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Biomedical subjects

M D Williams

Publications and source records attributed to M D Williams.

At least 37 records · Page 2Linked to original sources
PubMed2001

Middle ear prosthesis displacement in high-strength magnetic fields.

HYPOTHESIS: Middle ear prostheses made from nonmagnetic, magnetic resonance (MR)-compatible metals reportedly displace ex vivo in the presence of high magnetic fields used in MR imaging (MRI). The authors postulate that the prosthesis displacement seen with "nonmagnetic" MR-compatible prostheses ex vivo may not be clinically significant in vivo. METHODS: Middle ear prostheses made from ferromagnetic (420F stainless steel) and nonmagnetic MR-compatible metals (316L stainless steel and platinum) were examined for magnetic field interactions at 4.7 Tesla (T). Ex vivo testing consisted of measurements of the translational and rotational motion of the prosthesis induced by the static magnetic field. In vivo testing was assessed by implanting prostheses in cadaveric temporal bones and performing clinical MRI sequences. Prosthesis displacement was measured semiquantitatively. RESULTS: Angular deflection was observed in all samples made from nonmagnetic stainless steel. The negative control (platinum) demonstrated no deflection, and the positive controls (ferromagnetic stainless steel) deflected >90 degrees. Torque analysis showed movement in five of five nonmagnetic stainless steel prostheses. Prostheses made from nonmagnetic stainless steel remained in place without appreciable loosening in vivo after MRI. Prostheses made with known ferromagnetic properties were displaced at 4.7 T but not at 1.5 T. CONCLUSION: Middle ear prostheses made from low-magnetic stainless steel do move in the presence of high magnetic fields ex vivo; however, this does not appear to be clinically or statistically significant in vivo at 4.7 T. Magnetic resonance imaging should be undertaken with caution in individuals with prostheses made from stainless steel with strong ferromagnetic properties.

Electromagnetic Fields↗
PubMed2001

Increased expression of GPI-specific phospholipase D in mouse models of type 1 diabetes.

Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is a high-density lipoprotein-associated protein. However, the tissue source(s) for circulating GPI-PLD and whether serum levels are regulated are unknown. Because the diabetic state alters lipoprotein metabolism, and liver and pancreatic islets are possible sources of GPI-PLD, we hypothesized that GPI-PLD levels would be altered in diabetes. GPI-PLD serum activity and liver mRNA were examined in two mouse models of type 1 diabetes, a nonobese diabetic (NOD) mouse model and low-dose streptozotocin-induced diabetes in CD-1 mice. With the onset of hyperglycemia (2- to 5-fold increase over nondiabetic levels), GPI-PLD serum activity and liver mRNA increased 2- to 4-fold in both models. Conversely, islet expression of GPI-PLD was absent as determined by immunofluorescence. Insulin may regulate GPI-PLD expression, because insulin treatment of diabetic NOD mice corrected the hyperglycemia along with reducing serum GPI-PLD activity and liver mRNA. Our data demonstrate that serum GPI-PLD levels are altered in the diabetic state and are consistent with liver as a contributor to circulating GPI-PLD.

Animals↗
PubMed2001

Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis.

Heart mitochondria from heterozygous (Sod2(-/+)) knockout mice have a 50% reduction in manganese superoxide dismutase (MnSOD) activity. The decrease in MnSOD activity was associated with increased mitochondrial oxidative damage as demonstrated by a decrease in the activities of iron sulfhydryl proteins sensitive to oxygen stress (aconitase and reduced nicotinamide adenine dinucleotide-oxidoreductase). Mitochondrial function was altered in the Sod2(-/+) mice, as shown by decreased respiration by complex I and an increase in the sensitivity of the permeability transition to induction by calcium and t-butylhydroperoxide. The increased induction of the permeability transition in heart mitochondria from Sod2(-/+.)mice was associated with increased release of cytochrome c and an increase in DNA fragmentation. Cardiomyocytes isolated from neonatal Sod2(-/+) and Sod2(-/-) mice were more sensitive to cell death than cardiomyocytes from Sod2(+/+) mice after t-butylhydroperoxide treatment, and this increased sensitivity was prevented by inhibiting the permeability transition with cyclosporin A. These experiments demonstrate that MnSOD may play an important role in the induction of the mitochondrial pathway of apoptosis in the heart, and this appears to occur primarily through the permeability transition.

Aconitate Hydratase↗
PubMed2001

The Patient Informatics Consult Service (PICS): an approach for a patient-centered service.

The Patient Informatics Consult Service (PICS) at the Eskind Biomedical Library at Vanderbilt University Medical Center (VUMC) provides patients with consumer-friendly information by using an information prescription mechanism. Clinicians refer patients to the PICS by completing the prescription and noting the patient's condition and any relevant factors. In response, PICS librarians critically appraise and summarize consumer-friendly materials into a targeted information report. Copies of the report are given to both patient and clinician, thus facilitating doctor-patient communication and closing the clinician-librarian feedback loop. Moreover, the prescription form also circumvents many of the usual barriers for patients in locating information, namely, patients' unfamiliarity with medical terminology and lack of knowledge of authoritative sources. PICS librarians capture the time and expertise put into these reports by creating Web-based pathfinders on prescription topics. Pathfinders contain librarian-created disease overviews and links to authoritative resources and seek to minimize the consumer's exposure to unreliable information. Pathfinders also adhere to strict guidelines that act as a model for locating, appraising, and summarizing information for consumers. These mechanisms--the information prescription, research reports, and pathfinders--serve as steps toward the long-term goal of full integration of consumer health information into patient care at VUMC.

Drug Information Services↗
PubMed2001

Polymerase chain reaction for the detection of bacteremia.

Analysis of blood by polymerase chain reaction (PCR) is a more rapid and sensitive method to detect bacteremia than blood culture. The PCR was performed on blood obtained from patients during blood culture draws and on blood from normal volunteers. Eighty-seven patients provided 125 blood samples for blood culture comparison with PCR. Specific PCR primers for Staphylococcus aureus and Escherichia coli that targeted conserved regions common to gram-positive and gram-negative bacteria were used. Selective stringency conditions identified other gram-positive and gram-negative bacteria. The blood culture agreed with the PCR in 93 of the 125 patient specimens (74%). In 29 of these specimens the PCR was positive yet the blood culture was negative. When clinical information was included with positive blood culture to define sepsis in these patients and their specimens were added to the positive blood cultures the statistical accuracy of PCR was 93 per cent. Only three of the 78 specimens with negative PCR had positive blood cultures. The PCR was negative in all but one of the 50 volunteers. PCR is more sensitive than blood culture, and it can quickly rule out bacteremia.

Adult↗
PubMed2000

Should aminoglycoside antibiotics be abandoned?

BACKGROUND: Aminoglycosides can cause nephrotoxicity and ototoxicity. Alternatives are available. METHODS: Surgical service antibiotic use, aminoglycoside toxicity, and perioperative culture/sensitivity results from July 1998 to June 1999 were reviewed. RESULTS: Of 289 positive cultures in 243 patients, 92 cultures (32%) grew 151 Gram-negative rods (GNRs). Aminoglycosides were used in 26 patients and 4 of 26 (15%) suffered nephrotoxicity. Of the 112 GNRs tested against ceftazidime, 111 (99%) were sensitive to it which was significantly better than amikacin (56 of 61, 92%, P = 0.038), gentamicin (116 of 134, 87%, P <0.001), and tobramycin (67 of 81, 83%, P <0.001). The proportion sensitive to cefuroxime (26 of 30, 87%) was equivalent to the proportions sensitive to gentamicin (87%, P = NS) and tobramycin (83%, P = NS). Of the 35 GNRs that were resistant to gentamicin and/or tobramycin, 15 (43%) were Pseudomonas aeruginosa. CONCLUSION: Aminoglycosides produce a significant rate of nephrotoxicity. There are antibiotics with equal or better sensitivity profiles than aminoglycosides against GNRs and Pseudomonas. Aminoglycoside use is rarely, if ever, indicated.

Adult↗
PubMed1999

Wiskott Aldrich syndrome presenting as congenital thrombocytopenia.

The application of molecular biology to haematology has provided the opportunity to revisit previous diagnoses, many of which can now be redefined. This report is on a local family previously diagnosed and published as having X-linked thrombocytopenia in 1974, and shows how the application of molecular screening has confirmed the true diagnosis of Wiskott Aldrich syndrome.

Adult↗
PubMed1999

Congenital thrombophilia and thrombosis: a study in a single centre.

AIM: To identify the incidence of congenital thrombophilia in a cohort of children presenting with symptomatic thromboembolism. METHOD: A review of children with thromboembolism investigated for thrombophilia over a 12 month period. SUBJECTS: Thirty children with thromboembolic episodes and 16 of their family members. MEASUREMENTS AND DATA COLLECTION: Data were collected on age at diagnosis, underlying diagnosis, site of thrombosis, associated precipitating factors, occurrence of other thromboembolic events, and family history. Investigations included measurement of protein C activity, total and free protein S antigen, antithrombin III activity, screening for factor V Leiden and prothrombin 20210A, urinary homocysteine estimation, and a screen for lupus anticoagulant. RESULTS: Twenty seven of 30 patients had one or more risk factors present at the time of thromboembolism. Eighty three per cent had acquired precipitating factors present, and 43% had underlying congenital thrombophilia. CONCLUSIONS: There was a high incidence of congenital thrombophilia in this group of patients with symptomatic thromboembolism. These findings emphasise the importance of such defects in the pathogenesis of childhood thrombosis, and suggest that full thrombophilia investigations should be performed on all children presenting with thromboembolic disease.

Adolescent↗
PubMed1999

Differential substrate recognition capabilities of Janus family protein tyrosine kinases within the interleukin 2 receptor (IL2R) system: Jak3 as a potential molecular target for treatment of leukemias with a hyperactive Jak-Stat signaling machinery.

Substrate recognition by Janus family protein tyrosine kinases was examined utilizing recombinant baculovirus produced components of the interleukin 2 receptor (IL2R) system i.e. Jak1, Transducers and Activators of Transcription (STAT). Wild type Jak3 was able to tyrosine phosphorylate a kinase-dead Jak1 (Jak1E908). In contrast wild type Jak1 was unable to tyrosine phosphorylate kinase dead Jak3 (Jak3E851). This unilateral transphosphorylation between Jak3 and Jak1 prompts the hypothesis that in the IL2R system the activation of Jak3 precedes Jak1 activation. Both the IL2Rbeta and IL2Rgammac subunits underwent tyrosine phosphorylation when co-expressed with wild-type Jak3. By comparison only IL2Rbeta was recognized and tyrosine phosphorylated by wild-type Jak1. These results are consistent with the notion that Jakl is pre-associated with IL2Rbeta and Jak3 is pre-associated with IL2Rgammac. STAT1, STAT3, and STAT5 underwent tyrosine phosphorylation when co-expressed with Jakl and therefore are substrates for the respective Jak kinases. In contrast, Jak3 co-expression resulted in tyrosine phosphorylation of STAT3 and STAT5 but not STAT1. Notably a polypeptide representing the kinase domain of Jak3 (Jak3-JH1) gained the ability to tyrosine phosphorylate STAT1, suggesting that the changes in substrate recognition may be influenced by domains outside the kinase domain. These findings provide evidence that Jak1 and Jak3 differentially recognize specific substrates, thereby having the ability to contribute specific signals, and the substrate specificity may be influenced by multiple domains of these tyrosine kinases.

Amino Acid Sequence↗
PubMed1999

Outcome assessment of the rehabilitation of the visually impaired.

The purposes of this project are to establish the psychometric properties of instruments used to gather data relevant to blind rehabilitation outcomes, to refine the scaling and scoring protocols for the instruments, and to revise and refine the outcome instruments. This 3-year project will gather outcome and demographic data from an estimated 1,200 visually impaired veterans per year, along with a companion sample an estimated 1,200 visually impaired nonveterans per year, using the following core measures: Blind Rehabilitation Service Follow-up Outcome Survey (BRSFOutSur) measuring functional performance, Blind Rehabilitation Service Data Base (BRSDBase) recording subject characteristics, and Blind Rehabilitation Service Satisfaction Survey (BRSSatSur) measuring satisfaction with rehabilitation. As of July 1999, data from 2,624 veterans have been collected for the demographic instrument, from 1,630 veterans for the functional outcomes instrument, and from 1,655 veterans for the satisfaction instrument. Data collection and analysis are currently ongoing. These findings and the further development of outcome instruments in this area will contribute to greater efficiency and effectiveness of the delivery of blind rehabilitation services by the Department of Veterans Affairs.

Activities of Daily Living↗
PubMed1998

Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice.

This study characterizes mitochondria isolated from livers of Sod2(-/+) and Sod2(+/+) mice. A 50% decrease in manganese superoxide dismutase (MnSOD) activity was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice, with no change in the activities of either glutathione peroxidase or copper/zinc superoxide dismutase. However, the level of total glutathione was 30% less in liver mitochondria of the Sod2(-/+) mice. The reduction in MnSOD activity in Sod2(-/+) mice was correlated to an increase in oxidative damage to mitochondria: decreased activities of the Fe-S proteins (aconitase and NADH oxidoreductase), increased carbonyl groups in proteins, and increased levels of 8-hydroxydeoxyguanosine in mitochondrial DNA. In contrast, there were no significant changes in oxidative damage in the cytosolic proteins or nuclear DNA. The increase in oxidative damage in mitochondria was correlated to altered mitochondrial function. A significant decrease in the respiratory control ratio was observed in mitochondria isolated from Sod2(-/+) mice compared with Sod2(+/+) mice for substrates metabolized by complexes I, II, and III. In addition, mitochondria isolated from Sod2(-/+) mice showed an increased rate of induction of the permeability transition. Therefore, this study provides direct evidence correlating reduced MnSOD activity in vivo to increased oxidative damage in mitochondria and alterations in mitochondrial function.

Aconitate Hydratase↗
PubMed1998

Analysis of the transcriptional activity of the 5'-flanking region of the rat catalase gene in transiently transfected cells and in transgenic mice.

Transiently transfected cell lines and transgenic mice were used to study the transcriptional activity of the 5'-flanking region of the catalase gene. Fragments of the 5'-flanking region of the rat catalase gene ranging in length from 3,421 base pairs (bp) to 69 bp were fused to the chloramphenicol acetyltransferase (CAT) reporter gene, and the transcriptional activity of the reporter gene was measured following transient transfection in three cell lines: a human hepatoma cell line (HepG2), a porcine kidney epithelial cell line (LLCPK1), and a human glioma cell line (U-138 MG). The 3,421-bp fragment of the 5'-flanking region resulted in a high level of expression of the reporter gene in all three cell lines. Shorter fragments of the 5'-flanking region resulted in a decrease in the level of CAT reporter expression that varied among the three cell lines, implying the presence of tissue-specific regulatory sites. To study the tissue-specific regulation of the catalase promoter, transgenic mice containing the 3,421-bp 5'-flanking sequence attached to the CAT reporter gene were produced, and CAT expression was measured in various tissues of three independent transgenic lines. CAT activity was consistently high in muscle tissue (heart, skeletal muscle, and diaphragm) and low in most other tissues studied, particularly in liver and kidney. In contrast, the endogenous expression of catalase is low in muscle and high in liver and kidney; thus, the tissue-specific expression of the reporter gene driven by the 3,421-bp fragment of the 5'-flanking region of the catalase gene was not similar to the expression of the endogenous catalase gene.

Animals↗
PubMed1998

Production of recombinant DTctGMCSF fusion toxin in a baculovirus expression vector system for biotherapy of GMCSF-receptor positive hematologic malignancies.

The fusion toxin DTctGMCSF has been constructed by genetically replacing the native receptor-binding domain of diphtheria toxin (DT) with human granulocyte-macrophage colony stimulating factor (GMCSF). This recombinant fusion toxin preserves the catalytic (c) and membrane translocation (t) domains of DT and includes a sterically neutral peptide linker separating the toxin and growth factor domains. Previous work using DTctGMCSF produced in Escherichia coli has shown that this chimeric toxin is selectively cytotoxic to GMCSF receptor (R)-positive acute myeloid leukemia (AML) cells both in vitro and in vivo. Its clinical development has been hampered due to very low expression levels, requirements for solubilization with guanidine hydrochloride and subsequent refolding, and concerns about bacterial endotoxin contamination. These difficulties prompted us to investigate the utility of a baculovirus/insect cell expression system for the production of DTctGMCSF. Here, we report that a soluble form of DTctGMCSF can be produced in the baculovirus expression vector system (BEVS) and purified to homogeneity by column chromatography. The BEVS-derived DTctGMCSF fusion toxin caused apoptotic death in GMCSF-R-positive human AML cells at nanomolar concentrations. In contrast to the 100 microg/L yields of purified DTctGMCSF obtained from E. coli, the BEVS allows us to routinely generate 8-10 mg/L of purified DTctGMCSF. This increased capacity provided by the BEVS for the production of DTctGMCSF makes it now possible to obtain sufficient quantities to carry out preclinical and clinical trials. To our knowledge, this is the first report of the successful utilization of the BEVS for producing a therapeutic fusion toxin.

Acute Disease↗
PubMed1998

Routine intraoperative laparoscopic cholangiography.

BACKGROUND: Whether intraoperative laparoscopic cholangiography should be routine is debatable. METHODS: We reviewed the cholangiography experience in 669 consecutive laparoscopic cholecystectomies. RESULTS: Mean age of the patients was 39 years, 78% were female, and 29% had acute cholecystitis. Cholecystectomy was completed laparoscopically in 606 (91%). Laparoscopic cholangiography was completed in 562 (93%) and 348 (62%) were routine (no preoperative indication). The mean operating time in 1996 was 61 minutes. Out of the 348 routine cholangiograms, 17 demonstrated evidence of unsuspected choledocholithiasis. Five patients had choledocholithiasis documented by laparoscopic common bile duct exploration and/or endoscopic retrograde cholangiopancreatography. Two patients had normal postoperative cholangiopancreatography. One of 10 patients managed expectantly was readmitted postoperatively with obstructive jaundice. In 4 patients, routine cholangiography revealed unexpected anatomy, and in 2, this prevented misidentification and transection of the common bile duct. CONCLUSION: Laparoscopic cholangiography is safe, quick, detects unsuspected choledocholithiasis, and can prevent common bile duct transection. It should be routine.

Adolescent↗
PubMed1998

Nutritional support in children undergoing bone marrow transplantation.

Nutritional status and 'well-being' were compared prospectively in 39 children (mean age 8.1 years) who received nutritional support following bone marrow transplantion (BMT): 20 received enteral tube feeding (ETF; six received parenteral nutrition [PN] subsequently) and 19 with oral mucositis received PN (one received ETF subsequently). Poor nutritional status (height for age and/or weight for height and/or mid-arm circumference z-scores <-1) was present in 18 patients and was associated with a longer hospital stay (P = 0. 01). Both ETF and PN groups were comparable with respect to age, pretransplant nutritional status and conditioning regimens. No significant deterioration in anthropometric indices in either group occurred following BMT. However, significant correlations were found between the duration of ETF (and not PN) and improvements in nutritional status. Furthermore, PN was associated with more frequent exocrine pancreatic insufficiency than ETF (P = 0.001). Oral mucositis was associated with poorer 'well being' at the start of PN compared with ETF (P < 0.0001), but this was reversed by the end of PN. Bone marrow recovery, hospital stay and positive blood cultures were similar in the two groups. Hypomagnesaemia, hypophosphataemia and biochemical zinc deficiency were common in both groups but hypoalbuminaemia and biochemical selenium deficiency were worse in the PN group. In conclusion, both ETF and PN are effective in maintaining nutritional status post-BMT. When ETF is tolerated, it is associated with better nutritional response. With the existing ETF and PN regimens close monitoring of the trace element and mineral status is required.

Bone Marrow Transplantation↗
PubMed1998

Plasma 25-hydroxyvitamin D concentrations are inversely associated with blood pressure of Dahl salt-sensitive rats.

Dietary salt is a contributing factor to the development of hypertension in individuals who are salt-sensitive. The vitamin D endocrine system has been reported to modulate vascular structure and function. Since elderly hypertensive females with low plasma renin activity, typical of salt-sensitivity, had significantly lower 25-hydroxyvitamin D concentrations compared with normotensive elderly and young females, we have used Dahl salt-sensitive and salt-resistant rats fed high (80 g/kg diet) and low (3 g/kg diet) salt diets as models to examine the relationship between salt-sensitivity and 25-hydroxyvitamin D, the precursor of the hormonal form of vitamin D, 1,25-dihydroxyvitamin D. Plasma 25-hydroxyvitamin D concentrations of salt-resistant rats were unaffected by a high salt diet, but plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats were significantly reduced within three weeks to lower than 25%. There was a negative association between plasma 25-hydroxyvitamin D concentrations of salt-sensitive rats and the number of days that the rats were fed a high salt diet (r = -0.98, P < 0.02) and a positive association between blood pressure and the number of days that the rats were fed a high salt diet (r = 0.97, P < 0.05). An inverse relationship was found between plasma 25-hydroxyvitamin D concentrations and blood pressure (r = -0.99, P < 0.01). Spontaneously hypertensive rats did not have low plasma 25-hydroxyvitamin D concentrations, suggesting that reduction of plasma 25-hydroxyvitamin D concentration might be specific to salt-induced hypertension.

Animals↗
PubMed1998

Antineoplastic agents. 398. Isolation and structure elucidation of cephalostatins 18 and 19.

Continued investigation of murine leukemia (P-388) active fractions from the African marine worm Cephalodiscus gilchristi has resulted in the discovery of cephalostatins 18 (1b) and 19 (1c). The structures were determined by interpretation of their highfield (500 MHz) 1H, 13C, and 2D NMR and HRMS. Both of these new methoxy steroidal alkaloids exhibited strong activity against the murine P-388 lymphocytic leukemia cell line (ED50 ca. 10(-3) microg/mL), a mini panel of human cancer cell lines (GI50 <10(-3) microg/mL), and the U.S. National Cancer Institute's 60 human cancer cell line panel (mean panel GI50 ca. 10(-9) M).

Animals↗