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Biomedical subjects

M M Young

Publications and source records attributed to M M Young.

At least 19 recordsLinked to original sources
PubMed2004

Risk factors for invasive meningococcal disease in southern Queensland, 2000-2001.

AIM: The aim of this paper is to describe the risk factors for invasive meningococcal disease (IMD) in southern Queensland. METHODS: A case control study during the calendar years 2000-2001 was undertaken. RESULTS: Eighty-four laboratory-confirmed cases of IMD were notified. Four patients died and were excluded from the present study. Sixty-two (78%) eligible cases and 79 controls selected from the same age group and medical practice as cases, were interviewed. Univariate analysis found that IMD was associated with sharing bedrooms with two or more people (odds ratio (OR) 4.3; 95% confidence interval (CI) 1.2-17.0, P = 0.01), any exposure to tobacco smoke (smoker or passive exposure; OR 2.3; 95% CI 1.1-4.8, P = 0.02), passive exposure to tobacco smoke (OR 2.4; 95% CI 1.0-5.6, P = 0.03) and recent upper respiratory tract infection (OR 1.9, 95% CI 0.9-4.1, P = 0.06). Children who were breast-fed were less likely to develop IMD (OR 0.3; 95% CI 0.1-1.1, P = 0.04). Attendance at a childcare centre was not associated with an increased risk of IMD. In multivariate analysis, IMD was associated with children under 6 years of age who shared a bedroom with two or more people (OR 7.4; 95% CI 1.5-36.1, P = 0.01) or who had a primary carer who smoked (OR 9.1; 95% CI 2.1-39.9, P = 0.003). DISCUSSION: This is the second Australian study that identifies links between risk of IMD and exposure to cigarette smoke. The risk of IMD in young children could be further reduced if primary caregivers did not smoke. This information may contribute a new perspective to antismoking campaigns.

Adolescent↗
PubMed2001

Design, docking, and evaluation of multiple libraries against multiple targets.

We present a general approach to the design, docking, and virtual screening of multiple combinatorial libraries against a family of proteins. The method consists of three main stages: docking the scaffold, selecting the best substituents at each site of diversity, and comparing the resultant molecules within and between the libraries. The core "divide-and-conquer" algorithm for side-chain selection, developed from an earlier version (Sun et al., J Comp Aided Mol Design 1998;12:597-604), provides a way to explore large lists of substituents with linear rather than combinatorial time dependence. We have applied our method to three combinatorial libraries and three serine proteases: trypsin, chymotrypsin, and elastase. We show that the scaffold docking procedure, in conjunction with a novel vector-based orientation filter, reproduces crystallographic binding modes. In addition, the free-energy-based scoring procedure (Zou et al., J Am Chem Soc 1999;121:8033-8043) is able to reproduce experimental binding data for P1 mutants of macromolecular protease inhibitors. Finally, we show that our method discriminates between a peptide library and virtual libraries built on benzodiazepine and tetrahydroisoquinolinone scaffolds. Implications of the docking results for library design are explored.

Amino Acids↗
PubMed2000

High throughput protein fold identification by using experimental constraints derived from intramolecular cross-links and mass spectrometry.

We have used intramolecular cross-linking, MS, and sequence threading to rapidly identify the fold of a model protein, bovine basic fibroblast growth factor (FGF)-2. Its tertiary structure was probed with a lysine-specific cross-linking agent, bis(sulfosuccinimidyl) suberate (BS(3)). Sites of cross-linking were determined by tryptic peptide mapping by using time-of-flight MS. Eighteen unique intramolecular lysine (Lys-Lys) cross-links were identified. The assignments for eight cross-linked peptides were confirmed by using post source decay MS. The interatomic distance constraints were all consistent with the tertiary structure of FGF-2. These relatively few constraints, in conjunction with threading, correctly identified FGF-2 as a member of the beta-trefoil fold family. To further demonstrate utility, we used the top-scoring homolog, IL-1beta, to build an FGF-2 homology model with a backbone error of 4.8 A (rms deviation). This method is fast, is general, uses small amounts of material, and is amenable to automation.

Animals↗
PubMed2000

Videoendoscopic thoracic aorta-to-femoral artery bypass in the pig.

BACKGROUND: The thoracoscopic approach to the aorta has the advantages of easy aortic dissection, excellent inflow, improved exposure in the thorax without insufflation, and ability to employ both laparoscopic and traditional instruments. Our aim was to develop a thoracoscopic technique for descending thoracic aorta-to-femoral artery bypass (TAFB) in the pig that results in acceptable short-term survival and graft patency. MATERIALS AND METHODS: Thoracoscopic TAFB was performed in 11 pigs. Using two-lung ventilation, the animals were placed in a 45 degrees left lateral semidecubitus position. A fan lung retractor, two dissecting ports, intercostal artery loops, and camera were placed through five 10- to 20-mm thoracoscopic incisions. After aortic dissection, an 8-mm graft was passed through a retroperitoneal tunnel. Rumel tourniquets were used for aortic occlusion after placement of a shunt. End-to-side endoscopic anastomosis was completed with knots tied extracorporeally. The left femoral anastomosis was completed under direct vision. Duplex ultrasound of the graft was done on postoperative days 1, 3, and 7. RESULTS: Thoracoscopic TAFB was completed in all animals. Mean aortic anastomosis time was 57 min (range, 34-145); and mean cross-clamp time, 74 min (range, 53-155). Mean operative time was 310 min; the first six operations lasted longer than the last five (338 min vs 276 min, P < 0.04). Average blood loss was 611 ml (range, 250-1300). Two animals died due to anesthetic complications. One (11%) of the nine surviving pigs died on day 2 due to bleeding. Complications were paraplegia in one (11%) and graft thrombosis in another (11%). CONCLUSIONS: Videoendoscopic TAFB can be completed in pigs with acceptable short-term patency and survival. Further experience in thoracoscopic techniques can make TAFB a feasible and low-risk option for selected patients with aortoiliac occlusive disease.

Anastomosis, Surgical↗
PubMed2000

Esophageal reconstruction for benign disease: self-assessment of functional outcome and quality of life.

BACKGROUND: Little information exists regarding functional outcome and quality of life after esophagectomy and subsequent esophageal reconstruction for benign disease as evaluated by the patients themselves. METHODS: Eighty-one patients completed a combined two-part questionnaire regarding esophageal function and quality of life (MOS SF-36) a median of 9.8 years (range, 10 months to 18.9 years) after esophageal reconstruction for benign disease. There were 43 men (53.1%) and 38 women (46.9%). Median age at time of esophageal reconstruction was 51 years (range, 6 to 78 years). Intestinal continuity was established with stomach in 58 patients (71.6%), colon in 16 patients (19.8%), and small bowel in 7 patients (8.6%). RESULTS: Dysphagia to solids was present in 48 patients (59.3%) and 27 patients (33.3%) required at least one postoperative dilatation. Heartburn was present in 50 patients (61.7%) which required medication for control in 37 patients (45.7%). The number of meals per day was three to four in 58 patients (71.6%), more than four in 15 patients (18.5%), less than three in 6 patients (7.4%), and unknown in 2 patients (2.5%). The size of each meal was smaller than preoperatively in 46 patients (56.8%), larger in 22 patients (27.2%), unchanged in 12 patients (14.8%), and unknown in 1 patient (1.2%). The number of bowel movements per day increased in 37 patients (45.7%), was unchanged in 36 patients (44.4%), and decreased in 8 patients (9.9%). Resection for perforation was associated with smaller postoperative meals compared with resection for stricture (p < 0.05). Age, sex, and type of esophageal reconstruction did not affect late functional outcome. Regarding quality of life, physical functioning, social functioning, and health perception were decreased (p < 0.05). No significant change was observed in role-physical, mental health, bodily pain, energy/fatigue, and role-emotional scores. CONCLUSIONS: Self-assessment of postoperative esophageal symptoms after esophagectomy and reconstruction for benign disease demonstrates that symptoms are frequently present at long-term follow-up and unaffected by the type of reconstruction.

Adolescent↗
PubMed2000

Esophageal reconstruction for benign disease: early morbidity, mortality, and functional results.

BACKGROUND: Esophagectomy for benign disease is performed infrequently. We reviewed the Mayo Clinic's experience with patients who required esophageal reconstruction for benign esophageal disease. METHODS: From March 1956 to October 1997, all patients who required resection and reconstruction for a benign condition of the esophagus were reviewed. RESULTS: There were 255 patients (141 male, 114 female). Median age was 55 years (range, 2 to 100). The original diagnosis was an esophageal stricture in 108 patients (42%), primary motility disorder in 84 (33%), perforation in 36 (14%), hiatal hernia in 18 (7%), and other in 9 (4.0%). Reconstruction was with stomach in 168 patients (66%), colon in 70 (27%), and small bowel in 17 (7%). The anastomosis was intrathoracic in 144 patients (57%) and cervical in 111 (43%). There were 13 postoperative deaths (mortality 5%); 142 patients (56%) had at least one complication. Median hospitalization was 14 days (range, 6-95 days). Follow-up was complete in 226 patients (88.6%) for a median of 52 months (range, 1 month to 29 years). A total of 175 patients (77.4%) were improved. Functional results were classified as excellent in 72 patients (31.8%), good in 23 (10.2%), fair in 80 (35.4%), and poor in 51 (22.6%). CONCLUSIONS: Esophageal reconstruction for benign disease resulted in functional improvement in a majority of patients. It can be done with low mortality and acceptable morbidity. Early morbidity is adversely affected by the diagnosis of perforation and the route through which the conduit is placed. Late functional outcome is adversely affected by the diagnosis of paraesophageal hernia and a cervical anastomosis.

Adolescent↗
PubMed1999

NMDA and AMPA glutamate receptor subtypes in the thoracic spinal cord in lean and obese-diabetic ob/ob mice.

Quantitative autoradiography was used to characterise the binding of selective radiolabelled antagonists for the N-methyl-D-aspartate (NMDA) receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor in the dorsal, intermediate and ventral subregions of the grey matter of the upper thoracic spinal cord in male and female lean and obese-diabetic (ob/ob) mice. The density of binding sites for both receptor subtypes was greater in diabetic mice, in all three subregions of the grey matter, than the corresponding subregions in the lean mice. The affinity of the binding site for the NMDA antagonist was significantly higher in obese mice than lean mice, consistent with the presence of two subpopulations of NMDA receptors with different ligand binding affinities in obese mice. The increase in expression of the glutamate receptor subtypes, and altered ligand affinity for the NMDA receptor subtype in the obese mice may be causally involved in the peripheral neuropathies which can accompany diabetes mellitus.

Animals↗
PubMed1999

Effect of sympathectomy on the expression of NMDA receptors in the spinal cord.

The expression of NMDA receptors in the intermediolateral (IML) region of the upper thoracic spinal cord, was studied in 3 week old rats. The effect of section of the cervical sympathetic nerve on neuronal cell number and receptor expression was examined up to two weeks after the operation. Age-matched sham-operated and unoperated animals were used as controls. It was shown using quantitative autoradiography with the NMDA receptor antagonist [(3)H]MK-801 (dizocilpine maleate), that there was a marked downregulation of receptors in all groups of animals, beginning at approximately 4 weeks of age. However after sympathectomy, which resulted in the death of 44% of neurones in the IML by 7 days, there was a significant increase in receptor density per neurone compared to sham-operated controls. In the control animals there was a significant increase in the Kd value of the binding between 21 and 24 days after birth indicating an increased expression of a low affinity receptor, but no such increase was seen after axotomy. The results are consistent with two populations of NMDA receptors being transiently expressed in the IML in developing animals, and the higher affinity receptor being down-regulated between 4 and 5 weeks of age. The presence of the high affinity receptor subtype may predispose neurones to die after axotomy.

Animals↗
PubMed1999

A rapid method for exploring the protein structure universe.

We have developed an automatic protein fingerprinting method for the evaluation of protein structural similarities based on secondary structure element compositions, spatial arrangements, lengths, and topologies. This method can rapidly identify proteins sharing structural homologies as we demonstrate with five test cases: the globins, the mammalian trypsinlike serine proteases, the immunoglobulins, the cupredoxins, and the actinlike ATPase domain-containing proteins. Principal components analysis of the similarity distance matrix calculated from an all-by-all comparison of 1,031 unique chains in the Protein Data Bank has produced a distribution of structures within a high-dimensional structural space. Fifty percent of the variance observed for this distribution is bounded by six axes, two of which encode structural variability within two large families, the immunoglobulins and the trypsinlike serine proteases. Many aspects of the spatial distribution remain stable upon reduction of the database to 140 proteins with minimal family overlap. The axes correlated with specific structural families are no longer observed. A clear hierarchy of organization is seen in the arrangement of protein structures in the universe. At the highest level, protein structures populate regions corresponding to the all-alpha, all-beta, and alpha/beta superfamilies. Large protein families are arranged along family-specific axes, forming local densely populated regions within the space. The lowest level of organization is intrafamilial; homologous structures are ordered by variations in peripheral secondary structure elements or by conformational shifts in the tertiary structure.

Algorithms↗
PubMed1999

Troglitazone has no effect on red cell mass or other erythropoietic parameters.

OBJECTIVE: Troglitazone is a new anti-diabetic agent for the treatment of type 2 diabetes. In placebo-controlled trials troglitazone improves glycaemic control, reduces hyperinsulinaemia and has beneficial effects on blood lipids. However, minor, reversible reductions in erythrocyte count, haemoglobin and haematocrit with no associated clinical symptoms have been observed in some troglitazone-treated patients. The primary objective of the present study was to determine if these changes could be explained by a decrease in red cell mass or change in plasma volume. METHODS: Twenty-four healthy males were randomized in a double-blind manner to troglitazone (200 or 600 mg per day) or placebo for 6 weeks. Blood samples for the measurement of red cell mass and plasma volume were obtained in the 2 weeks prior to treatment and after 6 weeks of treatment. Reticulocyte and erythrocyte counts, haemoglobin and haematocrit were also measured. RESULTS: At the end of the treatment period there were no statistically significant changes in red cell mass. Similarly there were no changes in reticulocyte count, erythropoietin or soluble transferrin receptors. These data indicate that troglitazone does not affect erythropoiesis. In addition, troglitazone was not associated with increased red blood cell destruction or haemolysis. There was a trend towards increased plasma volume in the troglitazone groups: increases of 2.5 ml x kg(-1) (5.7% increase) in the troglitazone 200 mg group and 3.4 ml x kg(-1) (7.8% increase) in the troglitazone 600 mg group were observed compared with placebo. CONCLUSION: These data suggest that dilutional effects related to a modest increase in plasma volume may explain the haematological changes seen in other clinical trials with high doses of troglitazone, although this study has shown that the changes in plasma volume are not statistically significant.

Adult↗
PubMed1999

Lack of association between genetic variation in the beta3-adrenergic receptor gene and insulin resistance in patients with coronary heart disease.

The beta-adrenergic system plays a critical role in regulating lipolysis and thermogenesis. Recent studies have suggested that a missense Trp64Arg mutation in the beta3-adrenergic receptor gene is involved in visceral obesity and insulin resistance. We investigated the effect of this mutation on insulin resistance in patients with angiographically documented coronary heart disease ([CHD]n = 137) and normal subjects (n = 188). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance measured by the insulin suppression test, were determined in 58 (42%) patients with CHD and 121 (64%) controls. The genotype and allele frequency of the beta3-adrenergic receptor did not differ between patients with CHD and controls. The blood pressure, body mass index (BMI), waist to hip ratio, fasting plasma glucose, insulin, and lipid, and plasma glucose and insulin responses to the glucose load were relatively similar in subjects with and without the mutation in CHD and normal groups. The degree of insulin sensitivity, ie, the steady-state plasma glucose concentration, was not significantly different between subjects with and without the mutation in the CHD group (11.3 +/- 1.2, n = 11 v 11.9 +/- 0.6 mmol/L, n = 47, P = NS) and control group (8.4 +/- 0.7, n = 30 v 8.2 +/- 0.4 mmol/L, n = 91, P = NS). We conclude that Trp64Arg polymorphism of the beta3-adrenergic receptor gene does not likely play a major role in the development of CHD in the Chinese population. In addition, it appears to have no association with the insulin resistance syndrome in either CHD or non-CHD subjects.

Alleles↗
PubMed1999

Necrobiosis lipoidica: only a minority of patients have diabetes mellitus.

Although it is commonly accepted that necrobiosis lipoidica (NL) is associated with diabetes mellitus (DM), there is some controversy regarding the degree of this association. In a retrospective review of 65 patients with NL attending our dermatology out-patient clinics we found that just seven (11%) were known to have DM at the time of presentation. Seven further patients (11%) were diagnosed as having impaired glucose tolerance/DM at presentation and over a 15-year follow-up period. Thus, only a minority of our patients with NL had DM.

Administration, Topical↗
PubMed1999

Laparoscopic transureteroureterostomy: demonstration of its feasibility in swine.

PURPOSE: To evaluate the feasibility of laparoscopic transureteroureterostomy (TUU) in a porcine model. MATERIALS AND METHODS: Nine female pigs had bilateral ureteral stents placed 3 weeks prior to surgery. At surgery, a left-to-right laparoscopic TUU was performed. Ureteral stents were placed across the anastomosis in seven cases. Six weeks after surgery, the stents were removed. After an additional 3 weeks, an excretory urogram, retrograde ureteropyelogram, and ureteroscopic examination of the anastomosis were performed. Serum creatinine assay and urine cultures were performed at regular intervals. Antibiotic prophylaxis was used for 1 week after each procedure. RESULTS: Of the nine animals, eight underwent successful laparoscopic TUU. Excretory urograms revealed prompt function and washout in all these cases. One animal developed an anastomotic stricture; in this animal, the ureters had remained nondilated after initial stent placement. Serum creatinine values remained within the normal range for all animals undergoing successful surgery. Additional complications included one urinary tract infection and one postoperative ileus, which were treated without difficulty. The operative time ranged from 2.5 to 6 hours, with shorter procedures later in the series. CONCLUSIONS: Laparoscopic TUU is practical in the porcine model. It may prove to be an alternative to an open TUU in patients with lower ureteral lesions when ureteroneocystostomy is not feasible.

Anastomosis, Surgical↗
PubMed1997

Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers.

The oxidative modification of low density lipoprotein is of importance in atherogenesis. Antioxidant supplementation has been shown, in published work, to increase low density lipoprotein resistance to oxidation in both healthy subjects and diabetic subjects; in animal studies a contemporary reduction in atherogenesis has been demonstrated. Troglitazone is a novel oral antidiabetic drug which has similarities in structure with vitamin E. The present study assessed the effect of troglitazone 400 mg twice daily for 2 weeks on the resistance of low density lipoprotein to oxidation in healthy male subjects. Ten subjects received troglitazone and ten received placebo in a randomised, placebo-controlled, parallel-group design. The lag phase (a measure of the resistance of low density lipoprotein to oxidation) was determined by measurement of fluorescence development during copper-catalysed oxidative modification of low density lipoprotein. The lag phase was increased by 27 % (p < 0.001) at week 1 and by 24% (p < 0.001) at week 2 in the troglitazone treated group compared with the placebo group. A number of variables known to influence the resistance of low density lipoprotein to oxidation were measured. They included macronutrient consumption, plasma and lipoprotein lipid profile, alpha-tocopherol, beta-carotene levels in low density lipoprotein, low density lipoprotein particle size, mono and polyunsaturated fatty acid content of low density lipoprotein and pre-formed low density lipoprotein hydroperoxide levels in low density lipoprotein. Troglitazone was associated with a significant reduction in the amount of pre-formed low density lipoprotein lipid hydroperoxides. At weeks 1 and 2, the low density lipoprotein hydroperoxide content was 17% (p < 0.05) and 18% (p < 0.05) lower in the troglitazone group compared to placebo, respectively. In summary the increase in lag phase duration in the troglitazone group appeared to be due to the compound's activity as an antioxidant and to its ability to reduce the amount of preformed low density lipoprotein lipid hydroperoxides. This antioxidant activity could provide considerable benefit to diabetic patients where atherosclerosis accounts for the majority of total mortality.

Administration, Oral↗
PubMed1997

Effect of the non peptide angiotensin II antagonist, GR117289C on the vasoconstrictor actions of angiotensin II in the human forearm.

AIMS: GR117289C is a non peptide, selective angiotensin (AT1) receptor antagonist. The purpose of this study was to determine whether this agent, given orally, could attenuate the vasoconstrictor effects of angiotensin II(AII) infused locally into the forearm circulation in man. METHODS: Eight healthy male subjects were studied on four occasions in a randomized, double-blind, placebo controlled, crossover study. Five hours (approximate time of peak dynamic effect) following dosing with GR117289C (300 mg, 100 mg, 10 mg or placebo), A II was infused in incremental doses (0, 0.1, 0.4, 1.6, 6.2, 25 and 100 pmol min-1) into the left brachial artery, each for 10 min. Forearm blood flow was measured using venous occlusion plethysmography. RESULTS: GR117289C inhibits the vasoconstrictor effects of A II in a dose dependent manner. The active treatment: placebo ratios of forearm blood flow in the infused arm during the highest dose of AII (100 pmol min-1) were: GR117289C 10 mg, 1.12 (95% C.I. 0.81-1.55; P = 0.478), 100 mg, 1.43 (95% C.I. 1.01-2.01; P = 0.042) and 300 mg, 1.62 (95% C.I. 1.17-2.24; P = 0.006). There was no significant difference in blood pressure between each of the treatment groups and placebo. CONCLUSIONS: GR117289C is a pharmacologically active, oral A II antagonist in healthy men.

Administration, Oral↗
PubMed1996

Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland.

We have located three extended families in Ireland (population 3.5 million) with autosomal dominant simplex forms of Epidermolysis Bullosa (EBS). A mutation within the keratin type I (K14) gene (Met-->272-->Arg) in one family suffering from the generalized simplex (Koebner) form of the disease has been previously described (Humphries et al., Hum Mutat 2:37-42, 1993). Here we report on the identification of mutations within the remaining two families, both of whom suffer from the Weber-Cockayne form of the disease. These mutations, within the type II keratin (K5) gene, are Asn-->193-->Lys and Met-->327-->Thr. They have been shown in each case to co-segregate with the disease and are not present in the normal population. Within the three families, a total of 44 living persons with such mutations have been identified, providing a minimum prevalence estimate for the disease in the Irish population of approximately 1 in 80,000, compared to an overall estimated global incidence at birth for all forms of EB of 1 in 50,000. Therefore, these three mutations probably account for the majority of cases of EBS within this population.

Amino Acid Sequence↗