DNA microarrays and combinatorial chemical libraries: tools for the drug discovery pipeline.
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Antitubercular Agents↗
Biomedical subjects
R Lee
Publications and source records attributed to R Lee.
The neuropsychological effects of electrical injury. New insights.
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Adult↗
Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial.
BACKGROUND: Oxidative stress has been implicated in the pathophysiology of pre-eclampsia. This randomised controlled trial investigated the effect of supplementation with vitamins C and E in women at increased risk of the disorder on plasma markers of vascular endothelial activation and placental insufficiency and the occurrence of pre-eclampsia. METHODS: 283 women were identified as being at increased risk of pre-eclampsia by abnormal two-stage uterine-artery doppler analysis or a previous history of the disorder and were randomly assigned vitamin C (1000 mg/day) and vitamin E (400 IU/day) or placebo at 16-22 weeks' gestation. Plasma markers of endothelial activation (plasminogen-activator inhibitor 1 [PAI-1]) and placental dysfunction (PAI-2) were measured every month until delivery. Pre-eclampsia was assessed by the development of proteinuric hypertension. Analyses were done by intention to treat, and in the cohort who completed the study. FINDINGS: Supplementation with vitamins C and E was associated with a 21% decrease in the PAI-1/PAI-2 ratio during gestation (95% CI 4-35, p=0.015). In the intention-to-treat cohort, pre-eclampsia occurred in 24 (17%) of 142 women in the placebo group and 11 (8%) of 141 in the vitamin group (adjusted odds ratio 0.39 [0.17-0.90], p=0.02). In the cohort who completed the study (81 placebo group, 79 vitamin group), the odds ratio for pre-eclampsia was 0.24 (0.08-0.70, p=0.002). INTERPRETATION: Supplementation with vitamins C and E may be beneficial in the prevention of pre-eclampsia in women at increased risk of the disease. Multicentre trials are needed to show whether vitamin supplementation affects the occurrence of pre-eclampsia in low-risk women and to confirm our results in larger groups of high-risk women from different populations.
Adult↗
Induction of MHC class I expression on immature thymocytes in HIV-1-infected SCID-hu Thy/Liv mice: evidence of indirect mechanisms.
The SCID-hu Thy/Liv mouse and human fetal thymic organ culture (HF-TOC) models have been used to explore the pathophysiologic mechanisms of HIV-1 infection in the thymus. We report here that HIV-1 infection of the SCID-hu Thy/Liv mouse leads to the induction of MHC class I (MHCI) expression on CD4+CD8+ (DP) thymocytes, which normally express low levels of MHCI. Induction of MHCI on DP thymocytes in HIV-1-infected Thy/Liv organs precedes their depletion and correlates with the pathogenic activity of the HIV-1 isolates. Both MHCI protein and mRNA are induced in thymocytes from HIV-1-infected Thy/Liv organs, indicating induction of MHCI gene expression. Indirect mechanisms are involved, because only a fraction (<10%) of the DP thymocytes were directly infected by HIV-1, although the majority of DP thymocytes are induced to express high levels of MHCI. We further demonstrate that IL-10 is induced in HIV-1-infected thymus organs. Similar HIV-1-mediated induction of MHCI expression was observed in HF-TOC assays. Exogenous IL-10 in HF-TOC induces MHCI expression on DP thymocytes. Therefore, HIV-1 infection of the thymus organ leads to induction of MHCI expression on immature thymocytes via indirect mechanisms involving IL-10. Overexpression of MHCI on DP thymocytes can interfere with thymocyte maturation and may contribute to HIV-1-induced thymocyte depletion.
Animals↗
Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence.
Mycobacterium ulcerans is the causative agent of Buruli ulcer, a severe human skin disease that occurs primarily in Africa and Australia. Infection with M. ulcerans results in persistent severe necrosis without an acute inflammatory response. The presence of histopathological changes distant from the site of infection suggested that pathogenesis might be toxin mediated. A polyketide-derived macrolide designated mycolactone was isolated that causes cytopathicity and cell cycle arrest in cultured L929 murine fibroblasts. Intradermal inoculation of purified toxin into guinea pigs produced a lesion similar to that of Buruli ulcer in humans. This toxin may represent one of a family of virulence factors associated with pathology in mycobacterial diseases such as leprosy and tuberculosis.
Animals↗
Radial approach: a new concept in surgical treatment for atrial fibrillation I. Concept, anatomic and physiologic bases and development of a procedure.
BACKGROUND: The maze procedure cures atrial fibrillation; however, it isolates the pulmonary vein area and results in discordant activation in certain adjacent left atrial segments, which affects left atrial function. To preserve a more physiologic atrial transport function, we developed a new concept of surgical treatment for atrial fibrillation-the radial approach. The atrial incisions radiate from the sinus node toward the atrioventricular annular margins to allow a more physiologic atrial activation sequence and parallel the atrial coronary arteries to preserve blood supply to most atrial segments. METHODS: We examined the atrial coronary arteries and the activation sequence during sinus rhythm in normal canine hearts to design the atrial incisions according to the concept of a radial approach. RESULTS: The pattern of coronary artery distribution was centripetal, branching from the right coronary or left circumflex coronary artery at the right or left atrioventricular groove and spreading toward the sinus node. The endocardial mapping of the atria disclosed some important findings in designing the atrial incisions of the radial approach: the activation sequence at the left atrial septum and at the posterior left atrium between the pulmonary vein orifices. The atrial incisions were designed according to these findings. CONCLUSIONS: The radial approach may represent a more physiologic atrial transport function.
Animals↗
Radial approach: a new concept in surgical treatment for atrial fibrillation. II. Electrophysiologic effects and atrial contribution to ventricular filling.
BACKGROUND: In a previous study the atrial incisions that follow the concept of the radial approach were designed according to the activation sequence during sinus rhythm and the atrial coronary artery anatomy in normal dogs. The purpose of the present study was to determine whether the radial approach provides a more physiologic activation sequence and atrial transport function than the maze procedure. METHODS: Ten dogs that had undergone the radial approach (n = 5) or the maze procedure (n = 5) were studied 6 weeks postoperatively. Sinus node function and inducibility of atrial fibrillation were examined before and after operation. The atria were mapped endocardially with 212 electrodes, and atrial activation sequences during sinus rhythm and right atrial pacing were examined. Atrial transport function was assessed by transepicardial Doppler echocardiography. RESULTS: No dogs developed sinus node dysfunction postoperatively. Both the radial approach and the maze procedure equally prevented sustained atrial fibrillation. The atrial activation sequence was more synchronous after the radial approach than after the maze procedure. There was no electrically isolated region after the radial approach. The total activation time of the left atrium was significantly shorter after the radial approach than after the maze procedure (53.6+/-9.8 versus 70.5+/-9.6 ms, p<0.05). The ratio of peak flow velocity of the E wave to the A wave (peak E/A) of the transmitral Doppler flow was significantly smaller after the radial approach than after the maze procedure (1.7+/-0.4 versus 3.5+/-1.7, p<0.05). The atrial filling fraction of the transmitral Doppler flow was significantly larger after the radial approach than after the maze procedure (29.9%+/-7.3% versus 14.8%+/-5.0%, p<0.01). There was no significant difference in peak E/A and atrial filling fraction of the transtricuspid Doppler flow between the two procedures. CONCLUSIONS: The radial approach provides a more synchronous activation sequence and atrial transport function, and thus may represent a more physiologic alternative to the maze procedure as a surgical treatment for atrial fibrillation.
Atrial Fibrillation↗
The closed heart MAZE: a nonbypass surgical technique.
BACKGROUND: The MAZE-III is the surgical treatment of choice for medically refractory atrial fibrillation. Although a number of nonsurgical techniques are evolving to duplicate the transmural atrial lesions of the MAZE-III, the surgical atriotomy remains the gold standard for conduction block. It was the objective of this study to surgically create the atrial incisions of the MAZE-III without the use of cardiopulmonary bypass. METHODS: A technique was developed to create and intersect the linear incisions of the MAZE-III on 10 beating canine hearts without the use of cardiopulmonary bypass using a "tunnel" of atrial tissue. The effectiveness of the procedure was tested by atrial burst pacing. RESULTS: This technique was successfully performed on 10 mongrel dogs without operative mortality. Preoperatively, sustained atrial fibrillation (>30 seconds) was induced in all animals. Postoperatively, all the animals remained in sinus rhythm even after burst pacing. CONCLUSIONS: In an experimental canine model, the MAZE-III can be performed on beating hearts without the assistance of cardiopulmonary bypass using a "tunnel" technique. This technique allows for the immediate assessment of electrophysiologic and mechanical function after the MAZE-III, or any other type of procedure using the "maze principle" and may find future application in the clinical arena.
Animals↗
The reliability of postural x-rays in measuring pelvic obliquity.
OBJECTIVE: To assess the interrater and intrarater reliability of two methods of measurement of postural radiographs for determining the amount of pelvic obliquity. DESIGN: Four blinded raters evaluated the amount of pelvic obliquity using two measurement methods. SETTING: Physical medicine and rehabilitation outpatient clinic in a VA hospital. PARTICIPANTS: Fifty-two randomly chosen radiographs from 36 patients referred to a clinic to evaluate and treat pelvic obliquity. MEASURES: Amount of pelvic obliquity was determined by line of eburnation and by the intersulcate line. Pearson's correlation coefficients and percent agreements were calculated for each set of measurements. RESULTS: Pearson's correlation coefficients and percent agreements were higher for both interrater and intrarater measurements for the intersulcate line. CONCLUSION: Intersulcate line is the more reliable method for determining the amount of pelvic obliquity and will be used in future studies to assess the effectiveness of correcting pelvic obliquity to improve chronic back pain.
Adult↗
Outcome of liver transplantation in hepatitis C virus-infected patients who received hepatitis C virus-infected grafts.
BACKGROUND & AIMS: The present organ shortage has brought into question the suitability of hepatitis C virus (HCV)-positive grafts. This study reviewed the outcome of such transplantations in our institution. METHODS: Twenty-three HCV-positive patients who underwent orthotopic liver transplantation (OLT) for end-stage liver disease with HCV-positive grafts in 1992-1995 were studied. Only patients who survived more than 30 days were included in the analysis. Control group included 169 patients who underwent transplantation for HCV-related cirrhosis and received HCV-negative organs. RESULTS: Patients who received HCV-infected organs had a cumulative survival rate of 89% and 72% at 1 and 5 years, respectively, vs. 88% and 73% for the control group (NS). There was no difference in graft survival, incidence of cirrhosis, mean hepatitis activity index score, fibrosis, or mean activity of serum transaminases. There was a trend toward lower incidence of recurrent hepatitis C in the study group compared with control (21% vs. 23% at 1 year and 47% vs. 64% at 5 years; NS). Patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival than patients who retained their own HCV strain (P < 0.003). CONCLUSIONS: HCV-infected livers transplanted into HCV-infected recipients do not appear to convey a worse outcome in the initial years after OLT than HCV-negative grafts.
Adult↗
Arthropod vaccines.
Antigens located in the midgut of the tick are hidden from the host's immune system. Egg production of ticks can be reduced when ticks are fed on animals vaccinated with midgut antigens of the tick, and a subunit vaccine formulated with the recombinant antigen Bm86 is now available that can reduce the number of ticks infesting cattle grazing on pasture. Midgut antigens used in vaccines against insects that transmit pathogenic organisms to humans have not been as effective in reducing insect fecundity and an alternative approach may be necessary. Transmission-blocking vaccines directed at interfering with the vector-pathogen interaction could result in loss of vector competence and block the spread of disease-causing organisms.
Animals↗
Protective role of nitric oxide in ischemia and reperfusion injury of the liver.
BACKGROUND: The suppressed production of nitric oxide (NO), associated with endothelial dysfunction, is thought to be a cause of ischemia and reperfusion injury of the liver. But findings of the salutary effects of NO enhancement on such injury have been conflicting. In this study, we tested our hypothesis that NO enhancement would attenuate ischemic liver injury. For this purpose, an NO precursor, L-arginine, and a novel NO donor, FK409, were applied to a 2-hour total hepatic vascular exclusion model in dogs. STUDY DESIGN: L-arginine was administered IV at a dose of 100 mg/kg twice (n = 5), while 300 mg/kg twice of FK409 was infused continuously into the portal vein (n = 5). The drugs were given to the animals for 30 and 60 minutes before and after ischemia, respectively. Non-treated animals were used as the control (n = 10). Two-week survival, systemic and hepatic hemodynamics indices, liver function tests, energy metabolism, and histopathology were analyzed. RESULTS: Both treatments comparably augmented hepatic tissue blood flow, decreased liver enzyme release, and increased high-energy phosphate restoration during the reperfusion period, all of which contributed to rescuing all of the treated animals from the 2-hour total hepatic ischemia. In contrast, ischemia caused 70% mortality in the control group. Histologically, structural abnormality and neutrophil infiltration were markedly attenuated by the treatments. Systemic hypotension was observed in the animals treated with FK409, however. CONCLUSIONS: Our data demonstrate that NO enhancement alleviates the liver injury caused by ischemia and reperfusion. The supplementation of L-arginine, rather than FK409, is considered more applicable to clinical use because of the absence of systemic adverse effects.
Adenine Nucleotides↗
High frequency of de novo deletions in Mexican Duchenne and Becker muscular dystrophy patients. Implications for genetic counseling.
Duchenne muscular dystrophy (DMD) is the most common lethal hereditary neuromuscular disease. As there is no effective treatment, accurate carrier detection is essential for genetic counseling and prevention. Although linkage analysis has been widely used for this purpose, being an indirect analysis it has several limitations. Using linkage analysis for carrier detection, we found serious limitations, mainly because 82.9% of all proposita were isolated cases. We used quantitative polymerase chain reaction for direct carrier detection in families with exon deletions and found a higher than expected frequency of de novo deletions (62.2%). Furthermore, only 20.7% of the mothers of isolated deletion DMD/Becker muscular dystrophy (BMD) patients were found to be carriers. This result suggests that the Mexican population has a high frequency of de novo DMD mutations.
Creatine Kinase↗
Enhanced anti-tumor effects with microencapsulated c-myc antisense oligonucleotide.
A phosphorothioate c-myc antisense oligonucleotide was complexed with zinc and encapsulated into injectable biodegradable microspheres. The efficacy of this novel formulation was compared with intravenous administration of the unencapsulated drug in human melanoma and leukemia xenografts in immunocompromised mice. The microencapsulated formulation was more effective as shown by reduced tumor growth, a decreased number of metastases, reduced c-myc expression, and increased survival in the melanoma model, and decreased metastatic potential and increased survival in the leukemia model. These results show that, as has been demonstrated previously with protein and peptide drugs, greater therapeutic efficacy can be obtained when antisense oligonucleotides are delivered from sustained-release formulations.
Animals↗
Relationship of peritoneal membrane transport characteristics to the nutritional status in CAPD patients.
BACKGROUND: The study was carried out to evaluate the role of individual peritoneal membrane transport characteristics in the nutritional status expressed as the composite nutritional index (CNI) METHODS: Cross-sectional analyses of the overall nutritional status of 147 continuous ambulatory peritoneal dialysis (CAPD) patients were performed using the CNI. CNIs based on a scoring system of 10 nutritional indices including subjective global assessment, biochemical parameters and anthropometry were compared according to the results of a standard peritoneal equilibration test (PET) RESULTS: Patients were classified as low (n = 16, 10.9%), low average (n=59, 40.2%), high average (n=54, 36.7%) and high (n=18, 12.2%) transporters based on the D/P(Cr) after 4 h dwells. The mean 4 h D/P(Cr) was 0.65 +/- 0.12 (0.34-0.95), and there was no significant correlation between D/P(Cr) and other demographic parameters such as age, duration of peritoneal dialysis and body surface area. D/P(Cr) was correlated with dialytic albumin loss (r=0.47, P<0.001), serum albumin (r=-0.46, P<0.001), serum creatinine (r= -0.38, P<0.001), serum TGF-1 (r=-0.37, P<0.01) and LBM(Cr) (r= -0.26, P<0.05). In high transporters, the serum albumin was significantly lower while dialysate protein and albumin losses were significantly greater compared with low transporters. Serum creatinine and IGF-1 concentrations as well as LBM(Cr) were also decreased in higher transporters. The mean CNI score was 8.1 +/- 4.9, with a range of 0-24. CNI was positively correlated with age, duration of peritoneal dialysis, incidence of peritonitis, CRP and dialytic protein loss, whereas it was inversely correlated with ultrafiltration volume, haemoglobin and NPNA. The CNI score was significantly higher in high transporters compared with low transporters (11.7 +/- 4.3 vs. 5.9 +/- 1.6, P < 0.01). There was also a significant correlation between D/P(Cr) and CNI (r = 0.29, P < 0.05). Multiple regression analysis revealed that the incidence of peritonitis, duration of CAPD, CRP and D/P(Cr) were the independent factors affecting the CNI. CONCLUSION: Peritoneal membrane transport characteristics correlate with the overall nutritional status of peritoneal dialysis patients assessed by the scoring system of the CNI, although it is associated with a different impact on the individual nutritional indices. The results of this cross-sectional study also suggest that a high permeability state is a risk factor for malnutrition in CAPD patients. Prospective studies evaluating the changes in nutritional parameters among patients with different membrane transport rates are needed to understand better the relationship of peritoneal membrane characteristics to the nutritional status of CAPD patients.
Biological Transport↗
Consistency of orthodontic treatment planning decisions.
OBJECTIVE: (i) To analyse the consistency of a group of orthodontists' treatment decisions and (ii) to identify factors that may influence this consistency. DESIGN: Cross-sectional observational study. SUBJECTS: Ten orthodontists. METHODS: The orthodontists examined 60 case vignettes and recorded their treatment decisions on two separate occasions. MAIN MEASURE: Inter- and intra-examiner agreement was evaluated with the Kappa statistic. RESULTS: The consistency within each orthodontist was moderate. However, between-orthodontist consistency was poor. CONCLUSION: It appears that there is marked variation between orthodontists in treatment planning decisions and this may reflect the lack of evidence for the effectiveness of competing treatments.
Adult↗
Malignant mixed mesodermal tumors of the ovary: preoperative diagnosis.
Early diagnosis of malignant mixed mesodermal tumors of the ovary is very difficult because of the rarity and the insidious onset. The purpose of this report is to review the magnetic resonance imaging features of an ovarian malignant mixed mesodermal tumor, which occurred in a 52-year-old woman, aiding in the differential diagnosis.
Chemotherapy, Adjuvant↗
A chimeric form of osteoprotegerin inhibits hypercalcemia and bone resorption induced by IL-1beta, TNF-alpha, PTH, PTHrP, and 1, 25(OH)2D3.
Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation and activity and appears to be a critical regulator of bone mass and metabolism. In the current study, mice were challenged with various cytokines and hormones (interleukin-1beta, tumor necrosis factor-alpha, parathyroid hormone, parathyroid hormone-related protein, and 1alpha,25-dihydroxyvitamin D3) that are known to increase bone resorption and cause hypercalcemia and treated concurrently with either a recombinant chimeric Fc fusion form of human OPG, with enhanced biological activity (cOPG) (2.5 mg/kg/day) or vehicle. Mice receiving these bone-resorbing factors became hypercalcemic by day 3 after commencing treatment and had increased bone resorption as evidenced by elevated osteoclast numbers on day 5. Concurrent cOPG treatment prevented hypercalcemia (p < 0.05) and maintained osteoclast numbers in the normal range (p < 0.001). The demonstration that cOPG can inhibit bone resorption suggests that this molecule may be useful in the treatment of diseases including hyperparathyroidism, humoral hypercalcemia of malignancy, osteoporosis, and inflammatory bone disease, which are characterized, in part, by increases in osteoclastic bone resorption.
Animals↗