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Biomedical subjects

M D Williams

Publications and source records attributed to M D Williams.

At least 19 recordsLinked to original sources
PubMed1997

Prediction of trauma mortality using a neural network.

A neural network is a computerized construct consisting of input neurons (which process input data) connected to hidden neurons (to mathematically manipulate values they receive from all the input neurons) connected to output neurons (to output a prediction). Neural networks are created and trained via multiple iterations over data with known results. In 1993, 897 trauma patients were either declared dead in the emergency room (ER; 76 cases), admitted to the intensive care unit (427 cases, 36 deaths), or taken directly to the operating room (394 cases, 29 deaths). Using only data available from the ER, a neural network was created, and 628 cases were randomly selected for training. After 268 iterations, the network was trained to correctly predict death or survival in all 628 cases. This trained network was then tested on the other 269 cases without our providing the death or survival result. Its overall accuracy was 91 per cent (244 of 269 cases). It was able to predict correctly 60 per cent (12 of 20 cases) of the postoperative or post-intensive care unit admission deaths and 90 per cent (26 of 29 cases) of the deaths in the ER. Computerized neural networks can accurately predict a trauma patient's fate based on inital ER presentation. The theory and use of neural networks in predicting clinical outcome will be presented.

Age Factors↗
PubMed1996

Assessment of in vivo attachment/phagocytosis by alveolar macrophages.

Alveolar macrophages (AMs) are recognized as an important first line of cellular host defense within the lung. Although mechanisms underlying AM response to microorganisms or particulates are well characterized in vitro, experimental approaches to the study of AMs in vivo are limited. To circumvent these limitations, a new assay was developed using fluorescently labelled liposomes or Pneumocystis carinii (PC) organisms which were administered intratracheally into mechanically ventilated rats. After 30 min, the lungs were lavaged and the percentage of administered liposomes or PC bound to AMs was determined by quantifying fluorescence. Factors known to enhance attachment/phagocytosis by AMs in vitro were assayed to determine their effect in vivo. For example, vitronectin (VN)-coated liposomes increased attachment from 25.2 +/- 2.4% to 47.2 +/- 3.0% (p < 0.001), while addition of VN increased the binding of PC to AMs from 16.5 +/- 1.7% to 24.5 +/- 2.2% (p < 0.05). Confocal laser microscopy of cells obtained by lavage provided morphologic evidence of attachment/phagocytosis by AMs. This model will permit the quantitative assessment of the interaction of fluorescently labelled liposomes or microorganisms with AMs in the lower respiratory tract of living animals.

Animals↗
PubMed1996

The bryostatins inhibit growth of B16/F10 melanoma cells in vitro through a protein kinase C-independent mechanism: dissociation of activities using 26-epi-bryostatin 1.

Bryostatin 1 is a potential cancer chemotherapeutic agent in Phase II clinical trials, with positive responses observed for malignant melanoma, among other tumors. The bryostatins are known to be potent ligands for protein kinase C (PKC), functioning as partial antagonists. In the present study, we explore the mechanism by which the bryostatins inhibit growth to B16/F10 mouse melanoma cells in vitro. Three experimental approaches suggest that the growth inhibition is independent of PKC. First, we characterized in detail the translocation and down-regulation of the PKC isozymes alpha, delta, and epsilon in response to phorbol ester and bryostatin 1 in these cells. Although the dose-response curves obtained for the translocation-activation of PKC isozymes showed good correlation with the growth-enhancing activity of phorbol 12-myristate 13-acetate, for no PKC isozyme was there a good correlation with the growth-inhibitory activity of bryostatin 1. Second, inhibition PKC, inhibited the growth of the B16/F10 melanoma cell lines with potency similar to that of bryostatin 1. We confirmed here that 26-epi-bryostatin 1 showed 60-fold reduced affinity for PKC and 30-60-fold reduced potency to translocate and downregulate PKC isozymes compared with bryostatin 1. We presumed that the principal toxicity of bryostatin 1 reflects its interaction with PKC, and we would thus predict that epi-bryostatin 1 would be less toxic. Indeed, we found at least 10-fold reduced toxicity of 26-epi-bryostatin 1 in C57BL/6 mice compared with bryostatin 1. We conclude that the growth inhibition of the bryostatins, at least in this system, does not result from interaction with PKC. As exemplified by 26-epi-bryostatin 1, this insight permits the design of analogues with comparable growth inhibition to bryostatin 1 but with reduced toxicity.

Animals↗
PubMed1996

Expression of genes coding for antioxidant enzymes and heat shock proteins is altered in primary cultures of rat hepatocytes.

The expression of genes for heat shock proteins in the HSP70 family and genes for antioxidant enzymes was studied in rat hepatocytes cultured in either L-15 or Williams E media on a collagen matrix for up to 48 hours. The mRNA transcripts for the heat shock proteins hsp70, hsc70, and grp78 were induced dramatically when hepatocytes were cultured in L-15, and to a lesser extent when cultured in Williams E. The increase in hsp70 and hsc70 mRNA levels in the cultured hepatocytes was correlated with an increase in the nuclear transcription of these two genes and the binding activity of the heat shock transcription factor to the heat shock element. Culturing rat hepatocytes in either L-15 or Williams E resulted in a decrease in the levels of the mRNA transcripts for catalase and glutathione peroxidase and the activities of these two enzymes. However, the expression of Cu/Zn-superoxide dismutase, i.e., the level of the mRNA transcript or the enzymatic activity, did not change appreciably when hepatocytes were cultured for up to 48 hours. The decline in catalase and glutathione peroxidase expression in the cultured hepatocytes was correlated with a decrease in the GSH/GSSG ratio and an increase in lipid peroxidation. These data show that the expression of several genes involved in cellular protection change when hepatocytes are placed in primary cultures. Therefore, one must be careful in extrapolating from primary cultures to the liver in vivo, especially when studying processes that might be affected by heat shock proteins or antioxidant enzymes.

Animals↗
PubMed1996

Expression and analysis of a bacterial poly(hydroxyalkanoate) synthase in insect cells using a baculovirus system.

An improved method for expression of poly-beta-hydroxyalkanoate (PHA) synthase from Alcaligenes eutrophus has been developed using the baculovirus Autographa californica nuclear polyhedrosis virus (AcMNPV) in BTI-TN-5B1-4 Trichoplusia ni cells which results in high level production of active PHA synthase. Confirmation of expression of authentic PHA synthase was obtained by Western analysis which also revealed the presence of several apparent proteolytic cleavage products. N-terminal sequence data were obtained from the 64-kDa protein which verified its identity. The PHA synthase produced in this system constitutes approximately 50% of total protein after 60 h of viral infection and is found approximately equally distributed in both soluble and membrane-associated fractions. The expression level allowed rapid purification of the soluble form of PHA synthase to approximately 90% homogeneity in a single liquid chromatography step on hydroxylapatite. Using a direct spectrophotometric assay, analyses show that the enzyme has a pH optimum of 8.5, exhibits a concave-up Lineweaver-Burk plot, and a correlation between enzyme concentration and specific activity. Over 1000 units of soluble enzyme were obtained from a 250-ml culture of T. ni cells with an apparent initial specific activity of 12 mumol min-1 mg-1. The amount of PHA synthase activity is significantly higher than previously obtained from much larger bacterial cultures. The method described here should provide a general approach for the expression of active PHA synthases from a variety of bacterial sources to facilitate substrate specificity and mechanistic studies of these intriguing proteins.

Acyl Coenzyme A↗
PubMed1996

Isolation and structure of hemibastadinols 1-3 from the Papua New Guinea marine sponge Ianthella basta.

Further investigation of the Bismarck Archipelago (Papua New Guinea) marine sponge Ianthella basta for biologically active constituents has led to the isolation of hemibastadins 1 (2), 2 (3), and 3 (4) and the new brominated tyrosine derivatives hemibastadinols 1-3 (9, 13, and 14). Isolation and structure elucidation of the monomethyl ether derivatives (7 and 8) of hemibastadins 1 and 2 and the 3-bromotyramine amide of oxalic acid amide (1a) concluded our chemical investigation of I. basta. The hemibastadins and hemibastadinols represent important biosynthetic links to a series of bromotyrosine tetramers collectively known as the bastadins. The antimicrobial activity of the bastadins, hemibastadins, and hemibastadinols is summarized.

Animals↗
PubMed1996

Laparoscopic fundoplication.

Most reports on laparoscopic fundoplication are from large, tertiary referral medical centers. Presented here is an experience by a single surgeon (M.E.F.) in community hospitals with 74 cases. All patients had esophagitis. All but two patients were Visick grade IV off medication. All patients had an incompetent lower esophageal sphicter. Four with abnormally low esophageal contractions underwent a Toupet procedure; the rest had a Nissen fundoplication. The largest estimated blood loss was 300 cc. One case (1.4%) had to be converted intraoperatively to an open procedure because of bleeding from an iatrogenic liver laceration. There were two minor complications (a urinary tract infection and a pneumothorax) and one death (massive liver necrosis with an otherwise unremarkable post mortem, thus it was felt to be due to anesthesia). The mean length of hospital stay was 2.8 +/- 0.21 days. Eighty-nine percent of the operations totally relieved reflux. Nineteen patients (26%) had mild, early postoperative dysphagia, gas bloat, and/or early satiety. Four patients did not get any improvement in their reflux, three still require chronic medication, and one underwent a redo open fundoplication. Three early patients had severe, new-onset postoperative dysphagia secondary to too tight a fundoplication. Attention must be focused on creating a loose wrap, a "floppy" Nissen by routine division of the short gastric vessels and the use of a large dilator in the esophagus when the fundoplication is constructed. Laparoscopic fundoplication is technically feasible, safe, and effective in a community hospital and does not require a large, tertiary referral medical center.

Adolescent↗
PubMed1996

Myocardial bridging prevents safe laparoscopy? A case report.

A 49-year-old male presented with atypical chest pain. Complete cardiac evaluation was normal except for cardiac catheterization, which revealed a myocardial bridge across the LAD (left anterior descending coronary artery) that caused a 50% systolic stenosis. Abdominal ultrasound revealed cholelithiasis. The patient became asymptomatic and was discharged only to return with biliary pancreatitis, which resolved over 2 weeks and laparoscopic cholecystectomy was attempted. Upon establishment of a pneumoperitoneum, he began to suffer cardiac ischemia, which immediately resolved upon desufflation. The procedure was converted to an uneventful open cholecystectomy. He did well without any further problems. This is the first report of myocardial bridging, a well-known cardiac anomaly, possibly preventing safe laparoscopy. This was possibly due to transmitted intraperitoneal pressure effect on the pericardium pushing closed that myocardial bridge.

Cholecystectomy, Laparoscopic↗
PubMed1996

Laparoscopic versus open appendectomy.

This prospective clinical study was done because our initial retrospective review suggested that laparoscopic appendectomy (LA) offers no significant advantages over open appendectomy (OA) yet is significantly more expensive. From July 1992 to August 1993, 57 patients were approached preoperatively for randomization to either LA (n = 19) or OA (n = 18). There were no statistically significant differences between the LA and OA groups in operative risk: mean age, 28 +/- 2 vs 26 +/- 2 years; percent female, 26% vs 22%; body mass index, 24 +/- 0.8 vs 26 +/- 1.2 kg/m2. All patients were either ASA class I or class II, 78% in each group being class II. The differences between the LA and OA groups in mean operating time required (93 +/- 12 vs 87 +/- 8 minutes), postoperative intramuscular narcotic analgesic usage (24 +/- 6 vs 26 +/- 6 hours), postoperative hospital stay (57 +/- 12 vs 66 +/- 10 hours), and return to normal activity (20 +/- 6 vs 14 +/- 3 days) were also not significant. However, LA was much more expensive because of higher operating room charges. The mean total hospital bill was $4,600 +/- $160 for the LA group and $1,700 +/- $70 for the OA group. This prospective study corroborated our previous analysis. Laparoscopic appendectomy is safe, effective, and expensive and overall has no greatly significant advantages over open appendectomy.

Adolescent↗
PubMed1996

Production of a polyhydroxyalkanoate biopolymer in insect cells with a modified eucaryotic fatty acid synthase.

A novel pathway for the synthesis of poly-3-hydroxybutyrate has been engineered by simultaneous delivery of two genes into insect cells (Spodoptera frugiperda) by use of individual baculovirus vectors. This system includes expression of a dehydrase-domain mutant rat fatty acid synthase cDNA and the phbC gene encoding polyhydroxyalkanoate synthase from Alcaligenes eutrophus. The dehydrase-deficient fatty acid synthase provides de novo synthesis of R-(-)-3-hydroxybutyryl-coenzyme A as a premature termination product rather than palmityl-coenzyme A, the normal product of wild-type rat fatty acid synthase. High levels of this mutant multifunctional protein provide a suitable precursor pool of R-(-)-3-hydroxybutyryl-coenzyme A for conversion to poly-3-hydroxybutyrate in insect cells coexpressing the phbC gene product. This strategy for redesigning a poly-3-hydroxybutyrate biosynthetic pathway suggests a new method for generating structurally diverse polyhydroxyalkanoates by metabolic engineering.

Animals↗
PubMed1996

Diagnosis and clinical associations of zinc depletion following bone marrow transplantation.

Following the emergence of biochemical zinc deficiency after bone marrow transplantation, the clinical value of plasma alkaline phosphatase activity as an early indicator of biochemical zinc depletion was investigated in this group of patients. Serial measurements of plasma zinc and alkaline phosphatase activities in 28 consecutive children (median age 8.7 years; 16 males) undergoing bone marrow transplantation were carried out and clinical associations recorded. A significant fall in plasma zinc occurred after the bone marrow transplant, and 19 children developed biochemical zinc deficiency (Zn < 11 mumol/l) at a median of 7 days following the transplant. Zinc depletion was more common in younger patients and in children with diarrhoea. A positive correlation was found between plasma zinc and alkaline phosphatase activities. Zinc depleted patients had more febrile episodes of longer duration and were more likely to have a positive blood culture. Haemopoetic recovery was not affected by zinc deficiency. Following zinc supplementation, alkaline phosphatase showed a significant increase. The sensitivity of a low alkaline phosphatase as a screening test for biochemical zinc deficiency was 83%, with a specificity of 86%. Low alkaline phosphatase activity following bone marrow transplant is an indication for zinc supplements.

Adolescent↗
PubMed1996

Gastrointestinal and nutritional sequelae of bone marrow transplantation.

The nature of the gastrointestinal injury following bone marrow transplantation and its clinical and nutritional sequelae are poorly defined. Prospective assessments of gastrointestinal function, nutritional status, and wellbeing were therefore carried out in 47 consecutive patients (28 males, 19 females; mean age 8.4 years) undergoing bone marrow transplant. 31 diarrhoeal episodes (median duration 9.5 days) occurred in 27 patients at a median of 10 days after transplantation. Ninety one per cent of episodes were associated with protein losing enteropathy. Protein losing enteropathy was more severe in graft-versus-host disease (GVHD) comparing with other causes. It led to a substantial fall in serum albumin and there was a negative correlation between faecal alpha 1-antitrypsin concentrations and serum albumin. Transient pancreatic insufficiency developed in 18 patients, and pancreatitis in one. Intestinal permeability was normal in 12 patients who had no diarrhoea during the conditioning treatments. Diarrhoeal patients had a significantly greater decrease in nutritional status and wellbeing than patients without diarrhoea. Gastrointestinal injury following bone marrow transplantation is thus complex. Severe protein losing enteropathy in this context suggests the presence of GVHD.

Bone Marrow Transplantation↗
PubMed1996

Human surfactant protein A enhances attachment of Pneumocystis carinii to rat alveolar macrophages.

Pneumocystis carinii (PC) pneumonia remains one of the most important opportunistic pulmonary infections. The alveolar macrophage (AM) is likely the primary cell for recognition and removal of PC. The histopathology of PC pneumonia is characterized by a surfactant-like alveolar exudate. We hypothesize that surfactant protein A(SP-A), the major apoprotein of surfactant, mediates attachment of PC to rat AMs by acting as a ligand between the organism and the AM. In this study, attachment of PC was determined using (51)Cr-labeled PC incubated at 4 degrees C with normal rat AM monolayers in the presence or absence of human SP-A. SP-A significantly enhanced attachment of PC from 14.2 +/- 1.2% to 42.0 +/- 3.8% (P<0.05). This enhanced attachment was visualized and quantified morphologically with confocal microscopy. PC attachment by SP-A was calcium- and mannose-dependent as SP-A-mediated attachment was significantly reduced in the presence of EGTA and mannose to 13.1 +/- 1.6% and 19.3 +/- 2.6%, respectively (P<0.05). Addition of type V collagen and antibodies to SP-A also significantly reduced SP-A-mediated attachment to 4.9 +/- 1.2% and 10.1 +/- 1.2%, respectively (P<0.05). We conclude that SP-A can function as a ligand between PC and the AM and may represent an important detection and clearance mechanism of PC from the alveolar spaces.

Animals↗
PubMed1995

Number and ultrastructure of epithelial cells in crypts and villi along the streptozotocin-diabetic small intestine: a quantitative study on the effects of insulin and aldose reductase inhibition.

This study has quantified the effects of insulin treatment with and without aldose reductase inhibitor (ponalrestat) on intestinal epithelial cell morphology in streptozotocin-diabetic rats. Epithelial volumes, villous and microvillous surface areas and mean volumes of cells (and their nuclei) in crypts and villi were estimated in each of four segments and in the entire intestine. We derived total numbers of cells, quantified the ultrastructural features of average cells and explored variation along the intestine and between experimental groups. In crypts, insulin and ponalrestat had significant effects on cell number (reduced towards normal values) and size (volume and apex area increased beyond normal values). There were interaction effects between insulin and ponalrestat for cell volume and apex area (insulin producing more exaggerated effects when given without ponalrestat). On villi, insulin and ponalrestat returned cell numbers towards normal values but neither treatment normalised cell size or the number and area of microvilli per cell. Indeed, ponalrestat increased microvillous number and area beyond values found in untreated diabetic animals. Again, there were interaction effects between insulin and ponalrestat. Patterns of segmental variation seen in crypts of normal rats (values tending to be higher in proximal or mid-intestinal regions) were not preserved, and only some of the segmental differences seen on villi (higher values at proximal or mid-intestinal sites) were maintained during therapy. Apart from reducing the abnormally high numbers of cells in untreated diabetic rats, these results show that insulin and ponalrestat treatment fail to restitute epithelial cell morphology in the small intestines of experimental diabetic rats.

Animals↗
PubMed1995

Criterion variability in problem-drinking research on college students.

A persistent issue confronting research on problem drinking (PD) and heavy drinking (HD) among college-age adults is the lack of a consistent, valid definition and criteria for either of the two conditions. This article presents a review and analysis of the criteria used in a selected group of studies on college students' PD and HD from 1974 to 1993. All studies within the time period that employed a random sample of students were analyzed for variations in criteria used to define either PD or HD. Sample characteristics, the specific criteria used, and data on prevalence rates found with those criteria are described. Areas of uniformity and inconsistency were identified and effects of criterion variations were described for the 23 studies reviewed. Of particular note was the lack of differential criteria for gender.

Adult↗
PubMed1995

Antineoplastic agents, 326. The stereochemistry of bastadins 8, 10, and 12 from the Bismarck archipelago marine sponge Ianthella basta.

An investigation of cancer cell-growth inhibitory constituents of the Papua New Guinea marine sponge Ianthella basta led to isolation of the C-6 hydroxybastadins 8 [1] 10 [2], and 12 [3]. The absolute stereochemistry (6S) of each bastadin (or its tetramethyl ester derivative) was determined by means of the Mosher-Trost method. Bastadins 10 [2] and 12 [3] were found to significantly inhibit the growth of a selection of human cancer cell lines. Bastadins 8, 10, and 12 inhibited growth of the Gram-positive opportunists Staphylococcus aureus and Enterococcus faecalis.

Animals↗
PubMed1995

Antineoplastic agents, 325. Isolation and structure of the human cancer cell growth inhibitory cyclic octapeptides phakellistatin 10 and 11 from Phakellia sp.

The two new marine sponge (Phakellia sp., western Pacific Ocean) constituents, phakellistatin 10 [1] and 11 [2], were found to be cyclic octapeptides that significantly inhibited growth of the murine P-388 lymphocytic leukemia (ED50 values of 2.1 and 0.20 micrograms/ml, respectively) and human cancer cell lines. The structures were established based on results of extensive tandem ms/ms and high-field (500-MHz) 2D 1H- and 13C-nmr analyses. All of the amino acid units (except Trp, not determined) were found to correspond to the (S)-configuration.

Amino Acid Sequence↗