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Biomedical subjects

L Wood

Publications and source records attributed to L Wood.

At least 37 records · Page 2Linked to original sources
PubMed2001

Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance.

Adipose tissue expresses tumor necrosis factor (TNF) and interleukin (IL)-6, which may cause obesity-related insulin resistance. We measured TNF and IL-6 expression in the adipose tissue of 50 lean and obese subjects without diabetes. Insulin sensitivity (S(I)) was determined by an intravenous glucose tolerance test with minimal-model analysis. When lean [body mass index (BMI) <25 kg/m(2)] and obese (BMI 30-40 kg/m(2)) subjects were compared, there was a 7.5-fold increase in TNF secretion (P < 0.05) from adipose tissue, and the TNF secretion was inversely related to S(I) (r = -0.42, P < 0.02). IL-6 was abundantly expressed by adipose tissue. In contrast to TNF, plasma (rather than adipose) IL-6 demonstrated the strongest relationship with obesity and insulin resistance. Plasma IL-6 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S(I) (r = -0.71, P < 0.001). To separate the effects of BMI from S(I), subjects who were discordant for S(I) were matched for BMI, age, and gender. By use of this approach, subjects with low S(I) demonstrated a 3.0-fold increased level of TNF secretion from adipose tissue and a 2.3-fold higher plasma IL-6 level (P < 0.05) compared with matched subjects with a high S(I). Plasma IL-6 was significantly associated with plasma nonesterified fatty acid levels (r = 0.49, P < 0.002). Thus the local expression of TNF and plasma IL-6 are higher in subjects with obesity-related insulin resistance.

Adipose Tissue↗
PubMed2001

Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D.

Lipids that are synthesized de novo in the epidermis, including fatty acids, oxysterols, 1,25-dihydroxyvitamin D(3), and farnesol, can regulate the differentiation of normal human keratinocytes (NHK). Cholesterol sulfate (CS), an epidermal lipid that is produced in the upper nucleated layers of the epidermis coincident with terminal differentiation, has been shown to play a role in the regulation of the late stages of keratinocyte differentiation, including formation of the cornified envelope. In the present study, we determined i) whether CS regulates involucrin (INV), an early keratinocyte differentiation marker, and ii) the mechanism by which CS regulates differentiation. mRNA and protein levels of INV, a precursor protein of the cornified envelope, increased 2- to 3-fold in NHK incubated in the presence of CS. In contrast, cholesterol had no effect on INV protein or mRNA levels. Transcriptional regulation was assessed in NHK transfected with INV promoter-luciferase constructs. CS increased luciferase reporter activity approximately 2- to 3-fold in NHK transfected with a 3.7-kb INV promoter construct. Deletional analysis revealed a CS-responsive region of the INV promoter located between bp --2452 and --1880. A 5-base pair (bp) mutation of the AP-1 site (bp --2117 to --2111) within this responsive region abolished CS responsiveness, suggesting a role for the AP-1 complex in the regulation of INV transcription by CS. Electrophoretic mobility shift analysis demonstrated increased binding of nuclear extracts isolated from CS-treated NHK to AP-1 DNA as compared with vehicle-treated controls. Incubation of the nuclear extract with the appropriate antibodies showed that the AP-1 DNA-binding complex contained Fra-1, Fra-2, and Jun D. Western blots demonstrated that CS treatment increased the levels of Fra-1, Fra-2, and Jun D, and Northern analyses revealed that CS increased mRNA levels for these same AP-1 factors. These data indicate that CS, an endogenous lipid synthesized by keratinocytes, regulates the early stages of keratinocyte differentiation, and may do so through its ability to modulate levels of AP-1 proteins. -- Hanley, K., L. Wood, D. C. Ng, S. S. He, P. Lau, A. Moser, P. M. Elias, D. D. Bikle, M. L. Williams, and K. R. Feingold. Cholesterol sulfate stimulates involucrin transcription in keratinocytes by increasing Fra-1, Fra-2, and Jun D. J. Lipid Res. 2001. 42: 390--398.

Binding Sites↗
PubMed2000

Soluble urokinase receptor promotes cell adhesion and requires tyrosine-92 for activation of p56/59(hck).

The urokinase plasminogen activator receptor (uPAR) plays an important role in the migration of leukocytes. It occurs as a membrane-bound form that contains a glycosylphosphatidylinositol (GPI) anchor and also as a soluble form (suPAR) that lacks the GPI anchor. Recently, a sequence of amino acids, SRSRYLE, within the receptor has been found to become unmasked on uPA binding or chymotrypsin cleavage. Exposure of the epitope results in the activation of p56/p59(hck) kinase and chemotaxis of myelomonocytic cells. Using an epitope-tagged suPAR molecule, we found that both three-domain and two-domain suPAR promote the adhesion of differentiated THP-1 cells to fibronectin and vitronectin, indicating that suPAR can modify cell adhesion as well as cell migration. In addition, we found that the amino acid sequence RYLE, within the chemotactic peptide, is conserved across species and that alanine substitution of Tyr 92 decreased the ability of the peptide to activate p56/59(hck).

Amino Acid Sequence↗
PubMed2000

Identification of a novel human BCL-X promoter and exon.

BCL-XL is a key anti-apoptotic BCL-2 family protein that is widely expressed in human cancer cells and is induced in response to diverse survival signals. The translation initiation codon for BCL-XL is located in BCL-X exon II and previous analyses have indicated that BCL-XL RNAs initiate close to the start of exon II or additionally contain a non-coding first exon (exon IA) spliced to exon II. Using 5' RACE we have now identified a novel BCL-X non-coding exon (exon IB) which is spliced directly to exon II in place of exon IA. Exon IB-containing RNAs encoded BCL-XL and were detected in non-malignant lymphocytes and lymphoma cells from lymph node biopsies and were expressed at significant levels in cell lines derived from ovarian, colon and breast cancers. We identified two TATA-box sequences upstream of exon IB and demonstrated that surrounding genomic sequences contained strong promoter activity in lymphoma cells (approximately 300-fold active relative to controls). We have therefore identified a powerful new BCL-X promoter and a novel exon that contributes to BCL-XL expression.

Base Sequence↗
PubMed2000

Accuracy of assessment of pregnancy duration by women seeking early abortions.

BACKGROUND: Advances in medical abortion might allow women seeking early abortions to terminate their pregnancies safely and effectively without medical supervision. We investigated whether such women can calculate pregnancy duration accurately, a key step in unsupervised use. METHODS: 422 women seeking first-trimester abortions in two clinics (Pune, India, and Atlanta, USA) used a simple worksheet and calendar to calculate the duration of gestation from the date of last menstrual period (LMP) and/or of unprotected intercourse. Clinicians then used standard clinic practices to estimate pregnancy duration. We compared the two sets of estimates, focusing on women who fell into the "caution zone" (ie, had pregnancy durations >8 weeks according to providers, but < or =8 weeks by their own estimates). FINDINGS: The participants were generally representative of the women seeking abortion at the two clinics. 217 (97.7%) of 222 women in Atlanta and 173 (86.5%) of 200 in Pune could produce an estimate of pregnancy duration. Most (85.4% in Atlanta; 93.6% in Pune) of these estimates were within 2 weeks of those made by providers. For estimates based on LMP, only 10.0% (exact 95% CI 6.2-15.0) of women in Atlanta and 9.8% (5.8-15.3) in Pune fell into the caution zone. For estimates based on a date of intercourse, just 7.7% (4.0-13.1) of women in Atlanta and 3.4% (0-17.8) in Pune fell into the caution zone, although fewer women could use this method. INTERPRETATION: The vast majority of women seeking first-trimester abortion in this study could accurately calculate pregnancy duration within a margin of error clinically inconsequential for safe use of unsupervised medical abortion.

Abortion Applicants↗
PubMed2000

A phase II pharmacodynamic study of pyrazoloacridine in patients with metastatic colorectal cancer.

PURPOSE: To perform a phase II trial of pyrazoloacridine (PZA), a novel DNA intercalator, in patients with metastatic colorectal carcinoma and no previous therapy. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 h every 21 days. Pharmacokinetic studies to determine PZA plasma concentrations were performed. RESULTS: No responses were seen in 14 response-evaluable patients. Patients received a median of two cycles of PZA (range 1-6). Toxicity included neutropenia and neurologic side-effects, which were > or = grade III in 73% and 14%, respectively. High plasma concentrations of PZA (Cmax) correlated with low neutrophil counts (P = 0.04). CONCLUSIONS: PZA is inactive at this dose and schedule in colorectal cancer, and produces moderately severe toxicity.

Acridines↗
PubMed2000

The treatment of isolated ulnar fractures in adults: a systematic review.

The treatment of isolated ulnar fractures remains controversial, with different authors recommending both surgical and non-surgical management. We undertook a systematic review of the current literature in order to assess whether any conclusions can be drawn. A total of 33 series involving 1876 patients were identified as suitable for analysis. Data from these papers were combined by method of treatment. The results of the non-operative treatment of minimally displaced ulnar fractures with a stable configuration were uniformly good. Below elbow plaster cast, functional brace and early mobilisation all produced similar results. An above elbow cast was unnecessarily restrictive. To preserve forearm rotation, widely displaced or unstable fractures are best treated by open reduction and internal fixation. Guidelines based on cadaveric and clinical studies exist to predict fracture stability and the extent of acceptable displacement. However, these have not been verified in clinical studies. Compression plate fixation gave reliable results in these cases. Other methods lacked sufficient published data to be recommended.

Adult↗
PubMed2000

A phase II trial of triamcinolone hexacetanide for symptomatic recurrent malignant ascites.

Ascites is a common complication of advanced cancer and frequently requires paracentesis to reduce symptoms of pain, anorexia, and dyspnea. For many patients repeat paracenteses are required at short intervals. We prospectively studied 15 patients with recurrent ascites of malignancy to determine if intraperitoneal triamcinolone hexacetonide, a slowly metabolized corticosteroid, produced objective and symptomatic responses. After biochemical, radiological, and symptom assessment and the establishment of the interval between paracenteses, patients underwent large-volume paracentesis followed by intraperitoneal triamcinolone hexacetonide 10 mg/kg. Patients were followed after treatment for assessment of symptoms and physical signs of ascites. Repeat paracentesis was performed when symptomatic ascites recurred. Symptomatic ascites recurred in 13 of 15 patients, but the interval between paracenteses was extended from 9.5 +/- 1.6 days to 17.5 days (P = 0.0086). Symptom questionnaire scores assessing well-being, nausea, abdominal pain, dyspnea, appetite, appearance, and change in abdominal size on a scale from 0 to 6 averaged 3.2 +/- 0.3 at entry and 2.5 +/- 0.2 at the 2-week assessment (P = 0.026). Self-assessed symptoms, feeling of well-being, abdominal distention, and physical appearance improved significantly. The mean serum cortisol decreased from baseline, suggesting that some systemic corticosteroid absorption occurred. Thirteen of 15 patients have died, with a median survival of 42 days. Potential adverse effects included 1 episode each of transient abdominal pain, bacterial peritonitis, and localized herpes zoster infection. In patients with ascites of malignancy, intraperitoneal triamcinolone hexacetonide appears to postpone the requirement for repeat paracentesis and improve symptoms of malignant ascites.

Adult↗
PubMed2000

Preliminary evidence for impaired estrogen receptor-alpha protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis.

Although osteoporosis is usually associated with women, 1 in 12 men in the UK have the disease, and a third of these cases are idiopathic. Estrogen is now known to be associated with bone loss in older men, but we found, previously, that levels of this hormone were normal in younger cases of male idiopathic osteoporosis (MIO) in the age range 33-61 years. We therefore hypothesized that their estrogen responses in bone might be defective, through impaired estrogen receptor-alpha (ER)-alpha expression. Consequently, in the present study, we compared expression of ER-alpha by indirect immunofluorescence, semiquantitative image analysis, and in situ reverse transcription-polymerase chain reaction in bone sections from MIO patients (33-56 years) (N = 7); age-matched control men (N = 7); and, for reference, ovarian steroid (OS)-replete (N = 7) and OS-deficient women (N = 6). In the control men, 23 +/- 6% (mean +/- SEM) of osteoblasts and 14 +/- 2% of osteocytes expressed ER-alpha protein, similar to OS-replete women. Although receptor expression decreased in OS-deficient women, the loss of ER-alpha protein in MIO patients was more severe (1 +/- 0.5% osteocytes, 2 +/- 1% osteoblasts expressed receptor); however, ER-alpha messenger RNA (mRNA) was still expressed in controls and MIO patients. Bone loss in these patients may be due to deficient ER-alpha protein expression.

Adult↗
PubMed2000

CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells.

Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic bone marrow transplantation, but can be avoided by removing T lymphocytes from the donor bone marrow. However, T cell depletion increases the risk of graft rejection. In this study, two strategies are used to overcome rejection: (1) use of high doses of stem cells obtained from peripheral blood (PBSC), (2) admixture with a CD52 monoclonal antibody in order to deplete both donor and residual recipient lymphocytes. Two antibodies are compared: CAMPATH-1G (rat IgG2b) and its humanized equivalent CAMPATH-1H (human IgG1). A total of 187 consecutive patients at six centers received PBSC transplants from HLA-matched siblings between 1997 and 1999. A wide spectrum of diseases, both malignant and non-malignant, was included. The recovery of CD34+ cells after antibody treatment was close to 100%. The risk of acute GVHD (grade 2 to 4) was 11% in the CAMPATH-1G group and 4% in the CAMPATH-1H group (P = NS). The risk of chronic GVHD (any grade) was 11% in the CAMPATH-1G group and 24% in the CAMPATH-1H group (P = 0.03) but the risk of extensive chronic GVHD was only 2%. The overall risk of graft failure/rejection was 2%, not significantly different between the two antibodies. Antibody treatment was equally effective at concentrations between 10 microg/ml and 120 microg/ml and it made no significant difference to the outcome whether the patients received post-transplant immunosuppression or not (87% did not). Transplant-related mortality in this heterogenous group of patients (including high-risk and advanced disease) was 22% at 12 months. It is proposed that treatment of peripheral blood stem cells with CAMPATH-1H is a simple and effective method for depleting T cells which may be applicable to both autologous and allogeneic transplants from related or unrelated donors. Special advantages of this approach are the simultaneous depletion of donor B cells (which reduces the risk of EBV-associated lymphoproliferative disease) and the concomitant infusion of CAMPATH-1H to deplete residual recipient T cells and thus prevent graft rejection.

Alemtuzumab↗
PubMed2000

Tumor necrosis factor alpha can contribute to focal loss of cartilage in osteoarthritis.

UNLABELLED: OBJECTIVE; To evaluate the potential for tumor necrosis factor alpha (TNFalpha)-induced focal loss of cartilage in osteoarthritic (OA) knee joints. DESIGN: Fresh cartilage from specified regions of OA joints was immunostained for TNF-receptor (R) bearing chondrocytes. Cartilage explants from the same regions were cultured with or without small amounts of TNFalpha and cumulative GAG release into supernatants measured. Concentrations of TNFalpha, p55 and p75 soluble (s) TNF-R in supernatants from cultured OA and non-arthritic (NA) synovium were measured by ELISA. RESULTS: TNF-R bearing chondrocytes were identified in OA cartilage; more specimens contained p55 TNF-R- than p75 TNF-R-bearing chondrocytes and differences in TNF-R distribution were apparent in cartilage from different regions of the same knees. TNFalpha at 5, 1, 0.5 and 0.25 ng/ml (but not 0.1 ng/ml) significantly increased glycosaminoglycans (GAG) release from cartilage explants in a dose-dependent manner. Variation in susceptibility to TNFalpha was observed in explants from different sites. TNFalpha and p75 sTNF-R, but not p55 sTNF-R, concentrations were significantly higher in OA, as compared with NA, supernatants. A significant correlation between TNFalpha and p75 sTNF-R measurements was apparent only in NA supernatants. CONCLUSIONS: Variations in chondrocyte TNF-R expression occur in OA cartilage in vivo. TNFalpha at concentrations produced by OA synovium in vitro, can degrade cartilage matrix. In most OA supernatants sTNF-R concentrations were insufficient to abrogate the effects of TNFalpha. Thus conditions exist in some OA knees for TNFalpha to contribute to focal loss of cartilage.

Aged↗
PubMed2000

Esophageal candidiasis in pediatric acquired immunodeficiency syndrome: clinical manifestations and risk factors.

BACKGROUND: Little is known about the epidemiology and clinical features of esophageal candidiasis (EC) in pediatric AIDS. We therefore investigated the clinical presentation and risk factors of EC in a large prospectively monitored population of HIV-infected children at the National Cancer Institute. PATIENTS AND METHODS: We reviewed the records of all HIV-infected children (N = 448) followed between 1987 and 1995 for a history of esophageal candidiasis to characterize the epidemiology, clinical features, therapeutic interventions and outcome of esophageal candidiasis. To understand further the risk factors for EC in pediatric AIDS, we then performed a matched case-control analysis of 25 patients for whom control cases were available. RESULTS: There were 51 episodes of EC documented in 36 patients with 23 male and 13 female patients (0.2 to 17 years; median CD4, count 11/microl), representing a frequency of EC of 8.0%. Concurrent oropharyngeal candidiasis (OPC) was the most common clinical presentation of EC (94%); other signs and symptoms included odynophagia (80%), retrosternal pain (57%), fever (29%), nausea/vomiting (24%), drooling (12%), dehydration (12%), hoarseness (6%) and upper gastrointestinal bleeding (6%). The causative organism documented in 36 episodes (18 from OPC, 17 from endoscopic biopsy and 1 from autopsy) was Candida albicans in all cases. Patients received treatment for EC with amphotericin B (63%), fluconazole (29%), ketoconazole (4%) or itraconazole (1%). A clinical response was documented in all 45 evaluable episodes. In 6 other cases, EC was a final event without contributing to the cause of death. By a conditional logistic regression model for matched data, the best predictor of EC was the presence of prior OPC (P<0.0001), followed by CD4 count and CD4 percentage (P = 0.0002) and use of antibacterial antibiotics (P = 0.0013). The risks associated with low CD4 count were independent of that of prior OPC. CONCLUSION: EC in pediatric AIDS is a debilitating infection, which develops in the setting of prior OPC, low CD4 counts and previous antibiotics.

AIDS-Related Opportunistic Infections↗
PubMed2000

Emergence of resistance of Candida albicans to clotrimazole in human immunodeficiency virus-infected children: in vitro and clinical correlations.

Oropharyngeal candidiasis (OPC) is a common opportunistic infection in human immunodeficiency virus (HIV)-infected patients and other immunocompromised hosts. Clotrimazole troches are widely used in the treatment of mucosal candidiasis. However, little is known about the potential contribution of clotrimazole resistance to the development of refractory mucosal candidiasis. We therefore investigated the potential emergence of resistance to clotrimazole in a prospectively monitored HIV-infected pediatric population receiving this azole. Adapting the National Committee for Clinical Laboratory Standards M27-A reference method for broth antifungal susceptibility testing of yeasts to clotrimazole, we compared MICs in macrodilution and microdilution assays. We further analyzed the correlation between these in vitro findings and the clinical response to antifungal therapy. One isolate from each of 87 HIV-infected children was studied by the macrodilution and microdilution methods. Two inoculum sizes were tested by the macrodilution method (10(3) and 10(4) CFU/ml) in order to assess the effect of inoculum size on clotrimazole MICs. The same isolates also were tested using a noncolorimetric microdilution method. Clotrimazole concentrations ranged from 0.03 to 16 microg/ml. Readings were performed after incubation for 24 and 48 h at 35 degrees C. For 62 (71.2%) of 87 clinical isolates, the MICs were low (< or =0.06 microg/ml). The MIC for 90% of the strains tested was 0.5 microg/ml, and the highest MIC was 8 microg/ml. There was no significant difference between MICs at the two inoculum sizes. There was 89% agreement (+/-1 tube) between the microdilution method at 24 h and the macrodilution method at 48 h. If the MIC of clotrimazole for an isolate of C. albicans was > or =0.5 microg/ml, there was a significant risk (P < 0.001) of cross-resistance to other azoles: fluconazole, > or = 8 microg/ml (relative risk [RR] = 8.9); itraconazole, > or =1 microg/ml (RR = 10). Resistance to clotrimazole was highly associated with clinically overt failure of antifungal azole therapy. Six (40%) of 15 patients for whom the clotrimazole MIC was > or =0.5 microg/ml required amphotericin B for refractory mucosal candidiasis versus 4 (5.5%) of 72 for whom the MIC was <0.5 microg/ml (P = 0.001; 95% confidence interval = 2.3 to 22; RR = 7.2). These findings suggest that an interpretive breakpoint of 0.5 microg/ml may be useful in defining clotrimazole resistance in C. albicans. The clinical laboratory's ability to determine MICs of clotrimazole may help to distinguish microbiologic resistance from the other causes of refractory OPC, possibly reducing the usage of systemic antifungal agents. We conclude that resistance to clotrimazole develops in isolates of C. albicans from HIV-infected children, that cross-resistance to other azoles may develop concomitantly, and that this resistance correlates with refractory mucosal candidiasis.

AIDS-Related Opportunistic Infections↗
PubMed2000

Appropriate insulin regimes for type 2 diabetes: a multicenter randomized crossover study.

OBJECTIVE: To directly compare the rate of hypoglycemia and metabolic control achieved on once-daily ultralente insulin administration with twice-daily NPH insulin administration in patients with type 2 diabetes. Patient treatment satisfaction and quality of life were also examined before and during each treatment. RESEARCH DESIGN AND METHODS: A crossover study was performed involving five centers and 79 patients with type 2 diabetes (fasting blood glucose > 8 mmol/l) with a 2-month run-in followed by two 6-month periods of either NPH or ultralente insulin administration. Patients were managed by a specialist nurse using a dosage adjustment protocol. RESULTS: HbA1c was lower with NPH insulin therapy during each of the 6-month periods (9.7 +/- 0.2 vs. 9.1 +/- 0.3 and 9.8 +/- 0.2 vs. 9.0 +/- 0.3 mmol/l; both P < 0.01). The difference was accounted for by higher evening glucose levels with ultralente insulin (fasting 8.2 +/- 0.3 vs. 8.2 +/- 0.3 mmol/l, 6:00 P.M. 11.5 +/- 0.4 vs. 10.6 +/- 0.4 mmol/l). Despite worse control, the total number of hypoglycemic episodes was greater with ultralente insulin (220 vs. 171), and hypoglycemic episodes requiring third-party assistance occurred almost entirely with ultralente (14 vs. 1). Treatment satisfaction scores increased more with NPH insulin compared with ultralente and rose further upon changing to NPH insulin, but fell upon changing to ultralente insulin. These changes were highly significant (P < 0.001). Diabetes quality of life improved on both regimens. CONCLUSIONS: These data clearly demonstrate the lower hypoglycemia rate, better glucose control, and greater treatment satisfaction accompanying therapy for type 2 diabetes with twice daily NPH compared with once daily ultralente insulin.

Blood Glucose↗
PubMed2000

Cyclophosphamide and carboplatin and selective consolidation in advanced seminoma.

This prospective Phase II study assesses the clinical efficacy and complications of a treatment regimen of combination chemotherapy with cyclophosphamide and carboplatin and selective consolidation in advanced seminoma. Of 46 patients who entered the study between December 1992 and October 1998, 46 were evaluable. Thirty-two achieved a complete remission (70%; 95% confidence interval, 56-83%) after chemotherapy alone. Fourteen achieved a complete remission (30%; 95% confidence interval, 18-46%) after chemotherapy plus consolidation. Forty-three of the 46 patients (93%; 95% confidence interval, 82-97%) remained in remission after a median follow-up period of 27.4 months. No patient experienced nephrotoxic, neurotoxic, or ototoxic effects or hemorrhagic cystitis. No patient had neutropenic fever requiring hospitalization. Thirteen % required platelet transfusions, and 9% required transfusions of packed RBCs. For patients with advanced seminoma, treatment with cyclophosphamide and carboplatin and selective consolidation is safe and effective.

Adolescent↗