A randomized trial to examine the mechanisms of cognitive, behavioral and mindfulness-based psychosocial treatments for chronic pain: Study protocol.

This randomized trial will evaluate the mechanisms of three chronic pain treatments: cognitive therapy (CT), mindfulness meditation (MM), and activation skills (AS). We will determine the extent to which late-treatment improvement in primary outcome (pain interference) is predicted by early-treatment changes in cognitive content, cognitive process, and/or activity level. The shared versus specific role of these mechanisms across the three treatments will be evaluated during treatment (Primary Aim), and immediately post-treatment to examine relapse mechanisms (Secondary Aim). We will enroll 300 individuals with chronic pain (with low back pain as a primary or secondary condition), with 240 projected to complete the study. Participants will be randomly assigned to eight, 1.5 h telehealth group sessions of CT, MM, or AS. Mechanisms and outcomes will be assessed twice daily during 2-week baseline, 4-week treatment period, and 4-week post-treatment epoch via random cue-elicited ecological momentary assessment (EMA); activity level will be monitored during these time epochs via daily monitoring with ActiGraph technology. The primary outcome will be measured by the PROMIS 5-item Pain Interference scale. Structural equation modeling (SEM) will be used to test the primary aims. This study is pre-registered on clinicaltrials.gov (Identifier: NCT03687762). This study will determine the temporal sequence of lagged mediation effects to evaluate rates of change in outcome as a function of change in mediators. The findings will provide an empirical basis for enhancing and streamlining psychosocial chronic pain interventions. Further, results will guide future efforts towards optimizing maintenance of gains to effectively reduce relapse risk.

The influence of traditional herbal formulas on cytokine activity.

Many of the botanical "immunomodulators", a class of herbal medicines widely recognized in traditional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional remedies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-γ. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on cytokine related diseases/syndromes is necessary.

Urea metabolism in beef steers fed tall fescue, orchardgrass, or gamagrass hays.

Two experiments were conducted to assess effects of endophyte treatments (Exp. 1), forage species (Exp. 2), and supplementation (Exp. 2) on urea production, excretion, and recycling in beef steers. Infusion of (15,15)N-urea and enrichment of urea in urine samples were used to calculate urea-N entry and recycling to the gut. Acceptably stable enrichment of (15)N-urea in urine was obtained after 50 h of intrajugular infusion of (15,15)N-urea, indicating that valid data on urea metabolism can be obtained from steers fed forages twice daily. After adjustment by covariance for differences in N intake among treatments in Exp. 1, steers fed endophyte-infected tall fescue had less (P<0.10) urea-N entry, recycling to the gut, and return of recycled urea-N to the ornithine cycle than those fed endophyte-free or novel endophyte-infected tall fescue. However, urea-N urinary excretion or return to the gut was similar among endophyte treatments when expressed as a proportion of urea-N entry. Urea-N entry and return to the gut in Exp. 2 was similar in steers fed gamagrass or orchardgrass hay after adjustment by covariance for differences in N intake. Less (P<0.01) urinary excretion, expressed as grams per day or as a proportion of urea-N entry, with gamagrass than with orchardgrass was associated with faster in vitro NDF-N digestion with gamagrass. Supplementation of gamagrass or orchardgrass with 1.76 kg/d of readily fermentable fiber and starch decreased urea entry (P<0.06) and urinary excretion of urea (P<0.01). Interactions between hay source and supplement reflected a greater response to supplementation for steers fed orchardgrass than for those fed gamagrass. After adjustment for differences among treatments in N supply, results of both experiments support the concept of improved N use in response to increased carbohydrate fermentability in the rumen, due either to inherent differences in forage fiber or to supplementation with readily fermentable carbohydrate (starch or fiber). Closer coordination of ruminal fermentation of carbohydrate and N sources provided greater and more efficient capture of dietary N as tissue protein in forage-fed steers.

Novel inhibitors of the Gardos channel for the treatment of sickle cell disease.

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.

The interaction of harvesting time of day of switchgrass hay and ruminal degradability of supplemental protein offered to beef steers.

The objective of this study was to evaluate an interaction between harvest at 0600 (AM) vs. 1800 (PM) with high (HI) or low (LO) ruminal degradability of a protein supplement to change voluntary intake, digestion, or N retention by steers offered switchgrass (Panicum virgatum L.) hay. Black steers (255 +/- 14 kg of BW) were blocked by BW, and then randomly assigned (5 steers each) to AM/HI, PM/HI, AM/LO, or PM/LO treatment groups. Steers were group-housed in covered, outdoor pens with individual feeding gates. After adaptation and standardization, intake was measured for 21 d followed by a digestion trial (5 d of total collection). Steers were offered 767 (LO) or 825 (HI) g/d of supplement to provide 268 g of CP/d. Compared with AM, PM had greater (P = 0.01) concentrations of total nonstructural carbohydrate (TNC, 71 vs. 56 g/kg of DM), and lesser concentrations of NDF (760 vs. 770 g/kg of DM, P = 0.02), ADF (417 vs. 427 g/kg of DM, P = 0.02), and CP (55.9 vs. 58.6 g/ kg of DM, P = 0.07). Protein fractions A, B(2), and B(3) were similar for AM and PM, but HI contained more (P < 0.02) A (694 vs. 296 g/kg of protein) and less B(2) (174 vs. 554 g/kg of protein) fraction than LO. Harvest interacted with supplement to increase (P = 0.07) ad libitum digestible DMI for steers offered PM/HI (11.4 g/kg of BW daily) compared with steers offered PM/LO (10.2 g/kg of BW daily), but there was no difference for steers offered AM/LO or AM/HI (10.7 g/kg of BW). Apparent digestibilities of DM (594 vs. 571 g/kg of intake), NDF (591 vs. 562 g/kg of intake), ADF (585 vs. 566 g/kg of intake), and N (651 vs. 632 g/kg of intake) were greater (P < 0.04) for PM than for AM. Apparent digestibility of N was greater (P = 0.02) for HI (652 g/ kg of intake) vs. LO (631 g/kg of intake). Interactions between harvest and supplement for apparent digestibilities of NDF (P = 0.09) and ADF (P = 0.03) were due to no change or an increase in digestibility in response to increased ruminal degradability of supplement in steers offered PM harvest, whereas increased ruminal degradability of supplement decreased digestibility of NDF and ADF in steers offered AM harvest. Treatments did not affect hay intake (3.93 kg/d), N retained (15.8 g/d), or plasma urea N (5.25 mM) during ad libitum intake. Greater TNC in PM vs. AM harvest was not sufficient by itself to increase total voluntary DMI, but greater protein degradability interacted with harvest time to increase ruminal fiber digestibility and digestible DMI of beef steers offered PM vs. AM harvest.

Urea metabolism in beef steers grazing Bermudagrass, Caucasian bluestem, or gamagrass pastures varying in plant morphology, protein content, and protein composition.

Pastures of Bermudagrass (Cynodon dactylon, BG), Caucasian bluestem (Bothriochloa caucasica, CBS), and gamagrass (Tripsacum dactyloides, GG) were evaluated from the perspectives of forage composition, selection during grazing, and N metabolism in beef steers. All pastures were fertilized with 78 kg/ha of N approximately 60 and 30 d before sample collection. In 2000 and 2001, 12 steers (250 kg of BW) were blocked based on BW and then assigned randomly to a replicated, randomized complete block design, with 2 pastures of each forage and 2 steers per pasture. Three other steers with esophageal fistulas were used to collect masticate samples to represent intake preferences. Herbage mass was >1,900 kg/ha. After at least 14 d of adaptation, urine and blood samples were collected for determination of serum urea N and percentage of urinary N in the form of urea. One steer per pasture (6 steers per year) was infused i.v. with (15,15)N urea for 50 h before collecting urine for 6 h to measure urea N enrichment, urea entry rate, urinary urea excretion, gut urea recycling, and return of urea N to the ornithine cycle. The canopy leaf:stem DM ratio differed (P = 0.01) among BG (0.50), CBS (1.01), and GG (4.00). Caucasian bluestem had less CP (% of DM) than GG or BG in the canopy (9.6 vs. 12.0 or 12.3, P = 0.07) and in the masticate (9.8 vs. 14.7 or 13.9, P = 0.04). Bermudagrass had less true protein (% of CP) than CBS or GG in the canopy (72.9 vs. 83.3 or 83.0, P = 0.07) and in the masticate (73.7 vs. 85.8 or 88.0, P = 0.04). Compared with GG and BG, CBS had less serum urea N (10.1 or 12.2 vs. 2.5 mM, P = 0.01), urea entry rate (353 or 391 vs. 209 mmol of N/h, P = 0.07), and urinary urea excretion (105 or 95 vs. 18 mmol of N/h, P = 0.04), and a greater return of urea N to the ornithine cycle as a proportion of gut urea recycling (0.109 or 0.118 vs. 0.231, P = 0.02). Urea production and recycling in these steers responded more to the N concentration in the grasses than to differences in plant protein fractions. There was no evidence of improved N capture by the steers due to changes in the leaf:stem ratio among the grasses at the herbage mass evaluated.

Nitrogen metabolism of beef steers fed endophyte-free tall fescue hay: effects of ruminally protected methionine supplementation.

Level of nitrogen (N) intake and ruminally protected methionine supplementation were evaluated in eight Angus growing steers (initial BW 253+/-21 kg, final BW 296+/-21 kg) in a replicated 4+/-4 Latin square design. The steers were fed two endophyte-free tall fescue (Festuca arundinacea) hays that contained 2.2 (LO) or 2.8% (HI) of DM as N and were either supplemented or not with ruminally protected methionine (10 g metabolizable methionine/d). Diets were fed to provide adequate energy for 0.5 kg ADG and sufficient protein for maintenance (LO), or protein to support 0.5 kg ADG (HI). Following at least 14 d of adjustment, N balance was measured for 6 d. Isotopic urea was infused (15N15N-urea, 0.164 mmol urea N/h) via a jugular catheter for 56 h and urine was collected from 48 to 56 h to measure urea kinetics. Jugular blood was collected during the balance trial, and serum was analyzed for serum urea N (SUN). By design, daily N intake was greater (P < 0.05) for HI (112 g) than for LO (89 g). Compared with LO, steers when fed HI had greater (P < 0.05) daily DMI (4,217 vs 4,151 g), fecal N (34.4 vs 31.2 g), N digested (77.1 vs 57.7 g), urine N (48.3 vs 37.5 g), urine urea N excretion (34.6 vs 24.8 g), and N retained (29.8 vs 21.1 g). When fed HI steers also had higher (P < 0.05) urine urea N concentration (276 vs 219 mM), SUN (8.7 vs 6.7 mM), N digestibility (69.1 vs 64.9%), percentage of urinary N present as urea (71.5 vs 66.7%, P < 0.053), and rate of urea N production (59.6 vs 49.2 g/d) but lower (P < 0.05) percentage of urea N produced that was returned to the ornithine cycle (15.03 vs 19.2 1%) than when fed LO. Methionine supplementation decreased daily urine N (41.2 vs 44.6 g, P = 0.10) and increased both the amount of N retained daily (27.9 vs 23.7 g, P < 0.089) and the percentage of N digested that was retained (40.4 vs 34.6%, P < 0.094). In summary, supplemental methionine met a specific dietary limitation by increasing the amount of digested N that was retained by the steers.

A phytochemical investigation of Alchornea latifolia.

A phytochemical investigation of the chloroform leaf extract of Alchornea latifolia has been undertaken. Along with the triterpenoids taraxerone, friedelin, epifriedelinol, and taraxerol, the plant also contains seco-3,4-friedelin (dihydroputranjivic acid) (1) and seco-3,4-taraxerone (2). These A-ring-opened triterpenoids show in vitro cytotoxic activity against Hep-G2 and A-431 human cancer cell lines and are potent inhibitors of topoisomerase II.

Prediction of dietary flavonol consumption from fasting plasma concentration or urinary excretion.

OBJECTIVES: to predict flavonols content of the habitual diets of free-living subjects from urine and plasma concentrations of flavonols. DESIGN: Ten type 2 diabetic patients (five male, five female), mean age 60 (s.e.m. 7) y and BMI 30.2 (s.e.m. 3.5) kg/m2 were treated in a random crossover design for a 2 week period on either a low flavonoid diet or on the same diet supplemented at one of two high flavonols levels (total 77.3 or 110.4 mg/day) provided by supplements of 1500 ml tea daily and 400 g fried white onion in olive oil with and without tomato ketchup and herbs. SETTING: Glasgow Royal Infirmary, University of Glasgow, Scotland. MAIN OUTCOME MEASURES: Fasting plasma concentration, urine concentration and 24 h excretion of quercetin, isorhamnetin, kaempferol and myricetin. RESULTS: Plasma flavonol concentration (r=0.750, P=0.001), 24 h urine concentration (r=0.847, P=0.001) and 24 h urine excretion (r=0.728, P=<0.001) were all highly significantly related to dietary intake and gave similar estimates of intakes. Fasting plasma flavonols concentrations on habitual diets ranged from 0 to 43.7 ng/ml mean. Regression equations were constricted: total flavonols intake r=0.74, P<0.001 and quercetin intake r=0.744, P<0. 001. From these equations, flavonol intakes from habitual diets were estimated at 17-50, mean 35 mg/day. Of this, 91% was from quercetin. CONCLUSIONS: Dietary flavonols are absorbed and appear in plasma and urine as potential biomarkers in concentrations related quantitatively to intake. Estimation of dietary intake from plasma or urine concentrations appears possible. SPONSORSHIP: Rank Prize Funds and Rank Foundation of the Department of Human Nutrition; Ministry of Health and Medical Education, IR Iran. European Journal of Clinical Nutrition (2000) 54, 143-149

Aminoglycoside-resistance mechanisms for cystic fibrosis Pseudomonas aeruginosa isolates are unchanged by long-term, intermittent, inhaled tobramycin treatment.

Aminoglycoside-resistance mechanisms were characterized in Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients during a recent clinical trial of inhaled tobramycin. Impermeability, in which bacteria have reduced susceptibility to all aminoglycosides, was the predominant mode of resistance in isolates obtained both before and after 6 months of cyclic treatment with tobramycin or placebo administered by aerosol. Enzymatic resistance mechanisms were found in fewer than 10% of resistant isolates. P. aeruginosa from individual patients could be grouped on the basis of genetic relatedness. When enzymatic resistance was involved, all isolates in a group had elevated tobramycin MICs. When impermeability occurred, MICs of a genotypic group varied from susceptible to resistant. These findings suggest that impermeability resistance occurs in only a fraction of the P. aeruginosa population in lungs of persons with CF and that this form of resistance arises by a process involving multiple small changes in MIC.

Postneonatal circumcision with local anesthesia: a cost-effective alternative.

PURPOSE: Despite the controversy regarding the need for routine neonatal circumcision, most boys in the United States are circumcised. Physicians are commonly asked to perform circumcision after the neonatal period and are often unaware of the cost factors related to the timing and location of postneonatal circumcision. MATERIALS AND METHODS: We describe the medical and financial advantages of postneonatal circumcision with local versus general anesthesia. RESULTS: During a 30-month period 245 boys 6 months to 15 years old underwent circumcision under general anesthesia in the operating room. Hospital charges (facility and equipment) averaged $1,555 and anesthesia charges averaged $250. Therefore, the average cost for circumcision in the operating room was $1,805. During the same time period 287 infants 3 days to 9 months old (20% older than 3 months) underwent circumcision under local anesthesia in an office setting. The facility and equipment charge for these office procedures averaged $196. Overall, approximately $461,783 were saved in this 30-month period ($184,713 annually) by performing circumcision with local anesthesia in an office setting rather then in the operating room with general anesthesia. There was no significant difference in complication rates between the local and general anesthesia groups (1.4 versus 1.6%). CONCLUSIONS: Circumcision with local anesthesia can be performed easily and safely during the first several months of life and has many advantages. Parents prefer this method because it is more convenient and eliminates the risk of general anesthesia. The enormous cost savings using local as opposed to general anesthesia should prompt a reexamination of the location and timing of postneonatal circumcision.

Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA.

Diabetic patients have reduced antioxidant defenses and suffer from an increased risk of free radical-mediated diseases such as coronary heart disease. Epidemiological evidence has suggested that antioxidant dietary flavonoids may protect against heart disease, but a biological effect has yet to be demonstrated directly in humans. In this study, 10 stable type 2 diabetic patients were treated for 2 weeks on a low-flavonol diet and for 2 weeks on the same diet supplemented with 76-110 mg of flavonols (mostly quercetin) provided by 400 g of onions (and tomato sauce) and six cups of tea daily. Freshly collected lymphocytes were subjected to standard oxidative challenge with hydrogen peroxide, and DNA damage was measured by single-cell gel electrophoresis. Fasting plasma flavonol concentrations (measured by high-performance liquid chromatography) were 5.6 +/- 2.9 ng/ml on the low-flavonol diet and increased 12-fold to 72.1 +/- 15.8 ng/ml on the high-flavonol diet (P < 0.001). Oxidative damage to lymphocyte DNA was 220 +/- 12 on an arbitrary scale of 0-400 U on the low-flavonol diet and 192 +/- 14 on the high-flavonol diet (P = 0.037). This decrease was not accounted for by any change in the measurements of diabetic control (fasting plasma glucose or fructosamine) or by any change in the plasma levels of known antioxidants, including vitamin C, carotenoids, alpha-tocopherol, urate, albumin, and bilirubin. In conclusion, we have shown a biological effect of potential medical importance that appears to be associated with the absorption of dietary flavonols.

Perceived and physiological indicators of relaxation: as different as Mozart and Alice in chains.

The effects of listening to different types of music on perceived and physiological indicators of relaxation were evaluated. Fifty-six undergraduate students, 24 males and 32 females, mean age of 21, were randomly assigned to listen to classical, hard rock, self-selected relaxing music, or no music. Participants' relaxation level, skin temperature, muscle tension and heart rate were evaluated before and after exposure to a music condition. Analyses of variance using baseline measures as covariates indicated that skin temperature decreased for all conditions (p = 0.001) and the classical, self-selected relaxing music and no music groups reported significant increases in feelings of relaxation (p = 0.004). These results partially support the hypothesis that classical and self-selected relaxing music can increase perceptions of relaxation to a greater degree than listening to hard rock music. However, no differences were found between different types of music on physiological indicators of arousal. Implications for using music to reduce stress were discussed.

Panel discussion. Data needs in cancer.

A prospective, comprehensive outcomes database was recently initiated by the National Comprehensive Cancer Network (NCCN) after a 2-year study to test data collection methods and systems. It started with data on 400 patients with newly diagnosed breast cancer at five NCCN sites, and over the next 3 years is projected to grow to include more than 12,000 patients with common cancers treated at all eligible NCCN sites. Among the goals of the database are: 1) to establish the capability to select, analyze, and report patterns of care and outcomes; 2) to allow NCCN members to assess their compliance with NCCN clinical practice guidelines and benchmark their performance against the rest of the NCCN; 3) to establish a true databased continuous quality improvement program; 4) to support clinical disease-oriented research and methodologic studies; and 5) to provide the NCCN with a vehicle for forging partnerships with others in the health-care field, such as the pharmaceutical industry, regulatory agencies, and accrediting bodies. Many of those potential partners were represented on this panel. Panelists discussed the data needs of their organizations, what they are doing to meet those needs, and how a comprehensive database will ultimately help improve patient care.