Experimental pain sensitivity differs as a function of clinical pain severity in symptomatic knee osteoarthritis.

OBJECTIVE: Pain in knee osteoarthritis (OA) has historically been attributed to peripheral pathophysiology; however, the poor correspondence between objective measures of disease severity and clinical symptoms suggests that non-local factors, such as altered central processing of painful stimuli, also contribute to clinical pain in knee OA. Consistent with this notion, recent evidence demonstrates that patients with knee OA exhibit increased sensitivity to painful stimuli at body sites unaffected by clinical pain. DESIGN: In order to further investigate the contribution of altered pain processing to knee OA pain, the current study tested the hypothesis that symptomatic knee OA is associated with enhanced sensitivity to experimental pain stimuli at the knee and at remote body sites unaffected by clinical pain. We further anticipated that pain sensitivity would differ as a function of the OA symptom severity. Older adults with and without symptomatic knee OA completed a series of experimental pain assessments. A median split of the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) was used to stratify participants into low vs high OA symptom severity. RESULTS: Compared to controls and the low symptom group, individuals in the high symptom group were more sensitive to suprathreshold heat stimuli, blunt pressure, punctuate mechanical, and cold stimuli. Individuals in the low symptomatic OA group subgroup exhibited experimental pain responses similar to the pain-free group on most measures. No group differences in endogenous pain inhibition emerged. CONCLUSIONS: These findings suggest that altered central processing of pain is particularly characteristic of individuals with moderate to severe symptomatic knee OA.

Sex differences in pain: a brief review of clinical and experimental findings.

Recent years have witnessed substantially increased research regarding sex differences in pain. The expansive body of literature in this area clearly suggests that men and women differ in their responses to pain, with increased pain sensitivity and risk for clinical pain commonly being observed among women. Also, differences in responsivity to pharmacological and non-pharmacological pain interventions have been observed; however, these effects are not always consistent and appear dependent on treatment type and characteristics of both the pain and the provider. Although the specific aetiological basis underlying these sex differences is unknown, it seems inevitable that multiple biological and psychosocial processes are contributing factors. For instance, emerging evidence suggests that genotype and endogenous opioid functioning play a causal role in these disparities, and considerable literature implicates sex hormones as factors influencing pain sensitivity. However, the specific modulatory effect of sex hormones on pain among men and women requires further exploration. Psychosocial processes such as pain coping and early-life exposure to stress may also explain sex differences in pain, in addition to stereotypical gender roles that may contribute to differences in pain expression. Therefore, this review will provide a brief overview of the extant literature examining sex-related differences in clinical and experimental pain, and highlights several biopsychosocial mechanisms implicated in these male-female differences. The future directions of this field of research are discussed with an emphasis aimed towards further elucidation of mechanisms which may inform future efforts to develop sex-specific treatments.

Exploring the relationship between gratitude and depression among older adults with chronic low back pain: a sequential mediation analysis.

Introduction: Gratitude has been identified as a key factor in a number of positive health-related outcomes; however, the mechanisms whereby gratitude is associated with well-being among older adults with chronic pain are poorly understood. Using the Positive Psychological Well-Being Model as a theoretical framework, the objective of the present study was to examine the serial mediating effects of social support, stress, sleep, and tumor necrosis factor-alpha (TNF-α) on the relationship between gratitude and depressive symptoms. Methods: A total sample of 60 community-dwelling older adults with chronic low back pain (cLBP) provided blood samples for high-sensitivity TNF-α and completed the Gratitude Questionnaire, Perceived Stress Scale, and the PROMIS Emotional Support, Sleep Disturbance, and Depression forms. Descriptive statistics, correlation analyses, and serial mediation analyses were performed. Results: Gratitude was negatively associated with perceived stress, sleep disturbance, and depression, and was positively associated with social support. No significant association was observed between gratitude and TNF-α. After controlling for age and marital status, analyses revealed that perceived stress and sleep disturbance sequentially mediated the association between gratitude and depressive symptoms. Conclusion: Perceived stress and sleep disturbance may be potential mechanistic pathways by which gratitude impacts negative well-being. Targeting gratitude as a protective resource may be a potential therapeutic tool to improve psychological and behavioral outcomes in older adults with cLBP.

Stability of finite and infinite von Kármán vortex-cluster streets.

A wake of vortices with sufficiently spaced cores may be represented via the point-vortex model from classical hydrodynamics. We use potential theory representations of vortices to examine the emergence and stability of complex vortex wakes, more particularly the von Kármán vortex street composed of regular polygonal-like clusters of same-signed vortices. We investigate the existence and stability of these streets represented through spatially periodic vortices. We introduce a physically inspired point-vortex model that captures the stability of infinite vortex streets with a finite number of procedurally generated vortices, allowing for numerical analysis of the behavior of vortex streets as they dynamically form.

Blood levodopa levels and unified Parkinson's disease rating scale function: with and without exercise.

We studied 10 regular exercising men with Parkinson's disease on levodopa (LD) under two conditions--no exercise and vigorous exercise started 1 hour after LD ingestion. We compared LD levels and motor scores on the Unified Parkinson's Disease Rating Scale (UPDRS). There was a high degree of agreement between plasma LD level and the patients' UPDRS scores 30 minutes later (mean Eta2 = 0.84) in both conditions, with no difference between the two. We conclude that LD levels accurately reflect UPDRS motor function in these patients, and that vigorous exercise started 1 hour after LD ingestion does not influence LD or motor scores.

Fluorometric quantification of low-dose fluorescein delivery to predict amputation site healing.

This retrospective study evaluated quantification of skin fluorescein delivery by fiberoptic fluorometry as a means of predicting the healing potential of an amputation site. Fluorometry uses a dual-channel fiberoptic light guide--one channel transmits blue light to excite the fluorescein in the skin under study, and the other transmits emitted fluorescence from the skin to a photomultiplier tube where it is measured. Ten minutes after intravenous administration of sodium fluorescein (4 to 8 mg/kg), fluorometric readings were obtained at more than 100 reading sites. In the 86 cases without preoperative cellulitis at the site of amputation, preoperative fluorometry clearly distinguished between healing and nonhealing sites. Healing sites averaged 79% of the fluorescence of a healthy reference area (dye fluorescence index [DFI] = 79), while failing sites averaged only 27% (p less than 0.01 by ANOVA). In all but one case where the DFI was greater than 42, the amputation healed. In all cases where the DFI was less than 38, the amputation failed. In general, uncertainty was limited to sites with values between these limits. The technique maintained its high accuracy in patients with diabetes and for distal amputations. However, it was not accurate at sites of active cellulitis (12 cases). There were no significant adverse effects from the slow injection of the low dose of fluorescein used for this technique. We conclude that fluorometry is an effective means of predicting healing in patients undergoing amputation.

Thiamin and niacin in the rumen.

Thiamin analogs, produced in the rumen by thiaminase I, in the presence of a cosubstrate appear to be responsible for the central nervous system disorder, polioencephalomalacia (PEM). For PEM to occur, an analog must be produced that inhibits an essential thiamin-requiring reaction, and results from a cosubstrate present in the rumen. In high concentrate diets, thiaminase I is produced by rumen microbes. However, PEM can also be caused by thiaminase I of plant origin. Based on physical characteristics and cosubstrate specificity, the thiaminase I enzymes produced by Bacillus thiaminolyticus and Clostridium sporogenes appear to be different from the enzyme produced by the rumen. Because niacin and certain antihelmentics are thiaminase I cosubstrates, they should be used cautiously. Supplementary niacin increased microbial protein synthesis in vitro and in vivo, and was more effective with urea than soybean meal. Supplementary niacin (5 to 6 g X cow-1 X d-1) increased milk production in postpartum cows but not in those in mid-lactation, and in cows fed soybean meal but not in those fed urea. We believe the heating of soybean meal during commercial processing decreased the availability of niacin for rumen protozoa. Supplementary niacin for postpartum cows increased blood glucose, decreased blood ketones and reduced the incidence of ketosis. Niacin flow to the small intestine and its absorption from the small intestine increased with niacin supplementation. Supplemental niacin prevented the postpartum decrease in red blood cell niacin observed in control cows.

Rumen metabolism and absorption of a 14C-labelled elastomeric copolymer and its value as a roughage substitute for cattle.

Several synthetic elastomeric and plastomeric polymers were tested for suitability as artificial roughages. They were fed to rumenfistulated cattle fed grain only. Several of the polymers were regurgitated, remasticated and reswallowed, and they formed thin strands of intermeshed fiber that produced a large, loosely woven hay-like mass that floated on the rumen contents. An elastomeric polymer consisting of copolymers of 80 to 90% ethylene and 10 to 20% propylene, with a tensile strength at yield of 45.7 kg/cm2, a hardness of 30 units (Shore D hardness scale) and a tensile strength at 300% elongation of 51.0 kg/cm2, was selected for further testing. The copolymer was fed at about 90 g/head daily for 127 days to cattle fed grain only. At slaughter, rumens contained an average of 8.0 kg copolymer (dry basis). Cattle fed the copolymer had healthier rumen papillae and epithelia of the abomasum and small intestines than did control animals fed grain only. Using 14C-labeled copolymer, we found that the copolymer was not degraded by rumen microorganisms or acid-pepsin solution. When 14C-labeled copolymer was fed to milking cows, no 14C activity was found in milk, blood or urine. Upon slaughter, about 100% of the 14C activity was recovered from digesta and feces. We concluded that the copolymer was not absorbed from the digestive tract.

Effects of lasalocid or monensin on lactate-producing or -using rumen bacteria.

Lasalocid or monensin inhibited most of the lactate-producing rumen bacteria (Butyrivibrio fibrisolvens, Eubacterium cellulosolvens, E. ruminantium, Lachnospira multiparus, Lactobacillus ruminis, L. vitulinus, Ruminococcus albus, R. flavefaciens, Streptococcus bovis). Minimum inhibitory concentrations ranged from .38 to 3.0 micrograms/ml. Among the lactate producers, those that produce succinate as a major end product (Bacteroides, Selenomonas, Succinimonas, Succinivibrio) were not inhibited by lasalocid or monensin. Also, none of the major lactate fermenters (Anaerovibrio, Megasphaera, Selenomonas) was inhibited by lasalocid or monensin. Veillonella alcalescens was inhibited by 24 micrograms/ml of lasalocid but was resistant to monensin. Hence, the reported increase in propionate in lasalocid- or monensin-fed cattle may result from selection for succinate producers and lactate fermenters. Lasalocid and monensin appeared to inhibit selectively the production of L(+), but not D(-) lactic acid. The inhibition of major lactate-producing bacteria (Streptococcus and Lactobacillus) suggests that lasalocid or monensin may be used to prevent lactic acidosis in ruminants.

Effect of lasalocid, monensin or thiopeptin on lactic acidosis in cattle.

Lasalocid, monensin or thiopeptin was administered intraruminally each at .33, .65 or 1.3 mg/kg body weight and evaluated for its effectiveness in preventing experimentally induced lactic acidosis in cattle. Four rumen-fistulated cattle were used for each dosage level and the design was a 4 x 4 Latin square with each animal receiving lasalocid, monensin, thiopeptin or no antibiotic. Acidosis was induced by intraruminal administration of glucose (12.5 g/kg body weight). Control cattle exhibited the typical drop in rumen pH and concurrent increases in L(+) and D(-) lactate concentrations commonly observed in cases of lactic acidosis. Alkali reserves were depleted in the control cattle as evidenced by a decrease in blood bicarbonate and a negative shift in base excess. In all three trials, cattle given lasalocid had higher rumen pH and lower lactate concentrations than did control cattle or cattle given monensin or thiopeptin. Cattle given monensin had a significantly higher rumen pH and a lower lactate concentration than the controls only at the .65 and 1.3 mg/kg body weight dosages, whereas thiopeptin was effective only at the 1.3-mg dosage. Concentrations of total VFA in rumen fluid decreased in the controls but remained unchanged in cattle given antibiotics. A significant reduction in the molar proportion of acetate and an increase in the molar proportion of propionate were observed in the rumen fluid of the cattle given antibiotics. Colony counts of Streptococcus bovis and Lactobacillus were significantly reduced in rumen fluid of cattle given 1.3 mg antibiotic/kg body weight. Counts of lactate-utilizing bacteria increased in both control cattle and cattle given antibiotics. Cattle given antibiotics showed no evidence of lacticacidemia, hemoconcentration or change in acid-base balance.

Prevention of lactic acidosis in cattle by lasalocid or monensin.

Intraruminal administration of lasalocid or monensin (1.3 mg/kg body weight) effectively prevented in glucose- or corn-induced lactic acidosis in cattle. Administering the antibiotics for 7 days before experimentally inducing acidosis with corn (27.5 g/kg body weight), effectively prevented acidosis, while 2 days' were sufficient to prevent glucose-induced acidosis (12.5 g/kg body weight). The different responses observed in the two trials probably stemmed from the difference in amounts of carbohydrate used to induce acidosis. Antibiotic-treated cattle had higher rumen pH values and lower L(+) and D(-) lactate concentrations that control cattle that received no antibiotics. Ruminal VFA in control cattle decreased, while total VFA and the molar proportion of propionate increased in antibiotic-treated cattle after grain engorgement. Control cattle exhibited classic signs of acidosis, such as lowered blood pH; increased blood lactate, particularly D(-) isomer; hemoconcentration, and depleted alkali reserve with a pronounced based deficit. Antibiotic-treated cattle exhibited no signs of systemic acidosis.

Lasalocid toxicity in cattle: acute clinicopathological changes.

Thirty-six steers (148 to 500 kg) divided into six equal groups were used in a toxic syndrome study of lasalocid and monensin given as a single oral dose. One group was given a placebo, a second group received monensin (25 mg/kg body weight) and the other four groups received lasalocid at 1, 10, 50 or 100 mg/kg body weight (bw). No toxic signs developed in cattle given placebo or lasalocid at 1 or 10 mg/kg bw dose. The earliest toxic signs were muscle tremors, tachycardia and rumen atony. After 24 h, the cattle were dehydrated, anorectic and had diarrhea. Deaths occurred between d 1 and 22.5 in the groups receiving lasalocid at 50 and 100 mg/kg bw and monensin. Altered values in blood leucocytes, erythrocytes, hemoglobin, hematocrit, total protein, albumin, creatinine, urea nitrogen, total bilirubin, creatine kinase, lactic dehydrogenase, calcium, chloride and inorganic phosphate occurred 1 d after dosing: urine pH and specific gravity also changed 1 d after dosing. Maximum changes occurred at d 3. Most of the changes were indicative of dehydration rather than specific organ damage.

Ammonia toxicity in cattle. V. Ammonia concentration of lymph and portal, carotid and jugular blood after the ingestion of urea.

Four rumen-fistulated Holstein steers were fitted with cannulas for the collection of portal, jugular and carotid blood. In addition, the thoracic duct of one steer was cannulated for the collection of lymph. Steers were given .125, .25 or .5 g urea/kg body weight 16 hr after a previous feeding. Within 5 min after the administration of the .5-g dose, rumen ammonia increased from 9.7 to 32.0 mg/100 ml, rumen pH from 6.47 to 7.87; portal blood ammonia from 1.02 to 8.01 mg/100 ml, carotid blood ammonia from .18 to 1.17 mg/100 ml and jugular blood ammonia from .13 to .36 mg/100 ml. Lymph ammonia increased from .22 to .32 mg/100 ml within 15 minutes. The .125- and .25-g doses or urea produced proportionate changes. In a second experiment, three Jersey cows were given .5 g urea/kg body weight, and the rates at which urea appeared in carotid and jugular blood were determined. Only small amounts of urea appeared in carotid and jugular blood during the first 5 min after dosing, but the concentrations then increased slowly but progressively. We concluded that because carotid blood ammonia concentration increased so rapidly after dosing with urea, ammonia must leak past the liver, and it is therefore unlikely, that there is a liver threshold for ammonia which must be exceeded before ammonia will reach the carotid artery. The marked difference in ammonia concentrations in carotid and jugular blood suggests that the brain takes up ammonia rapidly. While some ammonia is absorbed via the lymph, and thus bypasses the liver, the lymph does not appear to be a major contributor of ammonia to carotid blood.

Effects of lasalocid or monensin on legume or grain (feedlot) bloat.

Doses of .66 to .99 mg monensin/kg body weight reduced legume bloat in cattle about 66% when compared with pretreatment bloat scores. Similar doses of lasalocid reduced legume bloat about 26%. A dose of 44 mg poloxalene/kg body weight (recommended dose for field use) reduced legume bloat 100%. Monensin or lasalocid combined with 25 or 50% of the recommended dose of poloxalene reduced bloat under that of the antibiotics alone, but did not achieve 100% reduction. The antibiotic thiopeptin provided no preventive effect on legume bloat. Lasalocid, monensin or an experimental polyether antibiotic (X-14,547 A) at a dose of 1.32 mg/kg body weight when tested on cattle bloated on high grain diets reduced bloat by 92, 64 and 25%, respectively. Lasalocid at .66 mg/kg effectively prevented bloat from developing when given to animals before the feeding of high grain diets; however, a 1.32-mg dose was required to control bloat in cattle that were already bloating before they were given lasalocid. A dose of 1.32 mg salinomycin was ineffective in controlling grain bloat.

Effect of dietary niacin supplementation on phlorhizin and 1,3-butanediol-induced ketonemia and hypoglycemia in steers.

1,3-Butanediol and phlorhizin were used to induce ketonemia and hypoglycemia in steers. Oral administration of butanediol increased blood beta-hydroxybutyrate (BHB) and plasma nonesterified fatty acids (NEFA) and decreased serum glucose. Subcutaneous injections of phlorhizin, given in addition to butanediol orally, further increased NEFA and BHB concentrations and decreased glucose. Dietary niacin supplementation of steers given phlorhizin and butanediol caused serum glucose concentration to increase and blood BHB and plasma NEFA concentrations to decrease.

Effect of dietary niacin supplementation on serum constituents of periparturient dairy cattle.

A total of 60 multiparous periparturient Holstein cows were used to determine the differences in serum constituents between cows given supplemental niacin in the diet and cows not given supplemental niacin. Serum inorganic phosphorus concentration was consistently higher (P less than 0.10) and serum potassium, total calcium, and sodium concentrations and alkaline phosphatase activities were consistently lower in cows given supplemental niacin than in cows not given supplemental niacin. Serum chloride, creatinine, and albumin values also tended to be lower in niacin-supplemented cows. Serum total protein tended to be slightly higher in niacin-supplemented cows. There was no consistent difference in urea nitrogen between groups of cows.

Comparative lethal effects on mice of ruminal fluid from cattle fed hay or grain.

Strained ruminal fluid from cattle fed hay or grain was lethal to mice when injected intraperitoneally, but the fluid from grain-fed cattle was approximately 3.7 times more toxic than that from hay-fed cattle. The lethal factor(s) was not resistant to heat, was nondialyzable, was retained on Seitz and membrane filters, and was associated with the bacterial fraction of ruminal fluid. We concluded that death of the mice resulted from infection produced by facultative bacteria normally in ruminal fluid. Ruminal fluid from grain-fed cattle contained a greater number of facultative bacteria than did that from hay-fed cattle.

Characterization of endotoxin from the rumen bacterium Megasphaera elsdenii.

Phenol-water extraction of Megasphaera elsdenii, a predominant gram-negative coccus in rumens of cattle fed high-grain diets, yielded material that exhibited typical characteristics of endotoxin. The extract was lethal to mice and to chicken embryos, caused biphasic fever in rabbits, leukopenia in mice, and local and generalized Shwartzman reactions; and induced tolerance to the lethal effect of the endotoxin in mice. The material contained carbohydrate, protein, lipid, phosphorus, and 2-keto-3-deoxyoctonate, but no nucleic acid. The beta-hydroxymyristic acid was absent. Results imply that M elsdenii endotoxin has many biological and chemical characteristics common to enterobacterial endotoxin. However, the median lethal doses in mice and in chicken embryos, and minimal dose required to elicit a local Shwartzman reaction, indicate that M elsdenii endotoxin's potency is low, which may explain why the large gram-negative bacterial population in the rumen of cattle is generally innocuous.

Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome.

BACKGROUND: Patients with musculoskeletal pain syndrome including fibromyalgia (FM) complain of chronic pain from deep tissues including muscles. Previous research suggests the relevance of impulse input from deep tissues for clinical FM pain. We hypothesized that blocking abnormal impulse input with intramuscular lidocaine would decrease primary and secondary hyperalgesia and FM patients' clinical pain. METHODS: We enrolled 62 female patients with FM into a double-blind controlled study of three groups who received 100 or 200 mg of lidocaine or saline injections into both trapezius and gluteal muscles. Study variables included pressure and heat hyperalgesia as well as clinical pain. In addition, placebo factors like patients' anxiety and expectation for pain relief were used as predictors of analgesia. RESULTS: Primary mechanical hyperalgesia at the shoulders and buttocks decreased significantly more after lidocaine than saline injections (p = 0.004). Similar results were obtained for secondary heat hyperalgesia at the arms (p = 0.04). After muscle injections, clinical FM pain significantly declined by 38% but was not statistically different between lidocaine and saline conditions. Placebo-related analgesic factors (e.g., patients' expectations of pain relief) accounted for 19.9% of the variance of clinical pain after the injections. Injection-related anxiety did not significantly contribute to patient analgesia. CONCLUSION: These results suggest that muscle injections can reliably reduce clinical FM pain, and that peripheral impulse input is required for the maintenance of mechanical and heat hyperalgesia of patients with FM. Whereas the effects of muscle injections on hyperalgesia were greater for lidocaine than saline, the effects on clinical pain were similar for both injectates.