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Biomedical subjects

M D Williams

Publications and source records attributed to M D Williams.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1995

Using the CAGE to screen for drinking-related problems in college students.

OBJECTIVE: As a brief alcohol screening instrument the CAGE has demonstrated a high degree of accuracy in identifying problem drinkers among adults. However, some studies have questioned its screening accuracy within a college population. The research presented in this article contains the results of two additional studies that examined the ability of the CAGE to identify problem drinkers within a college student population. METHOD: In both 1988 and 1992 a questionnaire of various drinking practices, including CAGE items, was mailed to a random sample of 1,000 students at a large midwestern university (response rate: 58.2%, 1988; 49.8%, 1992). Using identical problem-drinking criteria, sensitivity, specificity and positive predictive values at various cutoff scores of the CAGE were calculated for both sets of data and for gender. RESULTS: At the recommended CAGE cutoff score of > 2 for a positive test the sensitivity and positive predictive values (PPV) were slightly higher for the 1992 sample. The PPV values at that cutoff score were 46% (1988) and 49% (1992) and 48% for the combined data. In both samples the screening values were lower for women. CONCLUSIONS: These data from both surveys do not support the CAGE as a screening measure for problem drinking with this population. It appeared to be less accurate with women although that conclusion should be tempered by the fact that there was a relatively low percentage of problem drinkers found among women.

Adolescent↗
PubMed1995

Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications.

New structural modifications of the marine shell-less mollusk peptide constituent dolastatin 10 (1) have been synthesized, and evaluated against a variety of cancer cell lines and for their ability to inhibit tubulin polymerization. A number of useful structure-activity relationships were uncovered. The most important observation was that the dolaphenine unit of dolastatin 10 could be satisfactorily replaced with a phenethylamine. Peptide 11C, designated auristatin PE, was found to exhibit inhibition of cancer cell growth and tubulin assembly comparable to that of dolastatin 10.

Amino Acid Sequence↗
PubMed1995

Interaction of dolastatin 10 with tubulin: induction of aggregation and binding and dissociation reactions.

We have prepared [3H]dolastatin 10 and examined its interactions with tubulin. Binding kinetics appeared to be biphasic, with a rapid initial reaction that could not be accurately measured, followed by a slower second reaction. Bound drug was stable in centrifugal gel filtration, column gel filtration, and high performance liquid chromatography gel filtration, but the bound drug could be displaced by an active isomer of dolastatin 10. Scatchard analysis of binding data was consistent with two classes of binding sites. However, dolastatin 10 induced an aggregation reaction upon binding to tubulin, complicating analysis of the data, and incorporation of [3H]dolastatin 10 into large aggregates was readily demonstrated. The chromatographic properties of the smallest radiolabeled species that could be documented were most consistent with a complex consisting of two molecules of alpha/beta-tubulin dimer and two molecules of [3H]dolastatin 10. The coexistence of an aggregation reaction with a binding reaction at a single site probably underlies the biphasic binding kinetics and the biphasic Scatchard plot. Of peptides that strongly inhibit tubulin polymerization (dolastatin 10, dolastatin 10 isomers, segments, and analogs, dolastatin 15, and phomopsin A), only those previously shown to be strong inhibitors of vinblastine binding and nucleotide exchange also strongly inhibited [3H]dolastatin 10 binding and induced tubulin aggregation (dolastatin 10 itself, two chiral isomers of dolastatin 10, and phomopsin A). The morphology of dolastatin 10-induced aggregates was compared with that of vinblastine-induced aggregates under a variety of reaction conditions. With both drugs the aggregates had a more organized appearance when microtubule-associated proteins were included in the reaction.

Animals↗
PubMed1995

Antineoplastic agents 320: synthesis of a practical pancratistatin prodrug.

Owing to its sparingly soluble properties, the potential anticancer drug pancratistatin (1) resisted conventional drug formulation procedures and the synthesis of a water-soluble prodrug became necessary. That important objective for further pre-clinical development was met by devising a route to a disodium phosphate derivative (5). The key step in the synthesis of the phenolic phosphate was phosphorylation of 1,2,3,4-tetraacetoxy-pancratistatin (2) with dibenzyloxy(N,N-diisopropylamido)-phosphine. Subsequent oxidation with m-chloroperbenzoic acid afforded phosphate 4a. Hydrogenolysis of the benzyl esters followed by base-catalysed hydrolysis of the acetate groups led to the water-soluble prodrug 5 in high yield.

Amaryllidaceae Alkaloids↗
PubMed1995

Role of surfactant protein A in the pathogenesis of tuberculosis in subjects with human immunodeficiency virus infection.

Human immunodeficiency virus (HIV)-infected subjects are at increased risk for tuberculosis even before there is a significant loss of CD4 lymphocytes. A factor was found to be present in the bronchoalveolar lavage (BAL) of HIV-infected subjects that promoted the attachment of M. tuberculosis (MTB) organisms to alveolar macrophages (AMs). Using 51Cr-labeled MTB organisms, BAL from control subjects resulted in MTB attachment to AMs at 11.6% +/- 1.0%; in contrast, BAL from HIV-infected subjects increased attachment to 33.1% +/- 3.8% (P < 0.001). Surfactant protein A (SP-A) levels in BAL of normal controls was 1.9 +/- 0.3 micrograms/ml and was 5.5 +/- 0.4 micrograms/ml in the BAL of HIV-infected subjects (P < 0.01). When SP-A was removed by immunoprecipitation from the BAL of HIV-infected subjects, MTB attachment decreased from 33.1% +/- 3.8% to 11.3% +/- 0.4% (P < 0.001), a value identical to control levels. Exogenous human SP-A (5 micrograms/ml) was added back to the immunoprecipitated BAL and the enhanced attachment of MTB was restored. These data suggest that BAL from HIV-infected subjects contain a factor that facilitates MTB attachment to AMs, the first critical step in the establishment of infection. This factor appears to be SP-A.

Animals↗