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Biomedical subjects

D Lang

Publications and source records attributed to D Lang.

At least 55 records · Page 3Linked to original sources
PubMed2001

Antibody responses to recombinant Epstein-Barr virus antigens in nasopharyngeal carcinoma patients: complementary test of ZEBRA protein and early antigens p54 and p138.

Serological tests based on the antibodies directed against the Epstein-Barr virus early antigen (EA) and viral capsid antigen (VCA), which have been recognized as tumor markers for nasopharyngeal carcinoma (NPC), are routinely used to help in the diagnosis of this malignancy. The detection of these antibodies reveals very low titers, found only in a small proportion of young compared with older NPC patients. This is a problem for the diagnosis of NPC, especially among Maghrebians, among whom young people are also affected, and emphasizes the necessity to search for more reliable markers. The present study reports results of immunoglobulin G (IgG) and IgA responses of NPC patients to recombinant EA antigens p54 (BMRF1) and p138 (BALF2), VCA complex antigens p18 (BFRF3) and p23 (BLRF2), and EBNA antigen p72 (BKRF1). Our results show that IgA-EA-p54 and -p138 (IgA-EA-p54+138) antibodies have a diagnostic value for detection of NPC (70%), compared with IgA-VCA-p18+23 and IgA-EBNA-p72, which have limited diagnostic value, especially in young patients. It is also noteworthy that IgA-EA-p54+138 can detect a high percentage (64%) of NPC cases negative by immunofluorescence. These results, however, clearly show that a single test cannot achieve the objective of detecting all NPC patients, and it seems advisable to combine different tests for the diagnosis of NPC. The combination of IgG-ZEBRA with IgA-EA-p54+138 improved the sensitivity of detection of NPC to 95% in the overall NPC population. The use of IgA-EA-p54+138 in combination with IgG-ZEBRA will facilitate detailed studies on the pattern of antibody response, which may result in the development of useful serological markers to guide the treatment of NPC.

Adolescent↗
PubMed2001

Prospective study of omental transposition in patients with chronic spinal injury.

OBJECTIVES: This prospective study was designed to assess the effects of omental transposition in patients with a chronic spinal injury. METHODS: Neurological status was established to be stable and multiple baseline across patient studies were done preoperatively and repeated postoperatively. Assessments included activities of daily living (ADL), functional ability, degree of spasticity, motor power, sensation, pain perception, urodynamic studies, electromyography, sensory evoked potentials (SEPs), and infrared thermography to measure peripheral and general skin vascular responses. Each patient had MRI. Assessments were done at 3, 6, and 12 months after omental transposition in 17 patients. RESULTS: The detailed assessments failed to show significant improvement, although some patients showed minor objective and subjective change in some categories. Neurological deterioration occurred in one patient. There were 20 surgical complications including urinary tract infection, deep vein thrombosis, wound infection, and incisional hernia. CONCLUSIONS: Omental transposition has not been shown to improve neurological function in 17 patients with chronic spinal cord injury, and continued use of this operation in this situation is not supported by this study. Further advances in spinal cord repair may utilise the pedicled omental graft to provide an alternative vascular supply, but its current use should be limited to experimental models.

Activities of Daily Living↗
PubMed2001

Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs.

Left ventricular hypertrophy (LVH) is a cardiovascular risk factor. A possible role for endothelial dysfunction in this condition was investigated in a Dunkin-Hartley guinea pig aortic-banded pressure overload-induced model of LVH. Aortic banding produced significant elevation of fore- and hindlimb blood pressure (BP), heart-to-body weight ratios, plasma angiotensin II (ANG II), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha) levels, and coronary microvascular endothelial cell (CMEC) NAD(P)H-dependent superoxide (O) production, and a significant decrease in basal and stimulated CMEC cGMP levels. Treatment of aortic-banded animals with the angiotensin-converting enzyme inhibitor quinapril and the antioxidant vitamin C, either alone or in combination, did not affect BP but caused a significant inhibition of the increases in the heart-to-body weight ratio, ANG II, ET-1, and TNF-alpha levels, and O production and restored cGMP responses to levels comparable with sham-operated animals. These data suggest that quinapril and vitamin C are capable of inhibiting LVH development due to pressure overload via mechanisms that involve the inhibition of oxidative stress, an improvement in coronary endothelial function, and increased nitric oxide bioavailability.

Animals↗
PubMed2001

Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?

Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function in vivo and on intracellular superoxide in cultured endothelial cells. A randomized crossover study of folic acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD. Ten further patients were given intra-arterial 5-MTHF. Endothelial function was assessed by flow-mediated dilatation (FMD). Folic acid increased plasma folate (P<0.001), lowered homocysteine by 19% (P<0.001), and improved FMD (P<0.001). FMD improvement did not correlate with homocysteine reduction. Malondialdehyde and total plasma antioxidant capacity, markers of oxidative stress, were unchanged. 5-MTHF acutely improved FMD (P<0.001) without altering homocysteine (P=0.47). In vitro, 5-MTHF abolished homocysteine-induced intracellular superoxide increase (P<0.001); this effect was also observed with folic acid and tetrahydrobiopterin. Our data support the beneficial effect of folic acid on endothelial function in CAD but suggest that the mechanism is independent of homocysteine. Reduction of intracellular endothelial superoxide may have contributed to the effect.

Animals↗
PubMed2001

Report of normative sensory and motor performance in children using a standardized battery.

This study provided normative data for sensory and motor functioning of children from 2-15 years of age. Two hundred eighty-eight children without a history of neurological or psychiatric evaluation, diagnosis, or treatment served as subjects. Each child was administered the Dean-Woodcock Sensory and Motor Battery. This measure consists of 18 individual subtests. Nine subtests reflect visual, auditory, or tactile perception. The remaining 9 subtests involve motor functioning, with 3 of the subtests devoted to subcortical functioning. The results showed that the most rapid development occurred between the ages of 4 and 7 years. Indeed, some 76% of the sensory-motor tasks administered reached a plateau by age 7.

Child↗
PubMed2001

Patient-assessed outcomes after excision of acoustic neuroma: postoperative symptoms and quality of life.

OBJECT: The aim of this study was to assess whether outcomes from excision of acoustic neuroma vary among patients and have a material impact on their quality of life (QOL). METHODS: A questionnaire concerning postoperative symptoms and the Short Form 36 (SF-36) QOL instrument were mailed to 97 consecutive patients who had undergone acoustic neuroma surgery via the translabyrinthine approach. The survey response rate was 78% and the symptomatology was consistent with other reports, supporting the representativeness of the sample. The respondents' QOL was rated significantly below published norms and their work capacity was reportedly reduced. Specifically, the following SF-36 dimensions were reduced: physical functioning and role-physical, together with vitality, general health, and social functioning. Greater numbers of postoperative symptoms and larger tumors were associated with a worse rating of physical functioning. More severe balance problems were associated with lower ratings of social functioning. The disparity between the patient's self-estimate and self-measurement and the clinician's assessment of the patient's facial functioning raises doubts about the validity of subjective reports and assessment. CONCLUSIONS: The present study supports the use of generic QOL measures to assess outcome and to draw comparisons between different populations.

Adolescent↗
PubMed2001

The realities of postoperative disability and the carer's burden.

Outcome after high-risk, complex neurosurgery for progressive skull base pathology, and its effect on carers, has been examined. Two different outcome measures were used. The Glasgow Outcome Score (GOS) assesses overall social capability and dependence of the patient, while the 36 item short-form health survey (SF-36), a generic quality of life measure, can be compared directly with the general population. Overall outcome using the GOS indicated a favourable outcome for 13 of the 17 patients studied. The SF-36 demonstrated that more than half the patients were functioning at a level below the accepted norm. The reasons for this discrepancy and the validity of outcome scales have been analysed. In addition, the effect upon carers, its relevance to assessment of outcome, and the need to involve potential carers in the process of informed consent was stated. Our conclusions are applicable throughout the surgical specialities, and especially to high-risk complex surgery.

Caregivers↗
PubMed2001

Characterization of dextromethorphan O- and N-demethylation catalyzed by highly purified recombinant human CYP2D6.

The O-demethylation of dextromethorphan to dextrorphan in humans is catalyzed primarily by cytochrome P450 2D6 (CYP2D6). However, contrary to conventional wisdom, preparations of recombinant cytochrome P450 (P450) expressed from CYP2D6*1 cDNA also appear to produce significant amounts of 3-methoxymorphinan, the N-demethylated metabolite of dextromethorphan, when assayed in vitro. We hypothesized that both pathways were intrinsic to 2D6 and here further examine the kinetics of formation using a highly purified preparation of CYP2D6 in a reconstituted lipid system. Purified CYP2D6 protein with a measured molecular weight of 55772.0 (55769.6 Da predicted) was reconstituted into an active, lipid-vesicle environment with purified rat cytochrome P450 reductase before the addition of substrate and NADPH. Reaction kinetics were followed, and apparent Michaelis-Menten constants were determined for the appearance of each metabolite by high-pressure liquid chromatography, using both UV and fluorescence detection. In a 2-min assay, purified 2D6 catalyzed the formation of dextrorphan with an apparent K(m) value of 1.9 +/- 0.2 microM and a V(max) value of 8.5 +/- 0.2 nmol/nmol of P450/min and measured simultaneously the formation of 3-methoxymorphinan with an apparent K(m) value of 5000 +/- 700 microM and V(max) value of 176 +/- 12 nmol (nmol of P450)(-1) min(-1). These results indicate that at least two distinct binding orientations exist for dextromethorphan within the active site of CYP2D6.

Animals↗
PubMed2000

A snapshot of a transition state analogue of a novel thermophilic esterase belonging to the subfamily of mammalian hormone-sensitive lipase.

EST2 is a novel thermophilic carboxylesterase, isolated and cloned from Alicyclobacillus (formerly Bacillus) acidocaldarius, which optimally hydrolyses esters with acyl chain lengths of six to eight carbon atoms at 70 degrees C. On the basis of the amino acid sequence homology, it has been classified as a member of the mammalian hormone-sensitive lipase (HSL) subfamily. The crystal structure of EST2, complexed with a sulphonyl derivative, has been determined at 2.6 A resolution by a multiple wavelength anomalous diffraction experiment on a seleno-methionine derivative. EST2 presents a canonical alpha/beta hydrolase core, shielded at the C-terminal side by a cap region built up of five helices. It contains the lipase-like catalytic triad, Ser155, His282 and Asp252, whereby the nucleophile is covalently modified. This allows an unambiguous view of the putative active site of EST2, detecting the oxyanion hole, in whose formation the amino acid sequence motif His81-Gly82-Gly83-Gly84 is involved, and the hydrophobic binding pocket for the acyl chain. The structural model here reported provides the first example of a transition state analogue of an esterase/lipase belonging to the HSL group, thus affording useful information for the design of medical inhibitors. Moreover, as the first X-ray structure of a thermophilic carboxylesterase, the comparison with its mesophilic homologue, the Brefeldin A esterase (BFAE) from Bacillus subtilis, allows the identification of putative determinants of thermal stability.

Amino Acid Sequence↗
PubMed2000

Neutrophil superoxide anion--generating capacity, endothelial function and oxidative stress in chronic heart failure: effects of short- and long-term vitamin C therapy.

OBJECTIVES: First, we sought to study the effects of short- and long-term vitamin C therapy on oxidative stress and endothelial dysfunction in chronic heart failure (CHF), and second, we sought to investigate the role of neutrophils as a cause of oxidative stress in CHF. BACKGROUND: Oxidative stress may contribute to endothelial dysfunction in CHF. Vitamin C ameliorates endothelial dysfunction in CHF, presumably by reducing oxidative stress, but this is unproven. METHODS: We studied 55 patients with CHF (ischemic and nonischemic etiologies) and 15 control subjects. Flow-mediated dilation (FMD) in the brachial artery was measured by ultrasound wall-tracking, neutrophil superoxide anion (O2-) generation by lucigenin-enhanced chemiluminescence and oxidative stress by measurement of free radicals (FRs) in venous blood using electron paramagnetic resonance (EPR) spectroscopy and plasma thiobarbituric acid reactive substances (TBARS). Measurements were performed at baseline in all subjects. The effects of short-term (intravenous) and long-term (oral) vitamin C therapy versus placebo were tested in patients with nonischemic CHF. RESULTS: At baseline, FRs were higher in patients with CHF than in control subjects (p < 0.01), TBARS were greater (p < 0.005), neutrophil O2- -generating capacity was enhanced (p < 0.005) and FMD was lower (p < 0.0001). Compared with placebo, short-term vitamin C therapy reduced FR levels (p < 0.05), tended to reduce TBARS and increased FMD (p < 0.05), but did not affect neutrophil O2- -generating capacity. Long-term vitamin C therapy reduced FR levels (p < 0.05), reduced TBARS (p < 0.05) and improved FMD (p < 0.05), but also reduced neutrophil O2- -generating capacity (p < 0.05). Endothelial dysfunction was not related to oxidative stress, and improvements in FMD with vitamin C therapy did not relate to reductions in oxidative stress. CONCLUSIONS: Oxidative stress is increased in ischemic and nonischemic CHF, and neutrophils may be an important cause. Vitamin C reduces oxidative stress, increases FMD and, when given long term, decreases neutrophil O2- generation, but the lack of a correlation between changes in endothelial function and oxidative stress with vitamin C implies possible additional non-antioxidant benefits of vitamin C.

Anions↗
PubMed2000

Structural evidence for evolution of the beta/alpha barrel scaffold by gene duplication and fusion.

The atomic structures of two proteins in the histidine biosynthesis pathway consist of beta/alpha barrels with a twofold repeat pattern. It is likely that these proteins evolved by twofold gene duplication and gene fusion from a common half-barrel ancestor. These ancestral domains are not visible as independent domains in the extant proteins but can be inferred from a combination of sequence and structural analysis. The detection of subdomain structures may be useful in efforts to search genome sequences for functionally and structurally related proteins.

Aldose-Ketose Isomerases↗
PubMed2000

[Long-term problems after kidney transplantations].

Allogenic kidney transplantation is a widely established treatment option for patients with end-stage renal disease to gain independency from dialysis and recovery of excretory and hormonal functions. Transplantation is superior to dialysis with respect to quality of life, morbidity and mortality. Improvements in one-year graft survival have become evident during the last decades, but long-term outcome is not yet satisfying. The most common form of late transplant failure is chronic rejection or chronic allograft nephropathy, and as a consequence of higher ages of transplant recipients death of patients with functioning grafts. The histological hallmark of chronic rejection is intimal thickening of small arteries and arterioles, but the involved pathomechanisms are not well understood. Strict normalization of blood pressure and hyperlipidemia by drugs aims to prevent vascular alterations of chronic allograft nephropathy. In addition, in this overview some other late complications of renal transplant recipients are addressed which are associated to chronic immunosuppression, such as viral or malignant diseases.

Age Factors↗
PubMed2000

Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation.

The crystal structure of a constitutively active multiple site mutant of plasminogen activator inhibitor 1 (PAI-1) was determined and refined at a resolution of 2.7 A. The present structure comprises a dimer of two crystallographically independent PAI-1 molecules that pack by association of the residues P6 to P3 of the reactive centre loop of one molecule (A) with the edge of the main beta-sheet A of the other molecule (B).Thus, the reactive centre loop is ordered for molecule A by crystal packing forces, while for molecule B it is unconstrained by crystal packing contacts and is disordered. The overall structure of active PAI-1 is similar to the structures of other active inhibitory serpins exhibiting as the major secondary structural feature a five-stranded beta-sheet A and an intact proteinase-binding loop protruding from the one end of the elongated molecule. No preinsertion of the reactive centre loop is observed in this structure.A comparison of the present structure with the previously determined crystal structures of PAI-1 in its alternative conformations reveals that, upon cleavage of an intact form of PAI-1 or formation of latent PAI-1, the well-characterised rearrangements of the serpin secondary structural elements are accompanied by dramatic and partly unexpected conformational changes of helical and loop structures proximal to beta-sheet A. The present structure explains the stabilising effects of the mutated residues, reveals the structural cause for the observed spectroscopic differences between active and latent PAI-1, and provides new insights into possible mechanisms of stabilisation by its natural binding partner, vitronectin.

Amino Acid Sequence↗
PubMed2000

Coronary microvascular endothelial cell redox state in left ventricular hypertrophy : the role of angiotensin II.

Left ventricular hypertrophy (LVH) is associated with elevated plasma angiotensin II (Ang II) levels and endothelial dysfunction. The relationship between Ang II and endothelial dysfunction remains unknown, however, but it may involve an alteration in endothelial cell redox state. We therefore investigated the effect of Ang II on NADH/NADPH oxidase-mediated superoxide anion (O(2)(-)) production by cultured guinea pig coronary microvascular endothelial cells (CMVEs) and CMVEs freshly isolated from a guinea pig, pressure-overload model of LVH. Lucigenin chemiluminescence was used to measure O(2)(-) production in the particulate fraction of CMVE lysates. In cultured cells, incubation with Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) resulted in significant (P<0.01) increases in both NADH- and NADPH-dependent O(2)(-) production, with a peak effect at 1 nmol/L. The latter was significantly (P<0.01) inhibited by the AT(1) receptor antagonist losartan (1 micromol/L for 18 hours). In contrast, the O(2)(-) response to Ang II (0.1 nmol/L to 1 micromol/L for 18 hours) was largely unaffected by concomitant exposure to the AT(2) antagonist PD 123319 (1 micromol/L). In freshly isolated CMVEs from nonoperated animals, NADH- and NADPH-dependent O(2)(-) production was not different from that in sham-operated animals but was significantly (P<0.05) elevated in the aortic-banded animals. Plasma Ang II levels were significantly (P<0.001) elevated in the aortic-banded (1.25+/-0.12 microg/L, n=12) compared with sham-operated animals (0.63+/-0.06 microg/L, n=12). These data suggest that the endothelial dysfunction associated with LVH may be due, at least in part, to the Ang II-induced upregulation of NADH/NADPH oxidase-dependent O(2)(-) production.

Angiotensin II↗
PubMed2000

Expression of CHL1 and L1 by neurons and glia following sciatic nerve and dorsal root injury.

Cell adhesion molecules (CAMs), particularly L1, are important for axonal growth on Schwann cells in vitro. We have used in situ hybridization to study the expression of mRNAs for L1 and its close homologue CHL1, by neurons regenerating their axons in vivo, and have compared CAM expression with that of GAP-43. Adult rat sciatic nerves were crushed (allowing functional regeneration), or cut and ligated to maintain axonal sprouting but prevent reconnection with targets. In other animals lumbar dorsal roots were transected to produce slow regeneration of the central axons of sensory neurons. In unoperated animals L1 and CHL1 mRNAs were expressed at moderate levels by small- to medium-sized sensory neurons and L1 mRNA was expressed at moderate levels by motor neurons. Many large sensory neurons expressed neither L1 nor CHL1 mRNAs and motor neurons expressed little or no CHL1 mRNA. Neither motor nor sensory neurons showed any obvious upregulation of L1 mRNA after axotomy. Increased CHL1 mRNA was found in motor neurons and small- to medium-sized sensory neurons 3 days to 2 weeks following sciatic nerve crush, declining toward control levels by 5 weeks when regeneration was complete. Cut and ligation injuries caused a prolonged upregulation of CHL1 mRNA (and GAP-43 mRNA), indicating that reconnection with target tissues may be required to signal the return to control levels. Large sensory neurons did not upregulate CHL1 mRNA after axotomy and thus regenerated within the sciatic nerve without producing CHL1 or L1. Dorsal root injuries caused a modest, slow upregulation of CHL1 mRNA by some sensory neurons. CHL1 mRNA was also upregulated by many presumptive Schwann cells in injured nerves and by some satellite cells around large sensory neurons after sciatic nerve injuries and was transiently upregulated by some astrocytes in the degenerating dorsal columns after dorsal rhizotomy.

Animals↗
PubMed2000

Directed evolution of an enantioselective lipase.

BACKGROUND: The biocatalytic production of enantiopure compounds is of steadily increasing importance to the chemical and biotechnological industry. In most cases, however, it is impossible to identify an enzyme that possesses the desired enantioselectivity. Therefore, there is a strong need to create by molecular biological methods novel enzymes which display high enantioselectivity. RESULTS: A bacterial lipase from Pseudomonas aeruginosa (PAL) was evolved to catalyze with high enantioselectivity the hydrolysis of the chiral model substrate 2-methyldecanoic acid p-nitrophenyl ester. Successive rounds of random mutagenesis by ep-PCR and saturation mutagenesis resulted in an increase in enantioselectivity from E=1.1 for the wild-type enzyme to E=25.8 for the best variant which carried five amino acid substitutions. The recently solved three-dimensional structure of PAL allowed us to analyze the structural consequences of these substitutions. CONCLUSIONS: A highly enantioselective lipase was created by increasing the flexibility of distinct loops of the enzyme. Our results demonstrate that enantioselective enzymes can be created by directed evolution, thereby opening up a large area of novel applications in biotechnology.

Amino Acid Sequence↗
PubMed2000

Effects of low-dose aspirin on uterine and fetal blood flow during pregnancy: results of a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: This study was conducted to evaluate uteroplacental and fetal hemodynamics in fetuses exposed to low-dose aspirin (100 mg/d). DESIGN: Randomized, placebo-controlled, double-blind trial. SUBJECTS: The study protocol included singleton pregnancies of less than 20 gestational weeks at risk for pre-eclampsia or fetal growth restriction. Exclusion criteria were diabetes mellitus, pre-existing proteinuric hypertension or fetal malformations. Forty-three pregnant women were randomly allocated to daily treatment with 100 mg aspirin (n = 22) or placebo (n = 21). METHODS: Pulsed Doppler measurements of the uterine artery, fetal middle cerebral artery, fetal aorta, ductus arteriosus and atrioventricular valves were performed longitudinally at 14 day intervals starting from 18 gestational weeks until delivery. Results were expressed as group medians (aspirin vs. placebo) and were analyzed by Mann-Whitney U-test. RESULTS: There was no difference in uterine, umbilical, aortic, middle cerebral and ductus arteriosus blood flow between the aspirin group and controls. Median ductal peak flow velocities increased with gestational age in both groups, but differences between groups did not reach significance. In the third trimester of pregnancy, ductal peak velocities > 140 cm/s were occasionally observed in both groups. However, end diastolic velocities > 35 cm/s or atrioventricular valve regurgitation never occurred. CONCLUSIONS: Daily administration of low-dose aspirin during the second and third trimesters of pregnancy does not alter uteroplacental or fetoplacental hemodynamics and does not cause moderate or severe constriction of the ductus arteriosus.

Anti-Inflammatory Agents, Non-Steroidal↗