Direction of Temperature Control in the Thermal Biofeedback Treatment of Vascular Headache

In order to test for the specific therapeutic effects of thermal biofeedback (TBF) for hand warming on vascular headache (HA), 70 patients with chronic vascular HA were randomly assigned to TBF for hand warming, TBF for hand cooling, TBF for stabilization of hand temperature, or biofeedback to suppress alpha in the EEG. Patients in each condition initially had high levels of expectation of therapeutic benefit and found the treatment rationales highly credible. Participants in each condition received 12 treatment sessions on a twice-per-week basis. Based on daily HA diary data gathered for 4 weeks prior to treatment and 4 weeks after treatment, HA Index was significantly (p=.003) reduced as was HA medication consumption. There were no differential reducations in HA Index or Medication Index among the four conditions. Global self-reports of improvement gathered at the end of the post-treatment monitoring period also did not differ among the four conditions. We were unable to demonstrate a specific effect of TBF for hand warming on vascular HA activity.     

Comments on The Failure of Intensive Self-Regulatory Treatment with Chronic Daily Headache

Nonpharmacological therapy of primary headache conditions including chronic daily headache (CDH) is not well-studied. Barton and Blanchard report on their experience with intensive self-regulatory treatment in a cohort of patients with CDH. This negative trial provides preliminary observations that need further investigations in controlled, adequately powered clinical study.     

Comments on Barton and Blanchard

The paper by Barton and Blanchard (2001) posits that intensive self-regulatory treatment may be ineffective for chronic daily headache. This commentator has concerns about the lack of homogeneity of population, problems with the diagnostic criteria utilized, the validity of the medication index, and issues with analgesic rebound.     

Relaxation training as a treatment for chronic headaches in an individual having severe developmental disabilities

We have assessed effects of a simplified relaxation training on the frequency of headaches and consumption of analgesic headache medication in an adult male with severe developmental disabilities as well as chronic mixed headaches. The subject received Behavioral Relaxation Training (BRT) after a baseline period during which frequency of headache complaint, analgesic medication consumption, and independent relaxation behaviors were monitored. BRT consists of the utilization of modeling, prompting, feedback, and positive reinforcement in order to establish and maintain the subject's participation in 10 overt relaxed postures. The behaviors were learned to at least an 80% proficiency during a 10-minute alternating self-regulatory (1 min)/corrective feedback (1 min) relaxation phase across several sessions. Headache complaints were reduced by 48% and analgesic medication consumption by 51% as assessed during a 2-month posttreatment evaluation. These results should be considered not only as support of BRT as a viable method of relaxation training but also as a suggestion that BRT and other self-regulatory treatment should be considered for use with individuals having moderate to severe developmental disabilities.     

Neurological evaluation of chronic headache patients: is laboratory testing always necessary?

A review of records was conducted to examine the utility of doing routine laboratory testing (EEG and skull X rays) versus testing at the discretion of the attending neurologist on patients presenting for the nonpharmacological treatment of chronic headache. A total of 278 patients underwent neurological evaluation as part of a routine assessment prior to beginning self-regulatory treatment for headache. The first 112 subjects received routine laboratory tests of EEG and skull X-ray films. The second set of 166 subjects received laboratory tests only when deemed necessary by the neurologist. The rate of abnormal EEG in chronic headache sufferers was no greater than that found in the normal population, and only one or two potentially serious abnormalities were found on any laboratory test. A higher rate of abnormality was found when the CT scan was used in conjunction with clinical judgment. The majority of clients with abnormal laboratory tests (most of which were mildly abnormal) still saw substantial headache reduction with self-regulatory treatment for chronic headache. The authors suggest that routine laboratory testing may not be necessary and should be left to the discretion of a qualified neurologist.     

Relaxation training as a treatment for chronic headaches in an individual having severe developmental disabilities

We have assessed effects of a simplified relaxation training on the frequency of headaches and consumption of analgesic headache medication in an adult male with severe developmental disabilities as well as chronic mixed headaches. The subject received Behavioral Relaxation Training (BRT) after a baseline period during which frequency of headache complaint, analgesic medication consumption, and independent relaxation behaviors were monitored. BRT consists of the utilization of modeling, prompting, feedback, and positive reinforcement in order to establish and maintain the subject's participation in 10 overt relaxed postures. The behaviors were learned to at least an 80% proficiency during a 10-minute alternating self-regulatory (1 min)/corrective feedback (1 min) relaxation phase across several sessions. Headache complaints were reduced by 48% and analgesic medication consumption by 51% as assessed during a 2-month posttreatment evaluation. These results should be considered not only as support of BRT as a viable method of relaxation training but also as a suggestion that BRT and other self-regulatory treatment should be considered for use with individuals having moderate to severe developmental disabilities.This research was supported in part by grants from NIMH, MH-41341, and NINCDS, NS-23440.     

Neurological evaluation of chronic headache patients: Is laboratory testing always necessary?

A review of records was conducted to examine the utility of doing routine laboratory testing (EEG and skull X rays) versus testing at the discretion of the attending neurologist on patients presenting for the nonpharmacological treatment of chronic headache. A total of 278 patients underwent neurological evaluation as part of a routine assessment prior to beginning self-regulatory treatment for headache. The first 112 subjects received routine laboratory tests of EEG and skull X-ray films. The second set of 166 subjects received laboratory tests only when deemed necessary by the neurologist. The rate of abnormal EEG in chronic headache sufferers was no greater than that found in the normal population, and only one or two potentially serious abnormalities were found on any laboratory test. A higher rate of abnormality was found when the CT scan was used in conjunction with clinical judgment. The majority of clients with abnormal laboratory tests (most of which were mildly abnormal) still saw substantial headache reduction with self-regulatory treatment for chronic headache. The authors suggest that routine laboratory testing may not be necessary and should be left to the discretion of a qualified neurologist.This research was supported in part by grants from NINCDS, NS-15235 and NS-23440.     

The Effect of the Definition of Menstrually-Related Headache on the Response to Biofeedback Treatment

Twelve women with either pure migraine headache (HA) or a combination of migraine and tension-type HA monitored HA activity over two menstrual cycles while noting onset of menstruation and onset of ovulation. They then received 12 sessions of thermal biofeedback (TBF) with adjunctive autogenic training. Six women with only tension-type HA participated in similar monitoring before receiving 9 sessions of progressive relaxation training.Results for those with vascular HA showed a significant reduction in HA activity and a reduction in medication taken for HAs. Those with tension-type HA did not respond significantly to the relaxation training. Depending upon how one defined menstrually-related HAs among those with vascular HA, there either was, or was not, a differential effect of TBF on menstrual-cycle-related HA.     

Coadministration of Lopinavir/Ritonavir and Rifampicin in HIV and Tuberculosis Co-Infected Adults in South Africa

Background

In HIV-infected patients receiving rifampicin-based treatment for tuberculosis (TB), the dosage of lopinavir/ritonavir (LPV/r) is adjusted to prevent sub-therapeutic lopinavir concentrations. In this setting, South African clinicians were advised to administer super-boosted LPV/r (400 mg/400 mg) twice daily, instead of standard dosed LPV/r (400 mg/100 mg) twice daily. We sought to determine – in routine practice – the tolerability and HIV treatment outcomes associated with super-boosted LPV/r compared to unadjusted LPV/r in combination with rifampicin-based TB treatment.

Methodology/Principle Findings

We conducted a retrospective review of HIV-infected patients who receiving second-line ART with a LPV/r-containing regimen who required concomitant TB treatment. We identified 29 patients; the median age was 36 years (IQR 29–40), 22 (76%) were female, the median CD4 cell count and viral load at first-line ART failure was 86 cells/mm³ (IQR 21–159) and 39,457 copies/mL (IQR 6,025–157,500), respectively. According to physician preference, 15 (52%) of 29 patients received super-boosted LPV/r (400 mg/400 mg) every 12 hours during TB treatment and 14 (48%) of 29 patients received standard dose LPV/r (400 mg/100 mg) twice daily during TB treatment. Among patients who received super-boosted LPV/r there was a trend towards a higher rate of symptomatic transaminitis (27% vs. 7%; p = 0.3), gastrointestinal toxicity (20% vs. 0%; p = 0.2) and a significantly increased need for treatment discontinuation (47% vs. 7%; p = 0.035. The durability of coadministered treatment was significantly shorter in patients who received super-boosted lopinavir/ritonavir with TB treatment compared to patients who received standard lopinavir/ritonavir dosing (log rank, P = 0.036). The rate of virologic failure was not higher in patients with unadjusted LPV/r dosing.

Conclusions/Significance

We observed a high rate of toxicity and need for treatment discontinuation among patients on standard rifampicin-based TB treatment who received super-boosted LPV/r.     

Treatment of Alzheimer's Disease with Anti-Homocysteic Acid Antibody in 3xTg-AD Male Mice

Alzheimer''s disease (AD) is an age-associated progressive neurodegenerative disorder with dementia, the exact pathogenic mechanisms of which remain unknown. We previously reported that homocysteic acid (HA) may be one of the pathological biomarkers in the brain with AD and that the increased levels of HA may induce the accumulation of intraneuronal amyloid-beta (Aβ) peptides. In this study, we further investigated the pathological role of HA in a mouse model of AD. Four-month-old prepathological 3xTg-AD mice exhibited higher levels of HA in the hippocampus than did age-matched nontransgenic mice, suggesting that HA accumulation may precede both Aβ and tau pathologies. We then fed 3-month-old 3xTg-AD mice with vitamin B6-deficient food for 3 weeks to increase the HA levels in the brain. Concomitantly, mice received either saline or anti-HA antibody intraventricularly via a guide cannula every 3 days during the course of the B6-deficient diet. We found that mice that received anti-HA antibody significantly resisted cognitive impairment induced by vitamin B6 deficiency and that AD-related pathological changes in their brains was attenuated compared with the saline-injected control group. A similar neuroprotective effect was observed in 12-month-old 3xTg-AD mice that received anti-HA antibody injections while receiving the regular diet. We conclude that increased brain HA triggers memory impairment and that this condition deteriorates with amyloid and leads to subsequent neurodegeneration in mouse models of AD.     

Hyaluronic acid is radioprotective in the intestine through a TLR4 and COX-2-mediated mechanism

The intestinal epithelium is sensitive to radiation injury. Damage to the intestinal epithelium is dose limiting in radiation therapy of abdominal cancers. There is a need for agents that can be given before radiation therapy to protect the intestinal epithelium. C57BL6 mice were subjected to 12 Gy of total body radiation. Some mice received intraperitoneal hyaluronic acid (HA) before radiation. Mice were killed 6 h after radiation to assess radiation-induced apoptosis in the intestine; other mice were killed at 84 h to assess crypt survival. Total body radiation (12 Gy) resulted in increased expression of HA synthases and HA in the intestine and increased plasma HA (5-fold). Intraperitoneal injection of HA (30 mg/kg) before radiation resulted in a 1.8-fold increase in intestinal crypt survival and a decrease in radiation-induced apoptosis. The radioprotective effects of HA were not seen in Toll-like receptor 4 (TLR4)- or cyclooxygenase-2 (COX-2)-deficient mice. Intraperitoneal injection of HA induced a 1.5-fold increase in intestinal COX-2 expression, a 1.5-fold increase in intestinal PGE?, and the migration of COX-2-expressing mesenchymal stem cells from the lamina propria in the villi to the lamina propria near the crypt. We conclude that 1) radiation induces increased HA expression through inducing HA synthases, 2) intraperitoneal HA given before radiation reduces radiation-induced apoptosis and increases crypt survival, and 3) these radioprotective effects are mediated through TLR4, COX-2, and the migration of COX-2-expressing mesenchymal stem cells.     

A rapid transient increase in hyaluronan synthase-2 mRNA initiates secretion of hyaluronan by corneal keratocytes in response to transforming growth factor beta

Keratocytes of the corneal stroma produce transparent extracellular matrix devoid of hyaluronan (HA); however, in corneal pathologies and wounds, HA is abundant. We previously showed primary keratocytes cultured under serum-free conditions to secrete matrix similar to that of normal stroma, but serum and transforming growth factor beta (TGFbeta) induced secretion of fibrotic matrix components, including HA. This study found HA secretion by primary bovine keratocytes to increase rapidly in response to TGFbeta, reaching a maximum in 12 h and then decreasing to <5% of the maximum by 48 h. Cell-free biosynthesis of HA by cell extracts also exhibited a transient peak at 12 h after TGFbeta treatment. mRNA for hyaluronan synthase enzymes HAS1 and HAS2 increased >10- and >50-fold, respectively, in 4-6 h, decreasing to near original levels after 24-48 h. Small interfering RNA against HAS2 inhibited the transient increase of HAS2 mRNA and completely blocked HA induction, but small interfering RNA to HAS1 had no effect on HA secretion. HAS2 mRNA was induced by a variety of mitogens, and TGFbeta acted synergistically to induce HAS2 by as much as 150-fold. In addition to HA synthesis, treatment with TGFbeta induced degradation of fluorescein-HA added to culture medium. These results show HA secretion by keratocytes to be initiated by a rapid transient increase in the HAS2 mRNA pool. The very rapid induction of HA expression in keratocytes suggests a functional role of this molecule in the fibrotic response of keratocytes to wound healing.     

Organic matter transformations and kinetics during sewage sludge composting in a two-stage system

The use of different proportions of rape straw and grass as amendments in the composting of dewatered sewage sludge from a municipal wastewater treatment plant was tested in a two-stage system (first stage, an aerated bioreactor and second stage, a periodically turned windrow). The composition of feedstock affected the temperature and organic matter degradation in the bioreactor and the formation of humic substances, especially humic acids (HA), during compost maturation in the windrow. The total HA content (the sum of labile and stable HA) increased according to first-order kinetics, whereas labile HA content was constant and did not exceed 12% of total HA. Δlog K of 1.0–1.1 indicated that HA was of R-type, indicating a low degree of humification. Temperature during composting was the main factor affecting polymerization of fulvic acids to HA and confirmed the value of the degree of polymerization, which increased only when thermophilic conditions were obtained.     

Hypothalamic-pituitary-adrenal axis following glucocorticoid prophylaxis against acute mountain sickness.

The pituitary-adrenocortical and adrenomedullary response to high altitude (HA) stress was studied following daily single dose administration of prednisolone as a prophylaxis against altitude-induced acute mountain sickness (AMS). Forty healthy men, randomly divided into two groups of twenty, received placebo or prednisolone 20 mg once a day at 08.00 h for two days prior to induction to HA and during an initial three days stay at an altitude of 3450 m. The AMS score and circulatory levels of ACTH, cortisol, epinephrine and norepinephrine were measured at sea level (SL) and during residency at HA. The sensitivity of the hypothalamic-pituitary-adrenal axis in subjects receiving prednisolone therapy was evaluated at SL and on day four of stay at HA. Administration of prednisolone significantly (p < 0.01) decreased the severity of AMS in all the subjects. The steroid dose used did not inhibit endogenous secretion of ACTH, cortisol, epinephrine or norepinephrine, as HA response to adrenocortical and adrenomedullary hormones was identical in placebo and prednisolone treated subjects. The integrity of the hypothalamic-pituitary-adrenal axis was maintained well in subjects receiving low dose prednisolone therapy. These observations suggest that short-term administration of prednisolone is able to curtail AMS without causing suppression of the hypothalamic-pituitary-adrenal axis.     

The role of the mesenchyme in mouse neural fold elevation. II. Patterns of hyaluronate synthesis and distribution in embryos developing in vitro

Hyaluronate (HA) distribution patterns were examined in the cranial mesenchyme underlying the mesencephalic neural folds of mouse embryos maintained in roller tube culture. Using standard image-processing techniques, the digitized images of Alcian blue-stained or 3H-glucosamine-labeled sections digested with an enzyme specific for HA, were subtracted from adjacent, undigested sections. The resultant difference picture images (DPI) accurately depicted the distribution of stained or labeled HA within the cranial mesenchyme. 3H-glucosamine-labeled HA was distributed uniformly throughout the cranial mesenchyme as 12, 18, and 24 hr of culture. By contrast, the mesenchyme was uniformly stained with Alcian blue at 12 hr, but stain intensity decreased in the central regions of the mesenchyme at 18 and 24 hr. HA distribution patterns were also examined in the cranial mesenchyme of embryos cultured in the presence of diazo-oxo-norleucine (DON), a glutamine analogue that inhibits glycosaminoglycan and glycoprotein synthesis. In DON-treated mesenchyme, Alcian blue staining of HA was decreased from that in controls at 12, 18, and 24 hr. However, incorporation of 3H-glucosamine into HA was increased. The distribution of labeled HA within treated mesenchyme as 12, 18, and 24 hr resembled that in controls at 12 hr. These results indicate that the distribution of HA within the cranial mesenchyme of normal mouse embryos during neural fold elevation and convergence is not determined solely by regional differences in HA synthesis. We propose that HA distribution patterns result from the expansion of the HA-rich extracellular matrix of the central mesenchyme regions. This expansion may play a major role in fold elevation. These results also suggest that DON treatment reversibly inhibits HA synthesis, since treated mesenchymal cells retain the capability of synthesizing HA when provided with a glucosamine substrate. Patterns of 3H-glucosamine incorporation by DON-treated mesenchyme are similar to those observed in control mesenchyme prior to mesenchymal expansion at 12 hr.     

Comparison of once daily and twice daily FSH injections for superovulating beef cattle

Twelve cycling Angus-based crossbred cows were used in a crossover experimental design to evaluate two different injection schedules using Follicle Stimulating Hormone (FSH) for superovulating donor cattle. Females randomly assigned to Treatment (A) were given twice daily FSH injections of 5 mg each (12 hours apart) for five consecutive days starting on day 10 of the estrous cycle while those in Treatment (B) received the same daily dose level of FSH, except it was given in a 3.2% protein gelatin carrier vehicle and administered on a once daily injection schedule. Animals in both Treatments (A) and (B) were each given a 30 mg dose of commercially available prostaglandin-F(2alpha) agent 48 hours after the first FSH injection. Cows in estrus were initially handmated to a fertile bull then artificially inseminated 12 hours later with two units of frozen semen. All 12 animals (100%) given twice daily FSH injections and 11 of the females (91.6%) administered once daily FSH injections exhibited standing estrus within 5 days following injection of the luteolytic agent. On day 7 or 8 after the onset of standing estrus a laparotomy was performed to observe ovarian structures. When the superovulation response was evaluated, the mean number of corpora lutea per ovary ranged from 2.9 in the twice daily injection group to 4.1 in the once daily injected group. Unexpectedly, the once daily treated group had significantly more corpora lutea per animal (8.1 vs. 6.4) than those in the twice daily treated group. In addition, mean ovarian size score per animal increased significantly when pre-treatment scores were compared to those recorded following FSH treatment (laparotomy) in both Treatment (A) and (B), however, the post-treatment ovarian size scores were not different between these groups. When evaluating post-treatment follicular development, the once daily injection group had significantly more smaller follicles (<10 mm) and a greater number of ovulatory size follicles (>10 mm) than the twice daily injection group. Furthermore, viable appearing embryos were recovered from both treatment groups and no adverse reactions were observed with the gelatin carrier vehicle in Treatment (B). Since the once daily FSH injection schedule resulted in a superovulatory response equal to or greater than the twice daily FSH injection schedule, this approach to superovulation should not be overlooked by those involved in bovine embryo transplantation.     

替格瑞洛在急性冠脉综合征患者经皮冠状动脉介入治疗术后的应用价值

目的:评价替格瑞洛在急性冠脉综合征(acute coronary syndrome,ACS)患者经皮冠状动脉介入治疗(percutaneous coronary intervention,PCI)术后的应用价值。方法:将我院收治的565例成功行PCI的急性冠脉综合征(acute coronary syndrome,ACS)患者随机分为2组:氯吡格雷组253例,术后口服氯吡格雷75 mg、QD;替格瑞洛组312例,术后口服替格瑞洛首剂180 mg,维持量90mg、BID。两组患者术后常规口服阿司匹林100 mg、QD。研究主要终点为主要不良心血管事件(major adverse cardiovascular events,MACE),包括全因死亡、靶血管血运重建和脑梗塞;次要终点为TIMI主要出血(定义为血红蛋白下降50 g/L或颅内出血有关的临床显著出血事件)。结果:565例患者平均随访12个月,替格瑞洛组MACE发生率低于氯吡格雷组(3.8%vs.8.7%,P0.05),两组TIMI主要出血事件发生率比较,差异无统计学意义(2.9%vs.3.2%,P0.05)。结论:替格瑞洛能明显减少PCI术后主要不良心血管事件,并不增加主要出血。     

相转化水凝胶微针的制备和处方优化

目的:考察分子量为4 k Da的透明质酸,羧甲基纤维素钠对相转化水凝胶微针的影响以及对药物体外释放的影响。方法:制备含有不同浓度透明质酸或羧甲基纤维素钠的微针,利用显微镜观察微针的外观形态,用高效液相色谱法检测药物的体外释放,并用统计分析软件检测体外释放率的差异性。结果:含有透明质酸的微针出现相分离现象,体外释放24 h,释放率为55%左右;羧甲基纤维素钠的微针未出现相分离现象,体外释放24 h,释放率能达到60%左右,两种微针在3 h和24 h时体外释放率无显著性差异,在12 h时有显著性差异(P0.05)。结论:透明质酸与聚乙烯醇混合易出现相分离现象,可应用于微针的浓度范围较窄,羧甲基纤维素钠微针不易出现相分离现象。在12 h体外释放方面,含有羧甲基纤维素钠的微针处方优于含有透明质酸的微针处方,但是哪一种辅料更优还需要进一步的实验验证。     

Effect of different diluents on goat semen fertility

Skim milk (SM) is considered to be the most widely employed extender for goat sperm used for artificial insemination (AI). However, the fertilizing life span of sperm stored in milk or milk-based extenders does not exceed 12h. Besides some seminal plasma components, such as a protein fraction from the goat bulbourethral gland secretion (SBUIII), interacts with some milk fractions and inhibits the spermatozoa motility. The aim of this study was to prolong the survival of buck semen and its fertility. Buck ejaculates were diluted to a final concentration of 100x10(6)spermatozoa/ml with three different diluents: SM, TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) and TEMPOL+hyaluronic acid (TEMPOL+HA). At 7h from dilution 42 goats were inseminated with semen diluted with SM (short-term semen) while after storage for 24h, 44 and 45 goats were inseminated with semen diluted with TEMPOL and TEMPOL+HA (long-term storage), respectively. At day 50 from AI the percentages of pregnant goats were 71.4% (30/42) with SM, 61.4% (27/44) with TEMPOL and 48.8% (22/45) with TEMPOL+HA, with significant differences between SM and TEMPOL+HA. The kidding rate was 66.7% (28/42) with SM diluent, 61.4% (27/44) with TEMPOL and 48.8% (22/45) with TEMPOL+HA, without significant differences among treatment groups. In conclusion, it is possible to maintain good fertility in goats after AI with semen stored for 24h in TEMPOL.     

Brain histamine response to stress in 12 month old rats

The regional brain histamine regulation in response to stress was investigated in 12 month old Sprague-Dawley male rats. Air blast exposure (15 min) induced significant (26.5%) elevation in hypothalamic HA level; midbrain and cortical HA concentrations were not affected. Histamine methyltransferase activity was not altered by stress in any of the brain regions investigated. Plasma corticosterone levels of stressed rats were significantly elevated (6.5 fold). Hence, the response of hypothalamic HA to stress is still evident in 12 month old rats.