Search PubMed⌕ Search

Biomedical subjects

David A Williams

Publications and source records attributed to David A Williams.

At least 73 records · Page 4Linked to original sources
PubMed2005

Differences in unpleasantness induced by experimental pressure pain between patients with fibromyalgia and healthy controls.

Pain possesses both sensory and affective dimensions, which are highly correlated yet distinct. Comparison of these dimensions within experimental pain settings has resulted in the construct of relative unpleasantness. Relative unpleasantness is defined as the amount of affective unpleasantness elicited for a given sensory magnitude. The aim of this study was to determine the relationship between affective and sensory components of evoked pain in subjects with fibromyalgia (FM) and healthy controls. Here we show that patients with FM unexpectedly display less relative unpleasantness than healthy controls in response to random noxious pressure stimuli. Relative unpleasantness was not correlated with distress, anxiety, or depression, which were pronounced in the FM group. Clinical pain in patients with FM was perceived to be more unpleasant than the evoked pain stimuli. These results are consistent with the concept that chronic pain may reduce the relative unpleasantness of evoked pain sensations.

Adult↗
PubMed2005

Fibromyalgia after motor vehicle collision: evidence and implications.

OBJECTIVE: Assess currently available evidence regarding the ability of a motor vehicle collision (MVC) to trigger the development of fibromyalgia (FM). METHODS: Consensus standards developed by the American College of Rheumatology Environmental Disease Study Group were used to assess the ability of an MVC to trigger FM. RESULTS: Increasing evidence suggests that FM and related disorders are characterized by abnormalities in central nervous system function related to sensory processing, autonomic regulation, and neuroendocrine function. MVC trauma appears capable of triggering FM, but generally not through direct biomechanical injury. Instead, the evidence suggests that MVC trauma can act as a "stressor," which in concert with other factors, such as an individual's biologic vulnerability, psychosocial factors, cultural factors, and so on, may result in the development of chronic widespread pain and other somatic symptoms. MVC trauma is only one of many stressors which can trigger such disorders, and the environment within which the stressor is experienced (biological and psychosocial) may largely determine whether there is an adverse physiologic result or not. CONCLUSIONS: The evidence that MVC trauma may trigger FM meets established criteria for determining causality, and has a number of important implications, both for patient care, and for research into the pathophysiology and treatment of these disorders.

Accidents, Traffic↗
PubMed2005

Treatment of fibromyalgia with formula acupuncture: investigation of needle placement, needle stimulation, and treatment frequency.

OBJECTIVES: The objective of this study was to investigate whether typical acupuncture methods such as needle placement, needle stimulation, and treatment frequency were important factors in fibromyalgia symptom improvement. DESIGN/SETTINGS/SUBJECTS: A single-site, single-blind, randomized trial of 114 participants diagnosed with fibromyalgia for at least 1 year was performed. INTERVENTION: Participants were randomized to one of four treatment groups: (1) T/S needles placed in traditional sites with manual needle stimulation (n = 29): (2) T/0 traditional needle location without stimulation (n = 30); (3) N/S needles inserted in nontraditional locations that were not thought to be acupuncture sites, with stimulation (n = 28); and (4) N/0 nontraditional needle location without stimulation (n = 2 7). All groups received treatment once weekly, followed by twice weekly, and finally three times weekly, for a total of 18 treatments. Each increase in frequency was separated by a 2-week washout period. OUTCOME MEASURES: Pain was assessed by a numerical rating scale, fatigue by the Multi-dimensional Fatigue Inventory, and physical function by the Short Form-36. RESULTS: Overall pain improvement was noted with 25%-35% of subjects having a clinically significant decrease in pain; however this was not dependent upon "correct" needle stimulation (t = 1.03; p = 0.307) or location (t = 0.76; p = 0.450). An overall dose effect of treatment was observed, with three sessions weekly providing more analgesia than sessions once weekly (t = 2.10; p = 0.039). Among treatment responders, improvements in pain, fatigue, and physical function were highly codependent (all p < or = 0.002). CONCLUSIONS: Although needle insertion led to analgesia and improvement in other somatic symptoms, correct needle location and stimulation were not crucial.

Acupuncture Analgesia↗
PubMed2005

Promoting translational research in academic health centers: navigating the "roadmap".

The translation of hypothesis-driven research laboratory findings about basic disease mechanisms into clinically useful tests or therapies, particularly in pediatric diseases, is time-consuming, expensive, and not well supported by traditional research grant mechanisms. Accordingly, the development of new drugs and clinical assays has typically been largely the domain of the pharmaceutical industry. Aside from partnering with for-profit companies, academic health centers are challenged to find ways to actively engage in biomedical research to bridge the gap between basic and clinical research. The Translational Research Initiative (TRI) at Cincinnati Children's Hospital Medical Center was launched in 2001 with the mission to build an institutional infrastructure for promoting and facilitating the clinical implementation of investigator-initiated basic research. The TRI's goals are to provide grant support for proposals that are translational in nature and that address serious diagnostic or therapeutic deficiencies in pediatric illnesses; to create and support specialized research cores and a specialized office that provides support for research protocol development and regulatory affairs; and to organize educational opportunities focused on bridging communication between basic and clinical scientists and encouraging multidisciplinary interactions. The authors describe the program structure and provide an interim outcome report as measured by extramural funding obtained, Investigational New Drug applications filed, manuscripts published, clinical trials launched, and educational initiatives created. The broad success of this program suggests that it might serve as a model for other academic health centers in promoting and conducting translational research.

Academic Medical Centers↗
PubMed2005

Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure.

The hematopoietic-specific Rho GTPase, Rac2, regulates a variety of cellular functions including cell shape changes, motility, integrin-dependent adhesion, and apoptosis. In the study reported here, we demonstrate that wild-type (WT) hematopoietic stem cells/progenitors (HSC/P) preferentially engraft in nonablated Rac2(-/-) bone marrow. In addition, primitive Rac2(-/-) HSC/P transplanted into lethally irradiated WT recipients showed a significant competitive defect compared with WT cells. These defects appeared to be related to HSC/P-intrinsic defective microenvironment interactions, since Rac2(-/-) cells showed less adhesion to the femur bone marrow density 1 (FBMD-1) stromal cell line, a lower frequency of cobblestone area-forming cells, and lower performance in long-term marrow cultures in vitro when compared with WT cells. In contrast, primitive Rac2(-/-) hematopoietic cells exhibited normal progenitor colony formation in semisolid medium in vitro and normal proliferation in the steady state in vivo when compared with WT cells. Taken together, these data suggest that Rac2(-/-) stem/progenitor cells exhibit abnormal interaction with the hematopoietic microenvironment, which leads to defective long-term engraftment.

Animals↗
PubMed2005

Assessment of the qualitative variation in bacterial microflora among compartments of the intestinal tract of dogs by use of a molecular fingerprinting technique.

OBJECTIVE: To evaluate the qualitative variation in bacterial microflora among compartments of the intestinal tract of dogs by use of a molecular fingerprinting technique. ANIMALS: 14 dogs (similarly housed and fed identical diets). PROCEDURE: Samples of intestinal contents were collected from the duodenum, jejunum, ileum, colon, and rectum of each dog. Bacterial DNA was extracted from the samples, and the variable V6 to V8 region of 16S ribosomal DNA (gene coding for 16S ribosomal RNA) was amplified by use of universal bacterial primers; polymerase chain reaction amplicons were separated via denaturing gradient gel electrophoresis (DGGE). Similarity indices of DGGE banding patterns were used to assess variation in the bacterial microflora among different compartments of the intestine within and among dogs. Bacterial diversity was assessed by calculating the Simpson diversity index, the Shannon-Weaver diversity index, and evenness. RESULTS: DGGE profiles indicated marked differences in bacterial composition of intestinal compartments among dogs (range of similarity, 25.6% to 36.6%) and considerable variation among compartments within individual dogs (range of similarity, 36.7% to 579%). Similarities between neighboring intestinal compartments were significantly greater than those between non-neighboring compartments. Diversity indices for the colon and rectum were significantly higher than those of the duodenum, jejunum, and ileum. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the different intestinal compartments of individual dogs appear to host different bacterial populations, and these compartmental populations vary among dogs. In dogs, fecal sample analysis may not yield accurate information regarding the composition of bacterial populations in compartments of the gastrointestinal tract.

Animals↗
PubMed2005

Efficacy of milnacipran in patients with fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) is a common musculoskeletal condition characterized by widespread pain, tenderness, and a variety of other somatic symptoms. Current treatments are modestly effective. Arguably, the best studied and most effective compounds are tricyclic antidepressants (TCA). Milnacipran, a nontricyclic compound that inhibits the reuptake of both serotonin and norepinephrine, may provide many of the beneficial effects of TCA with a superior side effect profile. METHODS: One hundred twenty-five patients with FM were randomly assigned in a 3:3:2 ratio to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months in a double-blind dose-escalation trial; 92% of twice-daily and 81% of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg. RESULTS: The primary endpoint was reduction of pain. Both the once- and twice-daily groups showed statistically significant improvements in pain, as well as improvements in global well being, fatigue, and other domains. Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression, but placebo response rates were considerably higher in depressed patients, leading to significantly greater overall efficacy in the nondepressed group. CONCLUSION: In this Phase II study, milnacipran led to statistically significant improvements in pain and other symptoms of FM. The effect sizes were equal to those previously found with TCA, and the drug was generally well tolerated.

Analgesics↗
PubMed2005

Gene therapy in the treatment of Fanconi anemia, a progressive bone marrow failure syndrome.

Fanconi anemia (FA) is a genetic disease characterized by progressive, fatal bone marrow failure, congenital anomalies and predisposition to cancer. Although stem cell transplantation is therapeutic, human leukocyte antigen-identical sibling donors are available to a minority of patients. In murine models and human cells in vitro, gene transfer corrects the FA cellular phenotype of chromosomal breakage in response to DNA-damaging agents, suggesting therapeutic use of gene transfer is possible. However, disease-specific characteristics make application of viral vector technology difficult. Multiple studies are currently underway to develop a gene therapy approach for treating this disease, including phase I trials.

Clinical Trials as Topic↗
PubMed2005

Fibromyalgia syndrome.

The objectives of the first OMERACT Fibromyalgia Syndrome (FM) Workshop were to identify and prioritize symptom domains that should be consistently evaluated in FM clinical trials, and to identify aspects of domains and outcome measures that should be part of a concerted research agenda of FM researchers. Such an effort will help standardize and improve the quality of outcomes research in FM. A principal assumption in this workshop has been that there exists a clinical syndrome, generally known as FM, characterized by chronic widespread pain typically associated with fatigue, sleep disturbance, mood disturbance, and other symptoms and signs, and considered to be related to central neuromodulatory dysregulation. FM can be diagnosed using 1990 American College of Rheumatology criteria. In preparation for the workshop a Delphi exercise involving 23 FM researchers was conducted to establish a preliminary prioritization of domains of inquiry. At the OMERACT meeting, the workshop included presentation of the Delphi results; a review of placebo-controlled trials of FM treatment, with a focus on the outcome measures used and their performance; a panel discussion of the key issues in FM trials, from both an investigator and regulatory agency perspective; and a voting process by the workshop attendees. The results of the workshop were presented in the plenary session on the final day of the meeting. A prioritized list of domains of FM to be investigated was thus developed, key issues and controversies in the field were debated, and consensus on a research agenda on outcome measure development was reached.

Delphi Technique↗
PubMed2005

Development of a 13C-glycocholic acid blood test to assess bacterial metabolic activity of the small intestine in canines.

The objectives of this study were to establish optimal doses of 13C-glycocolic acid (GCA) for use in a GCA blood test as a marker for canine small intestinal bacterial metabolic activity. Four doses of GCA were administered orally to 8 healthy dogs. Blood samples were collected at various time points up to 480 min. The percent dose/min of 13C administered as GCA (PCD) and cumulative PCD (CUMPCD) were determined by fractional mass spectrometry. No dog showed any clinically obvious side effects. Doses of 1 and 2 mg/kg of bodyweight (BW) led to a significant increase in PCD and CUMPCD (P < 0.001). The mean CUMPCD was significantly higher for the 1 mg/kg BW dose compared with the 2 and 4 mg/kg BW doses (P < 0.05). Administration of 1 mg/kg BW of 13C-glycocholic acid led to an increase in CUMPCD over baseline in gas extracted from blood samples and appears to be the best parameter to evaluate for future clinical studies.

Administration, Oral↗
PubMed2004

Knee pain and radiographic osteoarthritis interact in the prediction of levels of self-reported disability.

OBJECTIVE: To determine predictors of disability depending on whether joint deformity and pain reporting exist independently or concurrently. METHODS: Subjects were 154 volunteers for an osteoarthritis screening examination. Eligible subjects completed questionnaires for physical function, pain, and depressive symptoms; underwent evoked pain testing for tenderness assessment; and had anteroposterior and lateral radiographs taken of both knees. Two blinded rheumatologists scored the images using Kellgren-Lawrence criteria to determine presence of deformity. RESULTS: Subjects were divided into 3 subgroups based on radiographic evidence of deformity and self-reported pain. Disability was greatest when pain and deformity occurred together (F[2,151] = 18.8, P < 0.0001). Self-reported disability in the absence of deformity was predicted by body mass index, pain threshold, and anxiety symptoms; disability was predicted by the number of osteophytes and depressive symptoms when pain and deformity occurred together. CONCLUSION: Self-reported disability in osteoarthritis of the knee is greatest with concurrent pain and joint deformity. When pain and deformity do not cooccur, disability appears to be related to separate factors, including anxiety and pain threshold (e.g., tenderness).

Aged↗
PubMed2004

Localization of Rac2 via the C terminus and aspartic acid 150 specifies superoxide generation, actin polarity and chemotaxis in neutrophils.

Despite having a high degree of sequence similarity, the Rho guanosine triphosphatases Rac1 and Rac2 regulate distinct functions in neutrophils. Here we demonstrate that the unique Rac2 localization and functions in neutrophils are regulated by two separate C-terminal motifs, the hypervariable domain and aspartic acid 150, one of which has not previously been linked to the function of Rho GTPases. In addition, we show an unexpected dependence of Rac1 localization on Rac2 activity in these same cells, demonstrating a degree of crosstalk between two closely related Rho GTPases. Thus, we have defined specific sequences in Rac that specify subcellular localization and determine the specificity of Rac2 in neutrophil chemotaxis and superoxide generation.

Actins↗
PubMed2004

Physiological concentrations of bile salts inhibit recovery of ischemic-injured porcine ileum.

We have previously shown rapid in vitro recovery of barrier function in porcine ischemic-injured ileal mucosa, attributable principally to reductions in paracellular permeability. However, these experiments did not take into account the effects of luminal contents, such as bile salts. Therefore, the objective of this study was to evaluate the role of physiological concentrations of deoxycholic acid in recovery of mucosal barrier function. Porcine ileum was subjected to 45 min of ischemia, after which mucosa was mounted in Ussing chambers and exposed to varying concentrations of deoxycholic acid. The ischemic episode resulted in significant reductions in transepithelial electrical resistance (TER), which recovered to control levels of TER within 120 min, associated with significant reductions in mucosal-to-serosal (3)H-labeled mannitol flux. However, treatment of ischemic-injured tissues with 10(-5) M deoxycholic acid significantly inhibited recovery of TER with significant increases in mucosal-to-serosal (3)H-labeled mannitol flux, whereas 10(-6) M deoxycholic acid had no effect. Histological evaluation at 120 min revealed complete restitution regardless of treatment, indicating that the breakdown in barrier function was due to changes in paracellular permeability. Similar effects were noted with the application of 10(-5) M taurodeoxycholic acid, and the effects of deoxycholic acid were reversed with application of the Ca(2+)-mobilizing agent thapsigargin. Deoxycholic acid at physiological concentrations significantly impairs recovery of epithelial barrier function by an effect on paracellular pathways, and these effects appear to be Ca(2+) dependent.

Animals↗
PubMed2004

Glucuronidation of haloperidol by rat liver microsomes: involvement of family 2 UDP-glucuronosyltransferases.

The purposes of this study were to develop a HPLC method to assay for haloperidol glucuronide (HALG); to apply this assay method to the in vitro determination of haloperidol (HAL) UDP-glucuronosyltransferase (UGT) enzyme kinetics in rat liver microsomes (RLM); and to identify the UGT isoforms catalyzing glucuronidation of HAL in rats. Incubation of Brij-activated RLM with HAL and UDP-glucuronic acid (UDPGA) in TRIS pH 7.4 buffer resulted in the formation of a single peak in the HPLC chromatogram at 270 nm. The identity of this peak was confirmed to be that of HALG by 1) beta-glucuronidase hydrolysis; 2) incubation without UDPGA; 3) UV spectral analysis; and 4) LC/MS/MS to yield the expected mass of 552.1. Enzyme kinetic studies using single enzyme Michaelis-Menton model showed an apparent Vmax = 271.9 +/- 10.1 pmoles min(-1) mg protein(-1) and Km = 61 +/- 7.2 microM. Glucuronidation activity in homozygous Gunn (j/j) rats was approximately 80% as compared to Sprague-Dawley RLM. HALG formation was approximately doubled in PB-induced RLM. There was no increase in glucuronidation activities in 3MC-induced RLM. The Gunn rat and the PB-induced RLM data suggest predominant but not exclusive involvement of the UGT2B family in the formation of HALG. Because the UGTs exhibit overlapping substrate specificities and most substrates are glucuronidated by more than one isoform, inhibition studies with UGT2B1 substrate probe testosterone and the UGT2B12 substrate probe borneol were conducted. UGT2B1 and UGT2B12 exhibited 40% and 90% inhibition of HAL glucuronidation, respectively. Thus, UGT2B12 and UGT 2B1 isoforms are responsible for catalyzing HAL glucuronidation in rats. Our HPLC assay provides a specific and sensitive technique for the measurement of in vitro HAL-UGT activity.

Animals↗
PubMed2004

Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts.

The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair.

Animals↗
PubMed2004

Evidence of augmented central pain processing in idiopathic chronic low back pain.

OBJECTIVE: For many individuals with chronic low back pain (CLBP), there is no identifiable cause. In other idiopathic chronic pain conditions, sensory testing and functional magnetic resonance imaging (fMRI) have identified the occurrence of generalized increased pain sensitivity, hyperalgesia, and altered brain processing, suggesting central augmentation of pain processing in such conditions. We compared the results of both of these methods as applied to patients with idiopathic CLBP (n = 11), patients with widespread pain (fibromyalgia; n = 16), and healthy control subjects (n = 11). METHODS: Patients with CLBP had low back pain persisting for at least 12 months that was unexplained by MRI/radiographic changes. Experimental pain testing was performed at a neutral site (thumbnail) to assess the pressure-pain threshold in all subjects. For fMRI studies, stimuli of equal pressure (2 kg) and of equal subjective pain intensity (slightly intense pain) were applied to this same site. RESULTS: Despite low numbers of tender points in the CLBP group, experimental pain testing revealed hyperalgesia in this group as well as in the fibromyalgia group; the pressure required to produce slightly intense pain was significantly higher in the controls (5.6 kg) than in the patients with CLBP (3.9 kg) (P = 0.03) or the patients with fibromyalgia (3.5 kg) (P = 0.006). When equal amounts of pressure were applied to the 3 groups, fMRI detected 5 common regions of neuronal activation in pain-related cortical areas in the CLBP and fibromyalgia groups (in the contralateral primary and secondary [S2] somatosensory cortices, inferior parietal lobule, cerebellum, and ipsilateral S2). This same stimulus resulted in only a single activation in controls (in the contralateral S2 somatosensory cortex). When subjects in the 3 groups received stimuli that evoked subjectively equal pain, fMRI revealed common neuronal activations in all 3 groups. CONCLUSION: At equal levels of pressure, patients with CLBP or fibromyalgia experienced significantly more pain and showed more extensive, common patterns of neuronal activation in pain-related cortical areas. When stimuli that elicited equally painful responses were applied (requiring significantly lower pressure in both patient groups as compared with the control group), neuronal activations were similar among the 3 groups. These findings are consistent with the occurrence of augmented central pain processing in patients with idiopathic CLBP.

Adult↗