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Biomedical subjects

M R Walters

Publications and source records attributed to M R Walters.

At least 19 recordsLinked to original sources
PubMed2002

Early clinical experience with the novel NMDA receptor antagonist CNS 5161.

AIMS: To investigate the safety, tolerability and pharmacokinetics of the novel NMDA antagonist CNS 5161 in humans. Excessive activation of glutamate receptors, especially of the N-methyl-d-aspartate (NMDA) subtype has been associated with neuropathic pain, and brain damage caused by focal ischaemia in mature brain or hypoxia-ischaemia (HI) in neonates. CNS 5161 is a novel NMDA ion-channel antagonist that interacts with the NMDA receptor/ion channel site to produce a noncompetitive blockade of the actions of glutamate. Pre-clinical studies have demonstrated neuroprotective effects of CNS 5161 in the adult rat model of focal cerebral ischaemia, as well as anticonvulsant and analgesic effects. This study reports the first administration of CNS 5161 to man. Its objectives were to investigate the haemodynamic effects of the compound, to assess its safety and tolerability in healthy male volunteers, and to provide some preliminary human pharmacokinetic data. METHODS: We performed a randomized, double-blind placebo controlled phase 1 dose escalation study of CNS 5161. Volunteers were randomized to receive CNS 5161 or placebo in a ratio of 3:1. Twenty-four of 32 healthy volunteers received intravenous infusion of CNS 5161 over 15 min, followed by serial measurements of plasma drug concentration and haemodynamic observations over 24 h. A dose escalation design was adopted and the volunteers were stratified into eight dosage groups, ranging from 30 microg to 2000 microg. RESULTS: The drug was well tolerated by recipients. Side-effects were dose-related, self limiting and comprised minor subjective sensory symptoms. A dose dependent rise in systolic, mean arterial and diastolic blood pressure was seen in subsequent dosage groups, reaching 23/19 mmHg. Maximal effects were seen between 60 and 120 min after commencement of infusion. All subjects returned to baseline haemodynamic values within 24 h. Putative neuroprotective concentrations of CNS 5161 were achieved transiently, although these levels were not sustained. The pharmacokinetic data were best described by a two compartment model. The mean half-life was 2.95 h (s.d. 0.75). Mean clearance was 106 l h(-1) (s.d. 17.8) mean volume of distribution was 296 l (s.d. 69). These parameters were not significantly affected by body weight. CONCLUSIONS: This study suggests that CNS 5161 is well tolerated in healthy volunteers within the dose range studied. In addition, information concerning the pharmacokinetics of the compound has been acquired. Studies to investigate the efficacy of the compound in man may now be justified.

Adolescent↗
PubMed2001

Purification and characterization of three antifungal proteins from cheeseweed (Malva parviflora).

Three potent antimicrobial proteins were purified from cheeseweed (Malva parviflora) seeds. These antimicrobial proteins, named CW-3, CW-4, and CW-5, showed different antimicrobial spectrum and potency compared to the two heterologous antimicrobial proteins (CW-1 and CW-2) purified previously. CW-3 and CW-4 possess antimicrobial activities against Phytophthora infestans (Pi), but not Fusarium graminearum (Fg). A database search indicated that CW-3 shares high homology to cotton vicilin, an abundant seed storage protein. CW-4 shares homology to 2S albumin, another seed storage protein from cotton. CW-5 has antimicrobial activity against Fg, but no activity against Pi was observed at protein concentration up to 50 ppm. Under low salt condition, CW-5 showed potent antimicrobial activity against Fg, but under high salt condition, the antimicrobial activity was drastically diminished. Database search indicated that CW-5 has high homology to a lipid transfer protein from grape. The IC(50) values of the three purified antimicrobial proteins under both low and high salt conditions were determined. The isolation of five antimicrobial proteins for the first time from a single plant source provides further understanding of the plant innate defense system and insight on how plants evolve their complex and complementary antimicrobial system that is important in the early stage of development.

Amino Acid Sequence↗
PubMed2001

Problem-based learning within endocrine physiology lectures.

Methods were needed to improve the interest of medical students in the 10-lecture Endocrine Physiology block at the end of the second semester of study. Other incentives for improvement included the possibility of attracting students into endocrine research electives and the pressure to improve teaching approaches that results from the high tuition they pay. The principal approach adopted was that of whole class problem-based learning sessions (PBLS) in which the lecture period begins with a brief overview of one to three simplified cases, followed by the usual didactic lecture. At the end of the lecture, each PBL case is read in detail, with several questions posed to the students. Their answers are then used to reinforce concepts from the lecture material. This method can also provide some continuity between lectures, either by using a case in several lectures to illustrate different points, or by posing a question at the beginning of class that illustrates a point from the prior lecture. The outcome of this approach has been very successful: student evaluations of the lecture block and their attendance have significantly improved.

Curriculum↗
PubMed2001

Effect of perindopril on cerebral and renal perfusion in stroke patients with carotid disease.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the effect of the angiotensin-converting enzyme inhibitor perindopril on mean arterial blood pressure (MABP), cerebral blood flow (CBF), and glomerular filtration rate in hypertensive stroke patients with moderate to severe internal carotid artery (ICA) disease or ICA occlusion. METHODS: Twenty-four nonacute ischemic stroke patients who had MABP readings >100 mm Hg and moderate to severe ICA stenosis or occlusion were randomized to receive perindopril 4 mg daily or placebo for 14 days. MABP, ICA flow, and both middle cerebral artery (MCA) velocity and resistance index were measured before dose, at 5 time points over the subsequent 24 hours, and finally at 2 weeks. Brain hexamethyl propylene amine oxide single photon emission computed tomography scans were performed before drug administration and at time of peak drug effect (6 to 8 hours) after the first dose. Glomerular filtration rate was measured with (51)Cr EDTA before medication and at 14 days. RESULTS: A placebo-corrected BP fall of 17/10 mm Hg was seen (P:=0.017), which was maximal at 5.5 hours. No significant change in ICA flow or MCA velocity was seen between groups. No significant change in hemispheric CBF was seen. The mean change from baseline in the treated group was -0.79 mL. 100 g(-1). min(-1) (95% confidence interval [CI], 1.65 to -3.23); mean change in the placebo group was -1.9 mL. 100 g(-1). min(-1) (95%CI, 3.02 to -6.92). Peri-infarct CBF was similarly unaffected. One of the treated patients developed transient acute renal impairment and was withdrawn from the study on day 4. CONCLUSIONS: Perindopril lowers BP without lowering CBF in hypertensive stroke patients with moderate to severe ICA stenosis or occlusion; monitoring of this patient population for the complications of renal artery stenosis should be considered.

Administration, Oral↗
PubMed2000

Finger replantation in the United States: rates and resource use from the 1996 Healthcare Cost and Utilization Project.

Although finger replantation has been performed by hand surgeons in the United States for over 30 years the epidemiology of this procedure has not been studied. We used a national sampling database from the Agency for Health Care Policy and Research to summarize descriptive statistics surrounding finger replantation in the United States. This sample contained 304 cases of finger replantation performed in 1996. Mean hospital length of stay was 5.5 days and mean total charges were $20,330. Of the 906 hospitals included in this database, only 136 performed finger replantation during 1996. Of those, 60% performed only one case and 2% performed 10 or more cases. This descriptive analysis provides an examination of the largest sample size to date of finger replantation in the United States. Epidemiologic studies using national databases can provide researchers and policy makers with the analyses needed to examine treatment options and appropriately allocate future health care resources.

Adult↗
PubMed1999

Predictors of patient satisfaction in an outpatient plastic surgery clinic.

Although outcome measurement in medical care has traditionally included various aspects of clinical and functional status, patient satisfaction is another important metric in the assessment of health care quality. Determining which factors contribute most to patient satisfaction can assist health care providers in improving care. In an era of diminishing resources, satisfaction ratings can further aid third-party payers in determining who provides those services. The authors used the ordinal logistic regression method to develop a predictive model for patient satisfaction in an outpatient plastic surgery clinic. Consecutive patients who attended a university outpatient plastic surgery clinic were asked to complete the Visit Specific Patient Satisfaction Questionnaire (VSQ) after their clinic visit. Type of clinic (e.g., hand clinic, aesthetic clinic, breast clinic) and demographic variables like age, gender, race, and education were added to the questionnaire to control for possible confounding effects. The authors constructed an ordinal logistic regression model using the overall visit response as the dependent variable and the eight other response categories as independent variables. A total of 345 patients completed the VSQ, which takes each patient less than 2 minutes to complete. The patient response rate was more than 95%. Statistically significant predictors included (1) personal manner of physician (odds ratio [OR], 18.0; p = 0.0002), (2) time spent with physician (OR, 4.7; p = 0.0099), (3) length of time to get an appointment (OR, 4.6; p = 0.0055), and (4) explanation of what was done (OR, 3.9; p = 0.0263). There was no statistically significant association between overall satisfaction scores and the following factors: (1) length of wait in the clinic (OR, 2.7; p = 0.0747), (2) getting through to the clinic by phone (OR, 0.71; p = 0.5439), (3) convenience of the clinic's location (OR, 2.3; p = 0.1368), and (4) technical skills of the physician (OR, 1.0; p = 0.9974). The predictive model was adjusted for possible confounding due to the type of clinic and demographic variables. In this study the most important predictors of patient satisfaction were those related to efficient clinic operation (scheduling of appointments and clinic waiting time) and the quality of the patient-physician interaction. Clinic facilities (like clinic location and ease of phone contact) were not significant predictors. Because patients often have difficulty assessing the technical skills of physicians, this variable was not a significant predictor. To improve patient satisfaction in plastic surgery outpatient clinics, efforts and resources should be directed toward expedient and empathic delivery of care.

Adolescent↗
PubMed1999

The Michigan Hand Outcomes Questionnaire (MHQ): assessment of responsiveness to clinical change.

Responsiveness is an important property of an outcomes questionnaire. It can be defined as the ability of an instrument to capture important changes in a patient's health status over time. The authors previously designed the Michigan Hand Outcomes Questionnaire (MHQ), a hand-specific outcomes instrument that contains six distinct scales: (1) overall hand function, (2) activities of daily living, (3) pain, (4) work performance, (5) aesthetics, and (6) patient satisfaction with hand function. In the first study, the authors demonstrated that the MHQ is a reliable and valid instrument for the hand. The purpose of this second study is to assess the responsiveness, or sensitivity, of the MHQ to clinical change in patient status. A total of 187 consecutive patients with chronic hand disorders completed a baseline MHQ prior to receiving treatment at a university plastic surgery clinic. Approximately 6 to 18 months after completing the first questionnaire, patients were sent a follow-up MHQ by mail. The second questionnaire was identical to the first, with the exception of one additional question added to each of the six MHQ scales. This additional question asked patients to rate the change in their hands since completing the last questionnaire using a seven-point response scale. Spearman's correlation coefficient was used to correlate the responses from patients' self-assessment questions with the actual score change (after score - before score). The response rate for the second administration was 49% (92 questionnaires returned)-a fairly good rate of return for mail surveys. There were no significant differences in gender, race, education, and income between responders and nonresponders. When patients' self-assessment of change was correlated with the change in the six scale scores over time, all six correlations were statistically significant, with p < 0.05. The correlations ranged from 0.25 for the aesthetics scale to 0.43 for the pain scale. The MHQ was responsive using patients' self-assessment of their clinical change. Future studies will evaluate the responsiveness of the MHQ compared with objective physiological measures such as grip strength, range of motion, and the Jebson-Taylor test. Additionally, research is underway to assess the responsiveness of the MHQ for specific procedures, including metacarpophalangeal arthroplasties for rheumatoid arthritis and microvascular toe-to-hand reconstructions.

Adult↗
PubMed1999

Knee joint kinematics during the sidestep cutting maneuver: potential for injury in women.

PURPOSE: There is a paucity of data describing female lower limb biomechanics during "high risk" movements linked to noncontact ACL injury. This study compared, across gender, knee kinematics associated with sidestepping maneuvers to provide insight into why women display a significantly higher incidence of this injury than do men. METHODS: Thirty participants (16 men, 14 women) had bilateral knee joint kinematic data recorded while sidestepping. A custom software package (JTMOTION) quantified maximum, minimum, and range of motion during stance for each of the three clinical knee joint rotations (flexion/extension, adduction/abduction and external/internal rotation) over 20 (leg x condition x trial (5)) trials. RESULTS: Gender differences possessed limited clinical significance with all maximum values well within safe ranges of knee motion. Women did, however, display increased intertrial variability for axial rotation patterns during cutting compared with men. This variability was thought to be unaffected by gender, with experience level found statistically (P < 0.01) to be the major determinant of knee kinematic variability during sidestepping. Hence, the level of exposure to sidestep cutting may have a large impact on the subsequent risk of ACL injury when when one performs these maneuvers. CONCLUSIONS: Gender differences in knee motions during cutting did not contribute to the increased risk of noncontact ACL injury in women compared with men. The reasons for this increased incidence, therefore, remain unclear. The potential relationship between gender and other parameters linked to ACL injury such as joint geometry, ligament morphology, and physical conditioning requires further investigation.

Adult↗
PubMed1998

Metronidazole may inhibit intestinal colonization with Clostridium difficile.

PURPOSE: Antibiotics suppress normal gut flora, allowing overgrowth of acquired or native Clostridium difficile, with release of toxins that cause mucosal inflammation. Oral metronidazole is used to treat antibiotic-associated colitis (pseudomembranous colitis). This study was designed to determine whether oral metronidazole, as part of preoperative bowel preparation, prevents or decreases incidence of antibiotic-associated colitis after elective colonic and rectal procedures. METHODS: Eighty-two patients (40 men) were prospectively, randomly assigned to receive one of two oral antibiotic regimens before colorectal surgery. All patients underwent mechanical bowel preparation with polyethylene glycol-electrolyte lavage solution before administration of oral antibiotics. Group 1 (n = 42) patients received three doses (1 g/dose) of neomycin and erythromycin. Group 2 (n = 40) patients received three doses (1 g/dose) of neomycin and metronidazole. Both groups received one preoperative and three postoperative doses of intravenous cefotetan (2 g/dose). Both groups had stool samples tested for C. difficile toxin in the preoperative and postoperative periods by enzyme-linked immunoabsorbent assay or by tissue culture cytotoxicity. Patients with preoperative stool studies positive for C. difficile were excluded from the study. RESULTS: Treatment groups were not different for age, gender, or surgical procedure. Mean age +/- 1 standard deviation was 67.6 +/- 13.6 (range, 34-94) years in Group 1 and 62.1 +/- 13.5 (range, 35-84) years in Group 2 (P = 0.069). Mean length of hospital stay +/- 1 standard deviation was 9.76 +/- 4.9 (range, 4-28) days for Group 1 and 8.05 +/- 2.6 (range, 3-14) days for Group 2 (P = 0.053). Five patients in Group 1 (neomycin and erythromycin) and one patient in Group 2 (neomycin and metronidazole) had positive stool studies for C. difficile. Relative risk of colonization with C. difficile in Group 1 was 4.76 times that in Group 2 (95 percent confidence interval, 0.581, 39). This difference was not statistically significant (P = 0.202). There were no significant differences in C. difficile colonization rates with respect to age, length of stay, or gender. CONCLUSIONS: This study suggests that there may be a clinical association between use of metronidazole preoperatively and inhibition of intestinal colonization by C. difficile in this patient population undergoing colonic and rectal surgery.

Adult↗
PubMed1998

Reliability and validity testing of the Michigan Hand Outcomes Questionnaire.

In this study, psychometric principles were used to develop an outcomes questionnaire capable of measuring health state domains important to patients with hand disorders. These domains were hypothesized to include (1) overall hand function, (2) activities of daily living (ADL), (3) pain, (4) work performance, (5) aesthetics, and (6) patient satisfaction with hand function. An initial pool of 100 questions was pilot-tested for clarity in 20 patients; following factor analysis, the number of questions was reduced to a 37-item Michigan Hand Outcomes Questionnaire (MHQ). The MHQ, along with the Short Form-12, a generic health status outcomes questionnaire, was then administered to 200 consecutive patients at a university-based hand surgery clinic and was subjected to reliability and validity testing. The mean time required to complete the questionnaire was 10 minutes (range, 7-20 minutes). Factor analysis supported the 6 hypothesized scales. Test-retest reliability using Spearman's correlation demonstrated substantial agreement, ranging from 0.81 for the aesthetics scale to 0.97 for the ADL scale. In testing for internal consistency, Cronbach's alphas ranged from 0.86 for the pain scale to 0.97 for the ADL scale (values >0.7 for Cronbach's alpha are considered a good internal consistency). Correlation between scales gave evidence of construct validity. In comparing similar scales in the MHQ and the Short Form-12, a moderate correlation (range, 0.54-0.79) for the ADL, work performance, and pain scales was found. In evaluating the discriminate validity of the aesthetics scale, a significant difference (p = .0012) was found between the aesthetics scores for patients with carpal tunnel syndrome and patients with rheumatoid arthritis. The MHQ is a reliable and valid instrument for measuring hand outcomes. It can be used in a clinic setting with minimal burden to patients. The questions in the MHQ have undergone rigorous psychometric testing, and the MHQ is a promising instrument for evaluation of outcomes following hand surgery.

Factor Analysis, Statistical↗
PubMed1998

Endoscopic versus open carpal tunnel release: a cost-effectiveness analysis.

Endoscopic carpal tunnel release is a controversial procedure used in the treatment of carpal tunnel syndrome. Although endoscopic carpal tunnel release is associated with less incisional pain and faster recovery time than the open carpal tunnel release, opponents of endoscopic carpal tunnel release suggest that its benefits are outweighed by its higher complication rates from median nerve transection and transient numbness of the fingers. Because of the huge economic and social impact of carpal tunnel syndrome in this country, we performed a cost-effectiveness analysis comparing endoscopic carpal tunnel release and open carpal tunnel release using guidelines established by the Panel on Cost-Effectiveness in Health and Medicine of the U.S. Public Health Service. A decision analytic model was used to measure differences in cost and effectiveness--expressed as quality-adjusted life-years (QALYs)--between endoscopic carpal tunnel release and open carpal tunnel release. The societal perspective was chosen, and probabilities for various outcomes for the two procedures were obtained from published randomized-controlled trials. Cost data were derived from the Medicare Resource-Based Relative Value Units published in the Federal Register. QALYs were obtained from two groups of health care providers using a utility-assessment questionnaire. Using probabilities for various outcomes from the two published randomized-controlled trials comparing endoscopic carpal tunnel release and open carpal tunnel release, we constructed a decision tree to derive both the cost and the QALYs for the two procedures. The incremental cost difference between endoscopic carpal tunnel release and open carpal tunnel release was $46, using Medicare cost and probabilities of various outcomes derived from a study by Brown et al. in 1993. We calculated QALYs for five age groups--25, 35, 45, 55, 65--assuming a life expectancy of 75 years. The marginal effectiveness (QALY of endoscopic carpal tunnel release minus QALY of open carpal tunnel release) ranged from 0.235 QALY for the 25-year-old age group to 0.066 QALY for the 65-year-old age group, giving a cost-effectiveness ratio of $195/QALY and $693/QALY, respectively. When compared with other accepted medical interventions such as breast cancer screening ($4836/QALY) and exercise to prevent coronary heart disease ($13,508/QALY), endoscopic carpal tunnel release seems to be cost-effective. However, our sensitivity analysis indicated that the cost-effectiveness ratio was very sensitive to a major complication such as median nerve injury. For endoscopic carpal tunnel release to be a cost-effective procedure, the incidence of median nerve injury must be one percentage point less for endoscopic carpal tunnel release than for open carpal tunnel release. Based on the data from the randomized-controlled trials, endoscopic carpal tunnel release seems to be a cost-effective procedure; however, before it can be recommended, greater emphasis must be given to the training of surgeons in this new technique, so that major complications such as median nerve injuries can be avoided. In addition, future studies must better define the actual incidence of nerve injuries for both endoscopic carpal tunnel release and open carpal tunnel release in the community setting.

Adult↗
PubMed1998

Homologous up-regulation of vitamin D receptors is tissue specific in the rat.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) receptors (VDR) are expressed in multiple tissues within the body. VDR levels are increased by 1,25(OH)2D3 in intestine and kidney and in numerous cell models. The ability of 1,25(OH)2D3 to affect VDR levels in other target tissues in vivo was studied by assessing VDR levels by the 3H-1,25(OH)2D3 binding assay under varied physiological conditions in the rat. When compared with vitamin D-deficient (-D) controls, rats raised on a normal vitamin D-sufficient (+D) diet showed elevated VDR levels in kidney (391 +/- 53 vs. 913 +/- 76 fmol/g of tissue;p < 0.05), but not in testis, heart, or lung. Up-regulation of the VDR also occurred in kidney of +D rats 1 day after a single 100-ng dose of 1,25(OH)2D3 (454 +/- 43 vs. 746 +/- 113 fmol/mg of DNA; p < 0.05), but no changes were seen in intestine, testis, or lung. Because 1,25(OH)2D3-induced hypercalcemia may independently affect VDR regulation, 1,25(OH)2D3 was infused into -D rats, and normocalcemia was maintained by reduced dietary calcium intake. In this model, the renal VDR was again up-regulated (446 +/- 115 vs. 778 +/- 58 fmol/mg of DNA; p < 0.05), but VDR levels in testis and lung were unaffected. Scatchard analysis and tests of 1,25(OH)2D3 dose (1-100 ng/day for 7 days) and temporal (100 ng/day for 1-7 days) responsiveness further supported the tissue-specific nature of the homologous VDR regulation. Assay of VDR levels by L-1-tosylamido-2-phenylethyl chloromethyl ketone-3H-1,25(OH)2D3 exchange assay ruled out differences in endogenous 1,25(OH)2D3 occupancy as the basis for the observed differences in VDR regulation. Finally, coidentity of the VDR-like sites in kidney versus testis was confirmed by competitive binding analysis comparing their relative affinities for 25(OH)D3 versus 1,25(OH)2D3 (30.5 +/- 6.4 vs. 35.6 +/- 3.6 in kidney and testis, respectively) and by immunoblot analysis using a highly specific monoclonal anti-rat VDR antibody. Thus, under a wide variety of experimental conditions, homologous up-regulation of the VDR occurs in the rat kidney in vivo, but not in several other target tissues which do not regulate plasma calcium homeostasis. Moreover, this differential VDR regulation did not result from secondary changes in plasma calcium, from differential 1,25(OH)2D3 responsiveness in the various tissues, nor from differences in endogenous 1,25(OH)2D3 occupancy of the VDR. These studies thus establish that, in contrast to observations in vitro, the widely described phenomenon of homologous VDR up-regulation in kidney and intestine is not a universal property of 1,25(OH)2D3 target tissues in vivo in the rat.

Animals↗
PubMed1998

A quantitative analysis of knee joint kinematics during the sidestep cutting maneuver. Implications for non-contact anterior cruciate ligament injury.

This study accurately quantifies the knee joint kinematics associated with sidestep cutting maneuvers in vivo. These data were subsequently evaluated to determine the relationship between sidestep cutting and non-contact anterior cruciate ligament (ACL) injury. Sixteen male subjects, proficient in the sidestep cutting maneuver, had knee joint kinematic data recorded during the stance phase of straight line running and sidestep cutting. Cutting speeds (5.5 msec-1 to 7.0 msec-1) and angles (30 degrees to 55 degrees) were chosen to reflect the sporting context. All subjects underwent medical screening prior to testing to ensure data represented joint biomechanics of healthy, ACL intact individuals. The temporal three dimensional positions of externally mounted (skin) markers were submitted to a custom software package (JTMOTION), which described in clinically meaningful terms, movements for the three rotational degrees of freedom at the knee joint. While mean patterns of motion for the three clinical knee rotations compared favorably between running and cutting data, sidestepping induced significantly (p < 0.01) greater maximum knee joint rotations during stance. Knee joint rotational ranges were also found to be significantly (p < 0.01) larger during cutting when compared to running. Increases in knee joint kinematics during cutting however, were not of a great enough magnitude to alone elicit spontaneous non-contact ACL injury, falling well within "safe" ranges of knee motion. Significant increases in inter-trial variability for the three rotations were observed in some subjects for sidestepping compared to running. It was concluded that a lack of consistency in knee joint biomechanics between cutting maneuvers increased the risk of ACL injury with the performance of an abnormal and potentially hazardous sidestep being more likely. The risk of non-contact ACL injury during cutting maneuvers was suggested to increase further when an individual displayed these "atypical" joint biomechanics in conjunction with specific joint structures, levels of experience and conditioning, and ligament morphologies.

Adult↗
PubMed1997

Altered phosphorylation of a 91-kDa protein in particulate fractions of rat kidney after protracted 1,25-dihydroxyvitamin D3 or estrogen treatment.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] treatment in vitamin D-deficient (-D) rats results in a dose-dependent decrease in phosphorylation of a 91-kDa protein (PP-D91) in particulate fractions of the kidney. This recently reported 1,25(OH)2D3 effect was examined in detail herein. In contrast to the pattern expected of a rapid signal transduction event, time course (4 h-7 days) experiments demonstrated that PP-D91 phosphorylation was not decreased until 3-5 days 1,25(OH)2D3 treatment, resulting in a 61 +/- 3% (P < 0.01, n = 3) decrease in PP-D91 phosphorylation by 7 days. These effects paralleled increases in plasma calcium from 9.3 +/- 0.6 to 13.9 +/- 0.7 mg/dl after 0 vs 7 days 1,25(OH)2D3 treatment, respectively. Subcellular fractionation demonstrated that the renal PP-D91 was predominantly localized and 1,25(OH)2D3-regulated in crude mitochondrial and microsomal fractions. Further, PP-D91 was present and 1,25(OH)2D3-regulated in enriched preparations of both proximal and distal renal tubule segments. Tissue distribution studies demonstrated that the PP-D91 was predominantly present and 1,25(OH)2D3 regulated in the kidney, although low levels of a vitamin D-independent phosphorylated band of similar size were observed in the lung and heart. In contrast to 1,25(OH)2D3, estradiol-17B treatment (1 mg/day x 7 day) significantly (P < 0.01) increased PP-D91 phosphorylation in kidney of both -D and +D rats (increased 118.5 +/- 10.6 and 81.9 +/- 6.3%, respectively). Phosphoamino acid analysis after PP-D91 phosphorylation, isolation, and proteolysis indicated that these hormones alter 32P incorporation into phosphoserine residues. In conclusion, the 1,25(OH)2D3 effect to reduce PP-D91 phosphorylation in particulate fractions of the rat kidney is a protracted, tissue-specific effect which parallels elevated plasma calcium levels in this model. Moreover, renal PP-D91 phosphorylation is differentially regulated by 1,25(OH)2D3 vs E2 treatment and occurs on phosphoserine residues. The parallel between decreased PP-D91 phosphorylation and 1,25(OH)2D3-induced hypercalcemia may suggest a role for PP-D91 in the renal response to hypervitaminosis D.

Animals↗
PubMed1997

The dynamics of bimanual circle drawing.

A bimanual circle drawing task was employed to elucidate the dynamics of intralimb and interlimb coordination. Right-handed subjects were required to produce circles with both hands in either a symmetrical (mirror) mode (i.e. one hand moving clockwise, the other counter-clockwise) or in an asymmetrical mode (i.e. both hands moving clockwise or counter-clockwise). The frequency of movement was scaled by an auditory metronome from 1.50 Hz to 3.25 Hz in 8 (8-sec) steps. In the asymmetrical mode, distortions of the movement trajectories, transient departures from the target pattern of coordination, and phase wandering were evidence as movement frequency was increased. These features suggested loss of stability. Deviations from circular trajectories were most prominent for movements of the left hand. Transient departures from the required mode of coordination were also largely precipitated by the left hand. The results are discussed with reference to manual asymmetries and mechanisms of interlimb and intersegmental coordination.

Adult↗
PubMed1996

On the crisis in biomedical education: is there an overproduction of biomedical PhDs?

The United States is the world leader in biomedical science (BMS) education and research. This preeminence is reflected in superior medical education, the attraction of U.S. educational institutions to foreign visitors seeking advanced training, and a high rate of transfer of knowledge between basic biomedical research and the delivery of health care at the bedside. The foundation for this excellence and leadership has been the research carried out by MD and PhD biomedical scientists. It has been suggested that there is now an oversupply of BMS PhDs, and thus that BMS PhD programs should be downsized. Full examination of the issues involved, including a case study of doctoral graduates and postdoctoral fellows at Tulane Medical Center, leads the authors to conclude that a biomedical PhD "glut" does not exist at the present time, that downsizing training programs would have a serious, long-term negative impact on biomedical research, and that medical school administrators and faculty should resist attempts to reduce biomedical research and training at the local and national level. However, times have changed and training programs must evolve to adapt to the technologic changes occurring in the workplace. Alternatives, such as new alliances with industry, must be sought to compensate for decreased resources at federal and institutional levels; new and innovative curricula must be developed to prepare biomedical scientists for nonacademic, as well as academic, job opportunities in the twenty-first century; and medical center administrators and faculties must work together to increase the visibility of BMS and stress its critical relationship to the research base of the nation.

Academic Medical Centers↗
PubMed1996

Identification of environmental chemicals with estrogenic activity using a combination of in vitro assays.

Environmental chemicals that function as estrogens have been suggested to be associated with an increase in disease and dysfunctions in animals and humans. To characterize chemicals that may act as estrogens in humans, we have compared three in vitro assays which measure aspects of human estrogen receptor (hER)-mediated estrogenicity. Chemicals were first tested for estrogen-associated transcriptional activity in the yeast estrogen screen (YES). This was created by expressing hER and two estrogen response elements linked to the lacZ gene in yeast. Second, chemicals that were tested in YES were then assayed for direct interaction with hER in a competition binding assay. Third, chemicals were tested in the estrogen-responsive MCF-7 human breast cancer cell line transiently transfected with a plasmid containing two estrogen response elements linked to the luciferase gene. Together, these assays have identified two metabolites of DDT, o,p'-DDD and p,p'-DDD, that have estrogenic activity. Interestingly, previous studies had reported that the DDD metabolites were nonestrogenic in whole animal models. Alachlor, the most frequently used herbicide in the United States, cis-nonachlor, and trans-nonachlor displayed weak estrogenic activity in the combined assays. The antifungal agent benomyl had no estrogenic activity. We propose that a combination of in vitro assays can be used in conjunction with whole animal models for a more complete characterization of chemicals with estrogenic activity.

Binding, Competitive↗