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Vasoconstrictor reserve and sympathetic neural control of orthostasis.

BACKGROUND: We tested the hypothesis that individual variability in orthostatic tolerance is dependent on the degree of neural and vasomotor reserve available for vasoconstriction. METHODS AND RESULTS: Muscle sympathetic nerve activity (MSNA) and hemodynamics were measured in 12 healthy young volunteers during 60 degrees head-up tilt (HUT), followed by a cold pressor test (CPT) in HUT. Orthostatic tolerance was determined by progressive lower-body negative pressure (LBNP) to presyncope. The same protocols were performed randomly in normovolemic and hypovolemic conditions. We found that mean arterial pressure increased and stroke volume decreased, whereas heart rate (HR), MSNA, and total peripheral resistance (TPR) increased during HUT (all P<0.01). Application of the CPT in HUT did not increase HR or decrease stroke volume further but elevated mean arterial pressure (P<0.01) and increased MSNA and TPR in some subjects. There was a positive correlation between the time to presyncope from -50 mm Hg LBNP (equivalent to 60 degrees HUT alone) and the changes in MSNA produced by the CPT under both conditions (r=0.442, P=0.039). Those who had greater increases in MSNA had greater increases in TPR during the CPT and longer time to presyncope (both P<0.05). One subject had dramatic increases in MSNA but small increases in TPR during the CPT, which indicates a disassociation between sympathetic activity and the increase in peripheral vascular resistance. CONCLUSIONS: These results support our hypothesis and suggest that vasoconstrictor capability is a contributor to orthostatic tolerance in humans. Vasoconstrictor reserve therefore may be one mechanism underlying individual variability in orthostatic intolerance.

Adult↗

Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To determine the tolerability and clinical effectiveness of intranasal ipratropium bromide for the treatment of symptoms of common colds. DESIGN: Multicenter, double-blind, randomized trial. SETTING: 3 university student health services. PATIENTS: 411 previously healthy persons 14 to 56 years of age who had cold symptoms that had lasted for no more than 36 hours, rhinorrhea subjectively judged to be of at least moderate severity, and documented nasal discharge of at least 1.5 g over a 1-hour observation period. INTERVENTION: Either 1) ipratropium bromide nasal spray 0.06% in buffered salt solution, two 42-micrograms sprays per nostril administered by metered pump spray; 2) control nasal spray, which consisted of buffered salt solution; or 3) no treatment. Treatments were self-administered three or four times daily during waking hours for 4 days. After receiving their morning dose, patients stayed at the study center for 6 hours on study day 1 and 3 hours on study day 2; symptom severity was recorded and nasal mucus discharges were collected and weighed hourly during these periods. RESULTS: Ipratropium recipients had 26% less nasal discharge than controls (P = 0.0024) and 34% less nasal discharge than untreated patients (P = 0.0001). Severity of rhinorrhea as judged subjectively was reduced in ipratropium recipients by 31% compared with controls and by 78% compared with untreated patients (P = 0.0001 for both comparisons). In addition to being associated with reductions in daily assessments of the severity of rhinorrhea (P < or = 0.003), ipratropium was associated with reduced sneezing on study days 2 (20% difference; P = 0.03) and 4 (30% difference; P = 0.02) but not with reduced nasal congestion compared with the control spray. Ipratropium was generally well tolerated but was associated with higher rates of blood-tinged mucus (16.8% in the ipratropium group compared with 3.6% in the control group; P = 0.01) and nasal dryness (11.7% in the ipratropium group compared with 3.6% in the control group; P = 0.021) than the control spray. Patient assessments of the overall effectiveness of treatment were more favorable for ipratropium than for the control spray (P < or = 0.026) or for no treatment (P < or = 0.002) on each day of inquiry (study days 1, 2, and 5). CONCLUSIONS: Intranasal ipratropium bromide provides specific relief of rhinorrhea and sneezing associated with common colds.

Administration, Intranasal↗

Single-pass carbon dioxide laser skin resurfacing combined with cold-air cooling: efficacy and patient satisfaction of a prospective side-by-side study.

BACKGROUND: Ablative skin resurfacing with carbon dioxide (CO(2)) and erbium:YAG lasers is still considered the gold standard for treating rhytides, photodamage, and acne scars. However, the prolonged downtime and undesired concomitant effects that are involved have sent dermatologists looking for less invasive nonablative laser techniques to rejuvenate skin. OBJECTIVE: To combine cold-air cooling with single-pass CO(2) laser skin resurfacing to generate as much benefit as possible while minimizing the spectrum of adverse effects. STUDY DESIGN: The efficacy of single-pass CO(2) laser skin resurfacing on perioral and periorbital wrinkles was examined prospectively during a 6-month follow-up period. In a side-by-side comparison, the influence of simultaneous cold-air cooling on concomitant effects, pain tolerance, therapeutic success, and patient satisfaction was also studied. Eight patients with perioral and/or periorbital wrinkles underwent the procedure. During laser treatment, only the right half of each face was cooled using a cold-air system. RESULTS: Six months after treatment, a mild improvement of the wrinkles was observed in all cases. The use of cold-air cooling did not have any impact on the long-term results, although in a direct comparison between sides, it was observed that cooling reduced the recovery period from 3.9 +/- 1.5 (mean +/- SD) days to 3.5 +/- 1.4 days (P = .09) and helped postoperative erythema fade more quickly, from an average of 21.3 +/- 17.9 days to 11.7 +/- 3.9 days (P = .17). The reduction of pain was significant, which led to a much higher level of patient acceptance: on a numerical analog scale of 1 to 10, the rate decreased from an average of 6.8 +/- 1.8 (mean +/- SD) to 3.6 +/- 1.7 (P = .006). CONCLUSIONS: Given the clear decline in demand for invasive laser technologies, single-pass CO(2) laser skin resurfacing in conjunction with cold-air cooling is a worthwhile alternative both to conventional resurfacing and to conventional subsurfacing. The use of cold-air cooling not only minimizes intraoperative and postoperative adverse effects, it also contributes strongly to patient satisfaction.

Adult↗

Pain perception as a function of self-focused rumination.

Pain sensitivity and tolerance were studied using the cold-pressor technique. A 3 independent groups design was employed using rumination as the independent variable. Group 1 was given a situation in which anger-related self-rumination was introduced. Group 2 was given a self-related rumination task in which anger was not induced. Group 3 received a rumination task not related to the self. In addition, the State-Trait Anger Expression Inventory was given prior to the experiment to test the hypothesis that ratings on the Anger-In subtest would correlate with pain sensitivity. In each group were 6 men and 6 women. Each participant took the anger and another inventory not relevant to the present study before the experiment. An anger measure was taken before and after the experiment for each group to see if the anger induction in Group 1 actually increased anger. There were no differences among the 3 groups on the second anger measure, so differences between Groups 1 and 2 could not be attributed to anger. A 1-way analysis of variance for 3 groups showed a strong main effect on pain tolerance but not pain sensitivity. Groups 1 and 2 were significantly more tolerant of pain than Group 3. The correlation of ratings on the Anger-In (internalized anger) subtest fell short of statistical significance with pain sensitivity and also was not significant for pain tolerance. Results were discussed in terms of the possibility that self-rumination may increase pain tolerance by requiring a greater cognitive load than nonself rumination.

Anger↗

Cold and warmth perception mapped for age, gender, and body area.

Reference data on cold and warmth perception at three different body areas are provided based on 24 young (20-30 years) and 24 elderly (55-65 years) healthy women and men. Perception thresholds (method of limits), perceived intensity (free-number magnitude estimation), and perceived quality (verbal descriptors) were assessed for cold and for warmth at thenar, the upper arm, the knee, and the foot. Inter-individual comparison of perceived-intensity scales for cold and warmth was achieved by a Master Scaling procedure utilizing thenar as a reference area. Perception thresholds showed gender difference for cold at thenar, and interaction effect of age and gender for heat-pain tolerance at the upper arm. In contrast, perceived intensity of cold and warmth showed multiple effects of age, gender, and specific body area (also for the nociceptive channels). For instance, at the knee, elderly women's perceived intensity for stimulation in the nociceptive range was elevated for both cold and warmth, as compared to young women and men, and to elderly men. Conversely, at the upper arm, elderly women's perceived intensity for the corresponding nociceptive range was lowered, as compared to young women and young men, and to elderly men. At the foot, both elderly women's and men's perceived intensity of cold and warmth was lowered, as compared to young women and men. Overall, the perceived quality of perceptions did not differ between groups. The present findings on age differences in perceived intensity of cold and warmth at the upper arm, knee and foot in healthy women and men provide reference data hitherto lacking for diagnostic work in patients with somatosensory dysfunctions and ongoing pain.

Adult↗

Cold-activation of Brassica napus BN115 promoter is mediated by structural changes in membranes and cytoskeleton, and requires Ca2+ influx.

Previous studies on cold-triggered events leading to Ca2+ influx during cold acclimatization have been conducted on either unicellular cyanobacterium Synechocystis or plant cell suspensions, and used transcript levels of cold-induced genes as end-point markers. Whether the results of these studies are valid for intact plants or their organs is not known. Here we examine cold signaling in transgenic Brassica napus seedlings carrying, in addition to the endogenous cold-inducible BN115 gene, the beta-glucuronidase (GUS) gene placed under control of the BN115 promoter. The activity of BN115 promoter was monitored at the transcriptional and translational levels by determining accumulation of BN115 transcripts and by histochemical assay of GUS activity. Cold-activation of BN115 was strongly inhibited by the membrane fluidizer benzyl alcohol, but mimicked at 25 degrees C by the membrane rigidifier dimethylsulfoxide (DMSO). The cold induction of BN115 was also inhibited by stabilizers of microtubules and actin microfilaments, taxol and jasplakinolide, respectively, but was mimicked at 25 degrees C by microtubule destabilizer oryzalin or colchicine, or by microfilament destabilizer latrunculin B. Gd3+ or ruthenium red prevented the cold activation of BN115, but Ca2+ ionophore A23187 or cyclic ADP-ribose activated it at 25 degrees C. Inhibitors of tyrosine kinases, protein kinase C and phosphoinositide kinases prevented the cold activation of BN115, but inhibitors of protein phosphatases (PP) 1 and 2 A activated BN115 at 25 degrees C. Constitutively expressed GUS activity in another transgenic line of the same cultivar of B. napus, was not affected by cold or any of the chemical treatments used in the experimentation. Activation of BN115 at 25 degrees C by DMSO, Ca2+ ionophore, cADPR, and by inhibitors of PP1 and 2A was accompanied by an increased freezing tolerance. It was concluded that the cold-activation of BN115 requires membrane rigidification, cytoskeleton reorganization, Ca2+ influx and action of several types of protein kinases.

Brassica↗

A new cold-induced alfalfa gene is associated with enhanced hardening at subzero temperature.

When alfalfa (Medicago sativa L. cv Apica) plants grown at room temperature are transferred to 2 degrees C, the temperature at which 50% of the plants fail to survive (LT50) decreases from -6 to -14 degrees C during the first 2 weeks but then increases to -9 degrees C during the subsequent 2 weeks. However, when plants are kept for 2 weeks at 2 degrees C and then transferred to -2 degrees C for another two weeks, the LT50 declines to -16 degrees C. These changes in freezing tolerance are paralleled by changes in transcript levels of cas15 (cold acclimation-specific gene encoding a 14.5-kD protein), a cold-induced gene. Cold-activation of cas15 occurs even when protein synthesis is inhibited by more than 90%, suggesting that cold-initiated events up to and including the accumulation of cas15 transcripts depend on preexisting gene products. cas15 shows little homology to any known gene at the nucleotide or amino acid level. The deduced polypeptide (CAS15) of 14.5 kD contains four repeats of a decapeptide motif and possesses a bipartite sequence domain at the carboxy terminus with homology to the reported nuclear-targeting signal sequences. Although the relative amount of cas15 DNA as a fraction of the total genomic DNA is similar in cultivars with different degrees of freezing tolerance, its organization in the genome is different. The possible role of cas15 in the development of cold-induced freezing tolerance is discussed.

Acclimatization↗

Molecular cloning and characterization of a CBF gene from Capsella bursa-pastoris.

A new CBF gene was cloned from Capsella bursa-pastoris(shepherd's purse) by rapid amplification of cDNA ends (RACE). The full-length cDNA of C. bursa-pastoris CBF gene (designated as Cbcbf) was 1034 bp long and contained a 657 bp open reading frame (ORF) encoding a putative DRE/CRT (LTRE)-binding protein of 219 amino acids. The predicted CbCBF protein was found to have a potential nuclear localization signal (NLS) in its N-terminal region followed by an AP2 DNA-binding motif and an acidic C-terminal half that might act as an activator domain. Bioinformatic analysis revealed that Cbcbf strongly resembled other CBF genes from Arabidopsis thaliana (cbf1, cbf2, cbf3) and Brassica napus (Bncbf5, Bncbf 7, Bncbf16 and Bncbf17). Subsequent cold acclimation assay showed that Cbcbf was relevant to cold acclimation. Our study implies that Cbcbf might have similar functions possessed by other CBF genes such as inducing the expression of some cold-regulated genes and increasing plants' freezing tolerance.

Adaptation, Biological↗

[An open label multi-center clinical trial to evaluate the efficacy of compound pseudoephedrine [corrected] hydrochloride sustained release capsules in patients with nasal symptoms associated with common cold].

OBJECTIVE: To evaluate the efficacy and safety of compound pseudoephedrine [corrected] hydrochloride (New Contact sustained release capsules) in the treatment of the nasal symptoms associated with common cold or influenza. METHOD: Open label multi-center clinical trial was adopted: one capsule twice daily with an interval of 12 hours, successively for 4 days to treat the nasal symptoms associated with common cold or influenza. RESULTS: A total of 416 patients were eligible for efficacy and safety analysis. The cure rates for nasal congestion from day 1 to day 4 were 7%, 31%, 64% and 88%, cumulatively; for runny nose were 9%, 36%, 68% and 89%; for sneezing were 20%, 51%, 76% and 93%, and for watery eyes were 36%, 68%, 89% and 96%, respectively. There were no serious adverse events during the study. Forty adverse events (AE's) with an incidence of 8% were developed in 35 patients. The most frequent AE's were drowsiness (24/416, 6%) and dry mouth (5/416, 1%). All AE's were in mild or moderate degree. CONCLUSION: The results indicated that New Contact sustained released capsule was effective in controlling the nasal symptoms associated with common cold or influenza and it was well-tolerated.

Adolescent↗

The hypoalgesic effect of imipramine in different human experimental pain models.

In a randomized, placebo-controlled, double-blind, cross-over study, the hypoalgesic effect of a single oral dose of 100 mg imipramine was investigated in 12 healthy volunteers. Test procedures performed before, 3, 6, and 9 h after medication included determination of (1) pain detection and tolerance thresholds to heat and pressure; (2) the thresholds of quadriceps femoris muscle withdrawal reflex to single and repeated electric stimulation of the sural nerve; (3) amplitude of the reflex evoked by 1.5 times the premedication reflex threshold; and (4) continuous pain rating during the cold pressor test. Imipramine significantly increased pain tolerance thresholds to heat (P = 0.03) and pressure (P = 0.01), and both the psychophysical pain tolerance threshold and the reflex threshold to single electric stimulation (P = 0.02 and P = 0.03, respectively). On the repeated stimuli, which consisted of 4 pulses given at 3 Hz, imipramine induced a significant increase in the threshold at which the pain summated through the stimulation series (P = 0.03), whereas the increase in the threshold at which the reflex summated was not significant (P = 0.09). Pain detection thresholds to heat and pressure, the amplitude of the reflex to single suprathreshold stimulation, and pain ratings during the cold pressor test were unaltered by imipramine. It is concluded that imipramine has a differential hypoalgesic effect on different human experimental pain tests. This provides new possibilities of assessing the differential effect of different tricyclic antidepressants on different pain modalities and intensities.

Adolescent↗

[Adaptive modifications of cold pain. III. Communication: short-term experiments with 1-min-intervals (author's transl)].

The subjective short-term habituation to pain-inducing cold stimuli is demonstrated for the first time by measuring the tolerated exposition time. It proves impossible to separate temporally a detection threshold of cold pain from the distress reaction level. The slope of subjective habituation is clearly dependent on the individual vegetative starting position. It is discussed why the blood pressure reaction may be used as a valid parameter for experienced intensity of a cold pain sensation only to a limited extent.

Adaptation, Physiological↗

HIF-1alpha involvement in low temperature and anoxia survival by a freeze tolerant insect.

Winter survival for many insect species relies on the ability to endure the freezing of extracellular body fluids. Because freezing impedes oxygen delivery to tissues, one component of natural freeze tolerance is a well-developed anoxia/ischemia resistance. The present study explores the responses of the hypoxia-inducible factor-1alpha (HIF-1alpha) to cold, freezing and anoxia exposures in the freeze tolerant goldenrod gall fly larva, Eurosta solidaginis. Reverse transcription-PCR was used to quantify hif-1alpha transcript levels; transcripts were significantly elevated by approximately 70% in chilled (3 ( composite function)C), frozen (-16 ( composite function)C) and thawed (returned to 3 ( composite function)C) insects, compared with 15 ( composite function)C controls. Transcripts also rose by approximately 3-fold in insects given anoxia exposure under a nitrogen gas atmosphere. Cold and freezing exposure also elevated HIF-1alpha protein content in the larvae and HIF-1alpha levels increased over the winter months in insects sampled from an outdoor population; levels peaked in February at 2.1-fold higher than in September. A partial sequence of HIF-1alpha that covers the bHLH and PAS domains of the protein was obtained from E. solidaginis and sequence analysis revealed that this segment shared 62% identity overall with Drosophila melanogaster HIF-1alpha and higher percent identities within specific domains: 76% within the bHLH domain and 70% within the PAS domain. The data provide the first documentation of a potential role for HIF-1 in regulating the expression of genes that can aid freezing survival in a cold-hardy animal.

Aerobiosis↗

Effect of adrenalectomy on the metabolism of glucose in obese (C57 Bl/6J ob/ob) mice.

The genetically obese mouse, C57 B1/6J ob/ob, has been suggested as an appropriate model for the study of obesity associated with diabetes mellitus. Employing glucose 14C(microliter) as a tracer, the data presented here indicate that obese mice are able to clear glucose from the blood compartment at the same rate as their lean littermates. This was demonstrated with or without an associated cold glucose load. The abnormal glucose tolerance curves observed in the obese animals may be a result of secretion of glucose into the blood. Removal of the adrenal glands from the obese mice and their lean littermate does not impair their ability to clear a glucose load from the vascular compartment. The capacity for endogenous glucose secretion of ob/ob mice is severely curtailed by adrenalectomy, in that the glucose tolerance curves of these adrenalectomized animals become similar to those of sham-operated lean littermates. Thus, it appears that a considerable component of the hyperglycemia in ob/ob mice reflects major adrenal involvement that is activated by stress, ie, ether anesthesia and blood sampling. The hyperglycemia in ob/ob mice may reflect glucocorticoid-dependent gluconeogenesis.

Adrenal Glands↗

The wheat wcs120 promoter is cold-inducible in both monocotyledonous and dicotyledonous species.

The wcs120 gene is specifically induced by low temperature (LT) and encodes a protein that is thought to play an important role in the cold acclimation process in wheat. To identify the regulatory elements involved in its LT responsiveness, the transient expression activity of different promoter regions was determined using the luciferase reporter gene. The data indicate the involvement of putative enhancer elements, negative and positive regulatory regions in the transcriptional regulation of this gene. The promoter was found to be cold-inducible in different freezing-tolerant and -sensitive monocot and dicot species, suggesting that universal transcription factors responsive to LT may be present in all plants. This promoter could be used to drive the genes needed for LT tolerance in sensitive species.

Acclimatization↗

Energy metabolism in uncoupling protein 3 gene knockout mice.

Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

Animals↗

Short-term ischaemic storage of human uterine myometrium--basic studies towards uterine transplantation.

BACKGROUND: Transplantation of the uterus has been suggested as a possible future treatment of absolute uterine infertility. The tolerability of human uterine tissue to cold ischaemic storage was tested in the present study. METHODS: Small tissue samples of human uteri were subjected to cold (4 degrees C) ischaemia (6 and 24 h) in Ringer acetate (RIN), the intracellular-like University of Wisconsin solution (UW) or the extracellular-like Perfadex solution (PER). The ability of myometrial strips to contract, histology by light and electron microscopy as well as tissue concentrations of glutathione, ATP and protein were used as parameters to detect cold ischaemic injuries. RESULTS: Contractile ability and response to prostaglandin F(2alpha) (PGF(2alpha)) was better preserved after 6 h cold ischaemia in UW and PER in comparison with the other groups. Histological examination did not reveal any major changes after 6 and 24 h cold ischaemic storage in UW and PER solutions, while specimens stored in RIN for 24 h displayed degenerative changes on the electron microscopy level. UW and PER preserved ATP concentrations significantly better than RIN. Myometrium stored in UW contained more total glutathione but also a larger proportion of oxidized glutathione than specimens stored in RIN and PER. Protein concentrations did not change with storage time in any of the solutions. CONCLUSIONS: The results show that human uterine myometrial tissue is resistant towards cold ischaemia for at least 6 h if stored in UW and PER solutions.

Adenosine↗