis of NP-EGTA in control cells resulted in an almost instantaneous increase in [Ca(2+)](i)followed by a bi-exponential recovery to baseline values. In cells stably expressing CaBP, the peak [Ca(2+)](i)levels were not statistically different from the controls, however, there was a significant prolongation of the initial portion of the slow recovery phase. In cells exposed to 4-Br-A23187, the presence of CaBP significantly reduced the rate of rise of [Ca(2+)](i), reduced the peak response, slowed the rate of recovery, and reduced the depolarization of mitochondria. In studies of delayed, Ca(2+)]-dependent cell death, CaBP transfected cells exhibited enhanced survival 24h after a 1-h exposure to 200 microM NMDA. However, necrotic cell death observed after the first 6h was not prevented by the presence of CaBP. These results provide direct evidence for a Ca(2+)-buffering effect of CaBP which serves to limit Ca(2+)entry and the depolarization of mitochondria, thereby protecting cells from death mediated most likely by apoptosis.

Animals↗

A prospective study of urinary retention and risk of death after proximal femoral fracture.

Older age, dementia syndrome and impaired mobility are well recognized risk factors for fatality after fracture of the proximal femur. Urinary retention is recognized as a common complication of elective total hip replacement. In this investigation, we estimated the incidence of urinary retention associated with hip fracture in older women and assessed its relationship to 2-year post-operative fatality. Over a 7-month period, 309 women aged 65 and over were admitted to one trauma unit with hip fracture. Readings of post-voiding residual volume were taken on admission (pre-operative), within 24 hours of operation (post-operative) and 5-7 days post-operatively (recovery). Of the 309 patients, 244 (79%) had readings of post-voiding residual volume taken on admission; 90/244 (37%) had retention pre-operatively, 122/216 (56%) post-operatively and 40/183 (22%) in the recovery phase. One year after operation 305 patients were traced and median follow-up was 2 years. Older age, cognitive impairment, polypharmacy, impaired mobility and urinary retention on admission and during recovery were associated with a higher fatality in the first post-operative year. Pre-operative urinary retention is common among older women with proximal femoral fracture and affects over half post-operatively. Retention is one of several factors associated with higher fatality.

Aged↗

Rat liver injury after normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor.

Hepatic ischemia occurs in liver transplantation, hemodynamic or cardiogenic shock, and liver resection associated with trauma or tumor. Ischemia/reperfusion (I/R) injury results in microcirculation failure followed by apoptosis and necrosis. Matrix metalloproteinases (MMPs) are involved in many physiological and pathological processes, but their expression and function during liver I/R remains poorly documented. In this study, we evaluated the expression of nine MMPs and their natural inhibitors, tissue inhibitors of MMPs (TIMPs), in a rat model of liver I/R. Analysis of MMP and TIMP expression show that although most of these genes are not constitutively expressed in the normal liver, they are induced in a specific time-dependent manner following I/R. Stromelysin-1, gelatinase B, and collagenase-3 are induced during the early phase of acute liver injury associated with inflammation and increased necrosis/apoptosis, whereas gelatinase A, membrane type-MMP, stromelysin-3, metalloelastase, TIMP-1, and TIMP-2 are essentially detectable during the recovery phase of liver injury corresponding to hepatocyte regeneration. This observation suggested that MMPs and TIMPs could play both deleterious and beneficial roles following I/R. We thus tested the effect of a specific phosphinic MMP inhibitor on acute liver I/R injury. Inhibition of MMP activity was shown to significantly decrease liver injury in ischemic/reperfused liver tissue as assessed by histological studies and serum hepatic enzyme levels. We therefore propose that MMP inhibitors may be of clinical relevance in liver-associated ischemic diseases or after liver transplantation.

Animals↗

Effect of aging on the recovery following contraction-induced injury in muscles of female mice.

By the age of 80 yr, the skeletal muscles of men and women decrease in mass and maximum force by approximately 30%. Severe contraction-induced injury may contribute to these age-related declines. One to two months after a 225 lengthening contraction protocol (LCP), muscles of young/adult male mice recovered completely, whereas those of old male mice sustained deficits of approximately 15% in mass and approximately 25% in maximum force. Although gender-related differences in the early events of contraction-induced injury have been reported, the recovery phase of muscles in old female animals has not been investigated. The hypothesis tested was that 2 mo after a severe LCP to the plantar flexor muscle group, the magnitude of recovery of mass and force for old female mice is less than that for adult female mice. The LCP was administered to muscles of adult and old, female C57BL/6 mice. At 3 days, 1 mo, and 2 mo following the LCP, maximum isometric force was measured, and muscles were removed and weighed. Two months following the LCP, the muscles of adult female mice recovered mass and force. In contrast, for old female mice, even after 2 mo, muscle masses were decreased by 11% and maximum forces by 38%. We conclude that, as reported previously for old male mice, a severe contraction-induced injury to muscles of old female mice results in prolonged deficits in mass and force.

Aging↗

Brainstem auditory evoked responses during the recovery of Wernicke's disease.

Serial brainstem auditory evoked responses (BAERs) during the acute and recovery phase of Wernicke's disease were studied in two patients. Both morphologic abnormalities and prolongation of absolute and interpeak latencies of wave I through V were noted during the acute and recovery periods. Normalization was found in one patient and incremental improvements in the other. This study suggests that the BAER may provide documental evidence of auditory tracts involvement in Wernicke's disease. The diagnostic value of the BAER is for establishing the presence of brainstem involvement when features of classical triad of Wernicke's disease are absent. This pathologic process may or may not be reversible with thiamine treatment.

Brain Stem↗

An investigation of postural control in postoperative anterior cruciate ligament reconstruction patients.

OBJECTIVE: To investigate quadriceps strength and static and dynamic balance in the anterior cruciate ligament (ACL)-reconstructed patient and to compare these findings with an age-matched, injury-free control group. DESIGN AND SETTING: A 2 x 2 mixed-design analysis of variance (group x leg) was applied to the static posture, dynamic balance, and strength data. In addition, Pearson product-moment correlations were calculated to determine the strength of the relationships among the dependent measures. All data were collected in the Motor Control Laboratory at Indiana University. SUBJECTS: The experimental group was composed of 20 individuals who had undergone ACL reconstruction with a patellar tendon autograft. The control group comprised 20 participants with no history of significant orthopaedic injuries to the lower extremities. MEASUREMENTS: The dependent variables were sway path linear mean for the static condition, dynamic-phase recovery time after perturbation for the dynamic measure, and quadriceps peak torque for strength. RESULTS: We found significant differences between the ACL and control groups on the measures of dynamic-phase duration and peak torque. The static sway variable did not show a significant difference. CONCLUSIONS: Evaluation of the postural control system under 2 conditions, static and dynamic, showed differences between the ACL and control groups for the dynamic condition only. These results suggest the presence of independent control mechanisms for the control of static and more dynamic postures. In addition, because there were no differences between the injured and noninjured legs of the ACL group, the theory of a central postural control scheme is supported.

Journal Article↗

Plasma atrial natriuretic peptide and endothelin levels in acute poststreptococcal glomerulonephritis.

Plasma levels of atrial natriuretic peptide (ANP) and of endothelin (ET) were significantly elevated (87.7 +/- 13.9 pg/ml and 79.7 +/- 10.8pg/ml, respectively) during the acute phase of acute poststreptococcal glomerulonephritis (APSGN). Plasma renin levels were normal, fractional excretion of sodium (FENa) was 0.5 +/- 0.1% and creatinine clearance (CCr) averaged 82.2 +/- 18.3 ml/min per 1.73 m2. In the recovery phase of the disease (n = 12), levels of ANP (23.6 +/- 6.7 pg/ml) and ET (43.1 +/- 2.4 pg/ml) fell and were not significantly different from those measured in 11 control subjects. FENa increased to 1.3 +/- 0.1% and CCr to 113.5 +/- 12.1 ml/min per 1.73 m2 (all values mean +/- standard error). ANP did not correlate with PRA, blood pressure, CCr or FENa. There was an inverse relationship between the ET level and FENa in the acute phase of the disease (r = 0.489, P < 0.05), but no significant correlation between ET and blood pressure, PRA, CCr or ANP was found. We suggest that, despite the sodium retention, the increased ANP level in APSGN indicates unresponsiveness of the kidneys to ANP; the increased ET levels may contribute to this.

Acute Disease↗

Leucine transport-induced activation of the Na+/H+ exchanger in human peripheral lymphocytes.

Adjustment of amino-acid-induced cytoplasmic pH decrease by the Na+/H+ exchange system in human lymphocytes has been studied using a fluorometric technique to monitor the intracellular pH change. When the interior of lymphocytes is acidified by addition of nigericin to medium, cytoplasmic pH is immediately corrected toward its resting value. This recovery of the cytoplasmic pH depends on extracellular Na+ and is inhibited by amiloride. A temporary (less than 2 min) decrease in the cytoplasmic pH, followed by a slow recovery phase, was observed in incubation with 1.0 mM leucine in Na+-containing medium. This leucine-dependent decrease of cytoplasmic pH persisted longer when amiloride was added to the medium. Cytoplasmic pH recovery from the leucine-induced acidification depends on external Na+ concentration. Amiloride-sensitive Na+/H+ exchanger was stimulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) in the lymphocytes and preincubation of the cells with TPA partially prevented the leucine-induced cytoplasmic acidification. We conclude that human peripheral lymphocytes are provided with an amino acid-H+ cotransport system, which is cooperatively coupled to the amiloride-sensitive Na+/H+ exchanger to correct the cytoplasmic pH anomaly.

Amiloride↗

"Fatigue" of medullary but not mesencephalic raphe serotonergic neurons during locomotion in cats.

Single unit activity of presumed serotonergic neurons in the medulla [n. raphe obscurus (NRO) and pallidus (NRP)] or the mesencephalon [n. raphe dorsalis (DRN)] was recorded in adult male cats during prolonged treadmill locomotion. Treadmill speed was set at a moderate level (0.4 m/s) in order to induce long-duration locomotion. The typical time to "fatigue" (failure to keep pace, falling behind and reluctance to continue) was approximately 40 min in both groups, at which point cats typically displayed marked panting and vocalization. The activity of DRN neurons was unchanged from baseline during the locomotion trial and during the recovery phase. By contrast, the activity of NRO/NRP neurons decreased steadily across the locomotion trial, reaching a mean decrease of approximately 50% (during the first min after the treadmill was turned off). Full recovery of single unit activity to a level approximating the baseline discharge rate required 30-45 min. Possible mechanisms underlying these changes are discussed as is the role of serotonin and fatigue in human pathology.

Animals↗

Caudal bupivacaine for postoperative analgesia in pediatric lower limb surgery.

One hundred children aged 1 to 15 years were randomly allocated to two equal groups. All underwent cold orthopedic surgery to the lower limb, of more than 1 hour's duration with a standard anesthetic technique. One group received caudal bupivacaine 0.25%, 0.7 mL/kg, and one group acted as controls. There were no cases of fecal incontinence in the theater complex but urinary incontinence in the immediate recovery phase increased from 14% in the control group to 34% in the caudal group (P < .05). The caudal block had a duration of effect lasting 5 to 6 hours, and provided better recovery room analgesia (P < .01). The advantages for the child are discussed.

Adolescent↗

Interleukin-2 receptor positive T and B cells in children with acute severe asthmatic attack.

Subpopulations of interleukin-2 receptor (IL-2R)-positive CD4 and CD8 T cells and IL-2R+CD20 B cells in the peripheral blood lymphocytes as well as serum concentrations of soluble IL-2R (sIL2R) were measured in children aged 1-7 years who suffered acute severe asthmatic attack. Subpopulations of CD4+IL-2R+ cells, CD8+IL-2R+ cells and CD20+IL-2R+ cells in the peripheral blood lymphocytes at acute severe asthmatic attack phase were significantly higher than those at non-asthmatic attack phase (P < 0.02, P < 0.03 and P < 0.02, respectively). Subpopulations of CD20+IL-2R+ cells in the peripheral blood lymphocytes significantly decreased 5-10 days after acute severe asthmatic attack (at recovery phase, P < 0.02) and were significantly correlated with clinical severity of asthmatic attack (P < 0.05). These results indicated that activation of both T cells and B cells was important in the pathogenesis of acute asthmatic attack in young children.

Asthma↗

Effects of calcium and guanosine-3',5'-cyclic-monophosphoric acid on receptor potentials of toad rods.

Membrane potential was recorded intracellularly from rod outer segments in the isolated retina of Bufo marinus. The composition of the solution flowing over the exposed receptor side of the retina was changed rapidly and ionophoretic injections were made into single rod outer segments. Lowering the external Ca2+ concentration, adding 3-isobutyl-1-methylxanthine (IBMX) to the bath, or ionophoretic injections of guanosine-3':5'-cyclic monophosphoric acid (cGMP) lead to depolarization of the rod membrane and an increase in the maximum peak amplitude of the receptor potential. Lowering the Ca2+ concentration or adding IBMX to the bath shifted the curve of response amplitude vs. long intensity of stimulus and sigma (intensity at half saturation) towards dimmer intensities. The ionophoresis of cGMP did not shift the position of the curve along the log stimulus intensity axis. Changing the external concentration of Ca or IBMX changes the form of the response amplitude vs. log intensity curve. This is most obvious at dim intensities. The amplitude of receptor potentials elicited by dim light was decreased by lowering Ca but increased by IBMX. The kinetics of receptor potentials were affected differently by solutions with a low Ca2+ concentration and those containing IBMX. The recovery phase of the receptor potential was slightly accelerated in the low Ca solution, whereas it was greatly slowed in the IBMX-containing solution. The ionophoretic injection of cGMP also slowed the recovery of the receptor potential. The data presented do not support the proposal that cGMP alone maintains membrane voltage in the dark and that the light-induced hydrolysis of cGMP results in the light-induced decrease in membrane conductance underlying the receptor potential. It is more likely that both Ca2+ and cGMP interact in the modulation of membrane voltage, perhaps as interrelated messengers.

1-Methyl-3-isobutylxanthine↗

Prenatal stress alters cardiovascular responses in adult rats.

Environmental factors in early life are clearly established risk factors for cardiovascular disease in later life. Most studies have focused on nutritional programming and analysed basal cardiovascular parameters rather than responses. In the present study we have investigated whether prenatal stress has long-term effects on cardiovascular responses in adult offspring. Female pregnant Sprague-Dawley rats were subjected to stress three times daily from day 15 to day 21 of gestation. Litters from stressed and control females were cross-fostered at birth to control for mothering effects. When the offspring were 6 months old, blood pressure was measured in the conscious rats through implanted catheters at rest, during restraint stress and during recovery. Basal haemodynamic parameters were similar in the different groups but the pattern of cardiovascular responses during stress and recovery differed markedly between prenatally stressed (PS) and control animals. PS rats had higher and longer-lasting systolic arterial pressure elevations to restraint stress than control animals. They also showed elevated systolic and diastolic blood pressure values during the recovery phase. PS rats demonstrated a greater increase in blood pressure variability compared with control animals during exposure to restraint stress, and showed more prolonged heart rate responses to acute stress and delayed recovery than controls. There was no effect of prenatal stress on baroreflex regulation of heart rate. PS females showed a greater increase in systolic arterial pressure and blood pressure variability and delayed heart rate recovery following return to the home cage then did PS males. These findings demonstrate for the first time that prenatal stress can induce long-term, sex-related changes in the sensitivity of the cardiovascular system to subsequent stress.

Adrenergic alpha-Agonists↗

Changes in extracellular [K+] and [Ca2+] induced by anoxia in neonatal rabbit medulla.

Ion-selective microelectrodes were used to record levels of extracellular K+ and Ca2+ concentrations ([K+]o and [Ca2+]o, respectively) and the changes evoked by anoxia in the medulla of anesthetized ventilated newborn rabbits, 1-14 days of age. Resting levels of [K+]o showed significant decline with increasing age. The mean initial level of [K+]o was 6.5 +/- 0.3 mM for the 1st neonatal wk and 5.1 +/- 0.4 mM for the 2nd wk. Brief periods of N2 inhalation (1-3 min) induced reversible increases in [K+]o that were smaller with progression of maturity. The duration of the initial increase (phase I) in [K+]o was twofold greater during the 1st wk than the 2nd wk. At the maximal steady-state level of change (phase III), [K+]o increased by 1.8 +/- 0.2 mM during wk 1 and by 0.9 +/- 0.1 mM during wk 2. Large transient bursts of increase were frequently observed during both early and recovery phases of the sustained [K+]o accumulation. Resting levels of [Ca2+]o also showed age dependence. The mean values during early neonatal days 1-3, compared with days 7-10, were 3.7 +/- 0.3 and 2.4 +/- 0.6 mM, respectively. Anoxia evoked multiphasic decreases in [Ca2+]o that were largest in the youngest pups. Early transient falls of 0.5 +/- 0.1 mM occurred at times similar to those for the earliest increases of [K+]o and negative focal potentials; larger decreases (0.9 +/- 0.2 mM) were recorded after reoxygenation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗