Biomedical subjects

David A Williams

Publications and source records attributed to David A Williams.

At least 145 records · Page 8Linked to original sources

PubMed2002

Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells.

Rho family GTPases activate intracellular kinase cascades to modulate transcription of multiple genes. Previous studies have examined the roles of the ubiquitously expressed Rho GTPase, Rac1, in regulation of gene expression in cell lines and implicated NF-kappaB, serum response factor, and kinase signaling pathways in this regulation. To understand the role of the closely related but hematopoiesis-specific Rho GTPase, Rac2, in regulation of gene transcription, we compared the gene expression profiles between wild-type and Rac2(-/-) bone marrow-derived mast cells. Our data demonstrate remarkable specificity in the regulation of gene expression by Rac2 versus Rac1. Microarray analysis demonstrated that expression of 38 known genes was significantly altered in Rac2(-/-) mast cells after cytokine stimulation compared with those in wild-type cells. Of these, the expression of the mouse mast cell protease 7 (MMCP-7) gene in wild-type cells was highly induced at the transcriptional level after stimulation with stem cell factor (SCF). In spite of compensatorily increased expression of Rac1 in Rac2-deficient cells, SCF-induced MMCP-7 transcription did not occur. Surprisingly, the loss of MMCP-7 induction was not due to decreased activation of NF-kappaB, a transcription factor postulated to lie downstream of Rac1 and known to play a critical role in hematopoietic cell differentiation and proliferation. However, the activities of c-Jun N-terminal kinases (JNKs) were markedly decreased in Rac2(-/-) mast cells. Our results suggest that cytokine-stimulated activation of MMCP-7 gene transcription is selectively regulated by a Rac2-dependent JNK signaling pathway in primary mast cells and imply a remarkable specificity in the regulation of transcriptional activity by these two highly related Rho GTPases.

Amino Acid Motifs↗

PubMed2002

Pore formation is not associated with macroscopic redistribution of P2X7 receptors.

The present study examines whether changes in P2X7 purinergic receptor density precede formation of the cytolytic pore characteristic of this receptor. We fused P2X7 receptors with enhanced green fluorescent protein (EGFP) at the amino or carboxy termini (EGFP-P2X7 and P2X7-EGFP). Electrophysiological characterization in Xenopus oocytes revealed wild-type responses to ATP for GFP-tagged receptors. However, differences in sensitivity to ATP were apparent with the P2X7-EGFP receptor displaying a threefold reduction in ATP sensitivity compared with control. Ethidium ion uptake was used to measure cytolytic pore formation. Comparison of tagged receptors with wild type in HEK-293 and COS-7 cells showed there was no significant difference in ethidium ion uptake, suggesting that fusions with EGFP did not interfere with cytolytic pore formation. Confocal microscopy confirmed that tagged receptors localized to the plasmalemma. Simultaneous monitoring of EGFP and ethidium ion fluorescence revealed that changes in receptor distribution do not precede pore formation. We conclude that it is unlikely that large scale changes in P2X7 receptor density precede pore formation.

Adenosine Triphosphate↗

PubMed2002

Inheritance of pancreatic acinar atrophy in German Shepherd Dogs.

OBJECTIVE: To assess the heritability of pancreatic acinar atrophy (PAA) in German Shepherd Dogs (GSDs) in the United States. ANIMALS: 135 GSDs belonging to 2 multigenerational pedigrees. PROCEDURE: Two multigenerational pedigrees of GSDs with family members with PAA were identified. The clinical history of each GSD enrolled in the study was recorded, and serum samples for canine trypsin-like immunoreactivity (cTLI) analysis were collected from 102 dogs. Dogs with a serum cTLI concentration < or = 2.0 microg/L were considered to have exocrine pancreatic insufficiency (EPI) and were assumed to have PAA. RESULTS: Pedigree I consisted of 59 dogs and pedigree II of 76 dogs. Serum cTLI concentrations were measured in 48 dogs from pedigree I and 54 dogs from pedigree II. A total of 19 dogs (14.1%) were determined to have EPI, 9 in pedigree I (15.3%) and 10 in pedigree II (13.6%). Of the 19 dogs with EPI, 8 were male and 11 were female. CONCLUSIONS AND CLINICAL RELEVANCE: Evaluation of data by complex segregation analysis is strongly suggestive of an autosomal recessive mode of inheritance for EPI in GSDs in the United States.

Animals↗

PubMed2002

Purification and partial characterization of canine pepsinogen A and B.

OBJECTIVE: To purify and partially characterize various isoforms of canine pepsinogen (PG) from gastric mucosa. SAMPLE POPULATION: Stomachs obtained from 6 euthanatized dogs. PROCEDURE: Mucosa was scraped from canine stomachs, and a crude mucosal extract was prepared and further purified by use of weak anion-exchange chromatography, hydroxyapatite chromatography, size-exclusion chromatography, and strong anion-exchange chromatography. Pepsinogens were characterized by estimation of molecular weights, estimation of their isoelectric points (IEPs), and N-terminal amino acid sequencing. RESULTS: Two different groups of canine PG were identified after the final strong anion-exchange chromatography: PG A and PG B. Pepsinogens differed in their molecular weights and IER Pepsinogen B appeared to be a dimer with a molecular weight of approximately 34,100 and an IEP of 4.9. Pepsinogen A separated into several isoforms. Molecular weights for the various isoforms of PG A ranged from 34,200 to 42,100, and their IEPs ranged from 4.0 to < 3.0. The N-terminal amino acid sequence for the first 25 amino acid residues for PG A and B had good homology with the amino acid sequences for these proteins in other species. CONCLUSIONS AND CLINICAL RELEVANCE: Canine PG B and several isoforms of canine PG A have been purified. Availability of these PGs will facilitate development of immunoassays to measure PG in canine serum as a potential diagnostic marker for gastric disorders in dogs.

Amino Acid Sequence↗

PubMed2002

Cellular immunolocalization of gastric and pancreatic lipase in various tissues obtained from dogs.

OBJECTIVE: To determine cellular immunolocalization of canine gastric lipase (cGL) and canine pancreatic lipase (cPL) in various tissues obtained from clinically healthy dogs. SAMPLE POPULATION: Samples of 38 tissues collected from 2 climically healthy dogs. PROCEDURES: The cGL and cPL were purified from gastric and pancreatic tissue, respectively, obtained from dogs. Antisera against both proteins were developed, using rabbits, and polyclonal antibodies were purified by use of affinity chromatography. Various tissues were collected from 2 healthy dogs. Primary antibodies were used to evaluate histologic specificity. Replicate sections from the collected tissues were immunolabeled for cGL and cPL and examined by use of light microscopy. RESULTS: Mucous neck cells and mucous pit cells of gastric glands had positive labeling for cGL, whereas other tissues did not immunoreact with cGL. Pancreatic acinar cells had positive labeling for cPL, whereas other tissues did not immunoreact with cPL. CONCLUSIONS AND CLINICAL RELEVANCE: We concluded that cGL and cPL are exclusively expressed in gastric glands and pancreatic acinar cells, respectively. Also, evidence for cross-immunoreactivity with other lipases or related proteins expressed by other tissues was not found for either protein. Analysis of these data suggests that gastric lipase is a specific marker for gastric glands and that pancreatic lipase is a specific marker for pancreatic acinar cells. These markers may have clinical use in the diagnosis of gastric and exocrine pancreatic disorders, respectively.

Animals↗

PubMed2002

Postprandial changes in serum unconjugated bile acid concentrations in healthy beagles.

OBJECTIVE: To investigate postprandial changes in serum concentrations of unconjugated bile acids in healthy Beagles. ANIMALS: 7 healthy Beagles. PROCEDURE: Blood samples were obtained from dogs at regular intervals up to 8 hours after consumption of a meal. Serum concentrations of 5 unconjugated bile acids were determined at each time point, using gas chromatography-mass spectrometry with selected ion monitoring. RESULTS: Total serum unconjugated bile acid concentration was significantly increased, relative to baseline values, at 360, 420, and 480 minutes after feeding. Unconjugated cholic acid was significantly increased at 360, 420, and 480 minutes. The proportion of total unconjugated bile acids represented by cholic acid was significantly increased at 240 to 480 minutes. Deoxycholic acid was significantly increased at 360 and 420 minutes. Chenodeoxycholic acid was significantly increased at 360 to 480 minutes. Lithocholic acid was significantly increased at 180 minutes, whereas no significant changes in ursodeoxycholic acid were detected at any time point. CONCLUSIONS AND CLINICAL RELEVANCE: Healthy Beagles had significant increases in serum concentrations and changes in the profile of unconjugated bile acids after a meal. These increases persisted > 8 hours, indicating that prolonged withholding of food is necessary to avoid the risk of a false-positive diagnosis when assessing serum unconjugated bile acid concentrations in dogs.

Animals↗

PubMed2002

Kinetics of urinary recovery of five sugars after orogastric administration in healthy dogs.

OBJECTIVE: To describe the kinetics of urinary recovery (UR) of 5 sugars used for gastrointestinal permeability and mucosal function testing following orogastric administration of lactose, rhamnose, xylose, methylglucose, and sucrose. ANIMALS: 7 healthy male Beagles. PROCEDURES: A sugar solution containing lactulose, rhamnose, xylose, methylglucose, and sucrose was administered by orogastric intubation to healthy dogs. Urine samples were collected immediately before sugar solution administration (baseline) and at 2-hour intervals thereafter. The UR of the 5 sugars was determined from urine concentrations measured by high pressure liquid chromatography and pulsed amperometric detection. Percent urinary recovery (%UR) of the total UR up to 12 hours after sugar solution administration was calculated for each sugar at 2-hour intervals. RESULTS: Mean %UR exceeded 85% for all 5 sugars at 6 hours after orogastric administration of the sugar solution and exceeded 90% after 8 hours. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy dogs, a urine collection period of 6 hours is sufficient for gastrointestinal permeability and mucosal function testing following orogastric administration of lactulose, rhamnose, xylose, methylglucose, and sucrose.

Administration, Oral↗

PubMed2002

Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention.

OBJECTIVE: Sustained improvement in physical functional status was the primary goal of a brief, 6 session cognitive behavioral therapy (CBT) protocol for fibromyalgia (FM). METHODS: One hundred forty-five patients with FM were randomly assigned to either (1) standard medical care that included pharmacological management of symptoms and suggestions for aerobic fitness, or (2) the same standard medical treatment plus 6 sessions of CBT aimed at improving physical functioning. Outcome measures included the Medical Outcome Study Short Form-36 Physical Component Score and McGill ratings of pain. Outcomes were treated dichotomously using a preestablished criterion for clinically significant success based upon the reliability of change index from baseline to one year posttreatment. RESULTS: Twenty-five percent of the patients receiving CBT were able to achieve clinically meaningful levels of longterm improvement in physical functioning, whereas only 12% of the patients receiving standard care achieved the same level of improvement. There were no lasting differences on pain ratings between groups. CONCLUSION: Lasting improvements in physical functioning have been among the most difficult outcomes to obtain in studies of FM. These data suggest that the inclusion of CBT to a standard medical regimen for FM can favorably influence physical functioning in a subset of patients.

Adult↗

PubMed2001

Truncation of the GABA(A)-receptor gamma2 subunit in a family with generalized epilepsy with febrile seizures plus.

Recent findings from studies of two families have shown that mutations in the GABA(A)-receptor gamma2 subunit are associated with generalized epilepsies and febrile seizures. Here we describe a family that has generalized epilepsy with febrile seizures plus (GEFS(+)), including an individual with severe myoclonic epilepsy of infancy, in whom a third GABA(A)-receptor gamma2-subunit mutation was found. This mutation lies in the intracellular loop between the third and fourth transmembrane domains of the GABA(A)-receptor gamma2 subunit and introduces a premature stop codon at Q351 in the mature protein. GABA sensitivity in Xenopus laevis oocytes expressing the mutant gamma2(Q351X) subunit is completely abolished, and fluorescent-microscopy studies have shown that receptors containing GFP-labeled gamma2(Q351X) protein are retained in the lumen of the endoplasmic reticulum. This finding reinforces the involvement of GABA(A) receptors in epilepsy.

Animals↗

PubMed1995

Cluster analyses of pain patients' responses to the SCL-90R.

This study sought to identify distinct subgroups of chronic pain patients based on responses to the Symptom Checklist 90-revised (SCL-90R), a measure of psychological distress. Two scoring methods were used: the standard scoring that accompanies the manual, and a scoring method based upon factor scores obtained in an earlier study using low back pain patients. Two separate cluster analyses assigned patients into 2 groups: one based on standard scores and one based on factor scores. Results of this study support the hypothesis that distinct and replicable subgroups of chronic pain patients can be identified using the SCL-90R. Depending upon group membership, patients significantly differed on measures of qualitative pain and quantitative pain report, depressive symptoms, medication usage, and pain-related behaviors. This study supports the use of SCL-90R factor scoring with pain patients as greater differentiation between clusters was found for pain report and pain-related behavior when this method was used. Guidelines for clinical application of SCL-90R cluster groups is provided.

Adolescent↗

PubMed1995

The influence of lockout intervals and drug selection on patient-controlled analgesia following gynecological surgery.

This study systematically compared 2 opioids, morphine (MOR) and fentanyl (FEN), and 2 lockout intervals, long (L) and short (S) in patients utilizing patient-controlled analgesia (PCA). Seventy-eight women undergoing gynecological surgery were randomly assigned to 1 of 4 groups: MOR-S (7 min), MOR-L (11 min), FEN-S (5 min), FEN-L (8 min). PCA measures obtained during the first 24 h after surgery included: number of demands/h, number of completed deliveries/h, dose/h, and demand/delivery ratio. Visual analog scales of pain and anxiety were also obtained. Results indicated that pain relief was equivalent with minimal side effects for both opioids. The selection of opioid, however, influenced the pattern of PCA use, with an improved demand/delivery ratio initially for FEN. The lockout intervals chosen for this study did not influence pain or anxiety levels.

Adolescent↗

PubMed1994

Pain beliefs: assessment and utility.

When pain becomes persistent, patients may abandon previously held cultural or personal beliefs about pain to form new pain beliefs that are more consistent with their persistent pain experience. The Pain Beliefs and Perceptions Inventory (PBPI) is an instrument to assess these new beliefs. This paper presents 4 studies examining the utility of the PBPI. Two studies are factor analytic and support recent literature identifying 4 belief factors associated with this instrument. The third and fourth studies used a new scoring method for the PBPI creating 4 scales: Mystery, Self-blame, Pain Permanence, and Pain Constancy. These scales were then correlated with important pain indices such as measures of pain quality, psychological states (i.e., depression and anxiety), personality traits, physical functioning, and coping strategies. Each belief appears to have a unique association with the pain indices thus supporting the rescoring of this instrument with 4 scales. Belief in pain constancy is associated with greater pain self-report, permanence is associated with anxiety, mystery is associated with greatest overall distress, and self-blame is associated with depressive symptoms. An appendix is included that provides clinical norms for the use of the PBPI and a revised scoring key.

Adaptation, Psychological↗

PubMed1991

Analyzing pain in rheumatoid arthritis patients. Pain coping strategies in patients who have had knee replacement surgery.

This study used the Coping Strategies Questionnaire (CSQ) to investigate pain coping strategies in 52 rheumatoid arthritis patients who reported having knee pain 1 year or more following knee replacement surgery. Data analysis revealed that, as a group, these patients were active copers in that they reported frequent use of a variety of pain coping strategies. Pain coping strategies were found to be related to measures of pain and adjustment. Patients who rated their ability to control and decrease pain high and who rarely engaged in catastrophizing (i.e., who scored high on the Pain Control and Rational Thinking factor of the CSQ) had much lower levels of pain and psychological disability than patients who did not. Coping strategies were not found to relate to age, gender, obesity status or disability/compensation status. Taken together, these results suggest that an analysis of pain coping strategies may be helpful in understanding pain in arthritis patients who have pain following joint replacement surgery.

Adaptation, Psychological↗

PubMed1991

Pain beliefs and the use of cognitive-behavioral coping strategies.

Patients' beliefs about chronic pain, such as how long it will last and whether it is a mysterious experience, have been shown to be related to compliance with treatment programs. The present study examined whether these pain beliefs related to a specific component of pain management, namely the frequency of use and the perceived effectiveness of cognitive and behavioral coping strategies. One hundred twenty chronic pain patients were administered the Pain Beliefs and Perceptions inventory (PBAPI) and the Coping Strategies questionnaire (CSQ). A cluster analysis of 2 pain beliefs (that pain is enduring and that pain is mysterious) was conducted revealing 3 distinct subgroups of patients based upon these 2 beliefs. Multivariate analysis of variance was used to detect whether the use of cognitive-behavioral pain coping strategies differed in patients in the 3 pain beliefs subgroups. The results indicated that patients belonging to the group characterized by the belief that pain was enduring and mysterious were less likely to use cognitive coping strategies (e.g., reinterpretation of pain sensation), more likely to catastrophize, and less likely to rate their coping strategies as effective in controlling and decreasing pain than patients believing their pain to be understandable and of short duration. The implications of these results for understanding the patient's choice of and compliance with treatment and coping efforts is discussed.

Adaptation, Psychological↗

PubMed1990

Analyzing chronic low back pain: the relative contribution of pain coping strategies.

Sixty-two chronic low back pain patients were administered the Coping Strategies Questionnaire (CSQ) to assess the frequency of use and perceived effectiveness of a variety of cognitive and behavioral pain coping strategies. Analysis of individual variables revealed that CSQ factors, gender, physical examination findings, and chronicity of pain had significant effects on one or more of a series of pain, psychological distress or behavioral measures. To assess the relative contribution of each of these variables hierarchical stepwise regression analyses were carried out. These analyses revealed that the Helplessness factor of the CSQ explained 50% of the variance in psychological distress (Global Severity Index of the SCL-90R), and 46% of the variance in depression (Beck Depression Inventory). Patients scoring high on this CSQ factor had significantly higher levels of psychological distress. None of the demographic or medical status variables explained a significant proportion of variance in the psychological distress measures. The Diverting Attention and Praying factor of the CSQ explained a moderate (9%), but significant amount of variance in pain report. Patients scoring high on this factor had higher scores on the McGill Pain Questionnaire. Coping strategies were not strongly related to pain behavior measures such as guarding or uptime. A consideration of pain coping strategies may allow one to design pain coping skills training interventions so as to fit the needs of the individual low back pain patient.

Adaptation, Psychological↗

PubMed1989

An empirical assessment of pain beliefs.

Pain beliefs represent patients' own conceptualizations of what pain is and what pain means for them. Such beliefs may be discordant with current scientific understanding and may serve to adversely affect compliance with modern methods of chronic pain treatment. This study attempts to assess several of the core dimensions around which pain beliefs develop and examines the relationship between pain beliefs and behavioral manifestations of the pain experience. An empirically and factorially derived product of this study, the Pain Beliefs and Perceptions Inventory (PBAPI) assess 3 dimensions of pain beliefs: (1) self-blame, (2) perception of pain as mysterious, and (3) beliefs about the duration of pain. These core pain beliefs were found to be predictive of subjective pain intensity, multidisciplinary chronic pain treatment compliance, poor self-esteem, somatization and psychological distress, and associated with attributions about health locus of control.

Adult↗

PubMedDate not supplied

Endurance training adaptations modulate the redox-force relationship of rat isolated slow-twitch skeletal muscles.

1. Studies have shown that, in isolated skeletal muscles, maximum isometric force production (Po) is dependent on muscle redox state. Endurance training increases the anti-oxidant capacity of skeletal muscles, a factor that could impact on the force-producing capacity following exogenous exposure to an oxidant. We tested the hypothesis that 12 weeks treadmill training would increase anti-oxidant capacity in rat skeletal muscles and alter their response to exogenous oxidant exposure. 2. At the conclusion of the 12 week endurance-training programme, soleus (slow-twitch) muscles from trained rats had greater citrate synthase (CS) and catalase (CAT) activity compared with soleus muscles from untrained rats (P < 0.05). In contrast, CAT activity of extensor digitorum longus (EDL; fast-twitch) muscles from trained rats was not different to EDL muscles of untrained rats. The CS activity was lower in EDL muscles from trained compared with untrained rats (P < 0.05). 3. Equilibration with exogenous hydrogen peroxide (H2O2, 5 mmol/L) increased the Po of soleus muscles from untrained rats for the duration of treatment (30 min), whereas the Po of EDL muscles was affected biphasically, with a small increase initially (after 5 min), followed by a more marked decrease in Po (after 30 min). The H2O2-induced increase in Po of soleus muscles from trained rats was less than that in untrained rats (P < 0.05), but no differences were observed in the Po of EDL muscles following training. 4. The results indicate that 12 weeks endurance running training conferred adaptations in soleus but not EDL muscles. These adaptations were associated with an attenuation of the oxidant-induced increase in Po of soleus muscles from trained compared with untrained rats. We conclude that endurance training-adapted soleus muscles have a slightly altered redox-force relationship.

Adaptation, Physiological↗

PubMedDate not supplied

Pain assessment in patients with fibromyalgia syndrome: a consideration of methods for clinical trials.

OBJECTIVE: This study was designed to compare 3 commonly used methodologies for assessing clinical pain during trials involving patients diagnosed with fibromyalgia syndrome. Baseline characteristics, characteristics over time, and compliance were evaluated for each of the methods. METHODS: Fourteen patients diagnosed with fibromyalgia syndrome were asked to monitor their symptoms of pain using 3 different strategies over a 12-week period: 1) real-time pain reports were collected on an electronic diary using randomly-scheduled audible prompts; 2) end-of-week reports asked patients to rate their mean pain over the past week on the electronic diary; and 3) monthly in-clinic reports asked patients to rate their mean pain for the week using a traditional paper and pencil diary. RESULTS: Significantly different baseline values were obtained for the 3 methods. Paper and pencil produced the highest values, and real-time pain reports produced the lowest baseline values. Pain ratings were more likely to reflect decreases in the 2 methods relying on recall than the real-time strategy. The average adherence with pain monitoring using the electronic diary was 85%, which was superior to the adherence for the recall measures completed during the clinic visits. CONCLUSION: Pain assessment methods relying on recall might contribute to an apparent improvement in clinical trials in the absence of an intervention; such an effect has been considered a "placebo response." Future clinical trials might consider using a real-time approach to pain assessment, which in this study appeared to mitigate against seeing improvement in the absence of an intervention and demonstrated higher levels of patient adherence.

Adult↗