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Biomedical subjects

L Burrows

Publications and source records attributed to L Burrows.

At least 19 recordsLinked to original sources
PubMed2003

Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma.

PURPOSE: To evaluate low-dose extended duration interferon alfa-2a as adjuvant therapy in patients with thick (> or = 4 mm) primary cutaneous melanoma and/or locoregional metastases. PATIENTS AND METHODS: In this randomized controlled trial involving 674 patients, the effect of interferon alfa-2a (3 megaunits three times per week for 2 years or until recurrence) on overall survival (OS) and recurrence-free survival (RFS) was compared with that of no further treatment in radically resected stage IIB and stage III cutaneous malignant melanoma. RESULTS: The OS and RFS rates at 5 years were 44% (SE, 2.6) and 32% (SE, 2.1), respectively. There was no significant difference in OS or RFS between the interferon-treated and control arms (odds ratio [OR], 0.94; 95% CI, 0.75 to 1.18; P =.6; and OR, 0.91; 95% CI, 0.75 to 1.10; P =.3; respectively). Male sex (P =.003) and regional lymph node involvement (P =.0009), but not age (P =.7), were statistically significant adverse features for OS. Subgroup analysis by disease stage, age, and sex did not show any clear differences between interferon-treated and control groups in either OS or RFS. Interferon-related toxicities were modest: grade 3 (and in only one case, grade 4) fatigue or mood disturbance was seen in 7% and 4% respectively, of patients. However, there were 50 withdrawals (15%) from interferon treatment due to toxicity. CONCLUSION: The results from this study, taken in isolation, do not indicate that extended-duration low-dose interferon is significantly better than observation alone in the initial treatment of completely resected high-risk malignant melanoma.

Adolescent↗
PubMed2001

The influence of acute rejection on long-term renal allograft survival: a comparison of living and cadaveric donor transplantation.

BACKGROUND: We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts. METHODS: A retrospective review was made of 296 renal transplantations performed at Mount Sinai Hospital. Only grafts functioning for at least 3 months were included in this analysis. Demographic variables of donor and recipient age, race, sex, and serum creatinine at 3 months after transplantation were compared between groups. RESULTS: Among the acute rejection-free cohort, the estimated 5-year graft survival was 90% for those receiving transplants from living relatives and 88% for those receiving cadaveric transplants (P=0.76). However, in grafts with early acute rejection, the 5-year survival was 40% for cadaveric recipients compared with 73% for living related graft recipients (P<0.014). Using the proportional hazards model, cadaveric donor source, older donor age, African American recipient race, and elevated 3-month serum creatinine were independent predictors of long-term graft loss caused by chronic rejection. The severity of acute rejection and recipient age had no impact on the risk of graft loss because of chronic rejection. CONCLUSION: These data indicate that the benefit of living related transplantation results from the fact that a living related graft progresses from acute to chronic rejection at a slower rate than a cadaveric graft. Furthermore, a cadaveric graft that is free of acute rejection 3 months after transplantation has an equal likelihood of functioning at 5 years as that of a graft from a living related donor.

Acute Disease↗
PubMed2000

Production of recombinant soluble human integrin alpha4beta1.

Integrin alpha4beta1 is a major leukocyte adhesion receptor that is a key target for the development of anti-inflammatory therapeutics. With the dual long-term goals of developing a reagent for use in high-throughput inhibitor screening assays and for crystallisation trials and subsequent structure determination, we have generated a recombinant soluble alpha4beta1 receptor. Both subunits were truncated prior to the transmembrane domains by site-directed mutagenesis and expressed using baculovirus infection of insect cells. The molecular weights of the recombinant subunits were as expected for post-translationally unmodified protein. In addition, as observed for the native subunit, a proportion of the alpha4 subunit was proteolytically processed into two fragments. ELISA and solid phase ligand-binding assays were performed to investigate the folding and functionality of the soluble integrin. The data suggest that the receptor was correctly folded and that it bound recombinant ligands with similar kinetics to the native molecule.

Animals↗
PubMed2000

Isotretinoin improves the appearance of photodamaged skin: results of a 36-week, multicenter, double-blind, placebo-controlled trial.

Photodamaged skin occurs as a result of long-term exposure to ultraviolet radiation. The incidence of photodamage in European and North American populations with Fitzpatrick skin types I, II, and III is estimated at 80% to 90%. We conducted a double-blind clinical trial to test the efficacy and safety of 0.1% isotretinoin versus vehicle cream in 800 patients with moderate to severe photodamaged skin. Patients applied either 0.1% isotretinoin or matching vehicle cream to the face, forearms, and hands once nightly for 36 weeks. Local irritation and adverse events were assessed, and plasma retinoid levels were measured before and during treatment. Treatment response increased throughout the 36-week treatment period and the overall appearance of photodamaged skin was significantly better than with the vehicle alone. Topical application of 0.1% isotretinoin is an effective and well-tolerated treatment leading to clinically apparent improvement in the appearance of photodamaged skin of the face, forearms, and hands.

Double-Blind Method↗
PubMed1999

Fine mapping of inhibitory anti-alpha5 monoclonal antibody epitopes that differentially affect integrin-ligand binding.

The high-affinity interaction of integrin alpha5beta1 with the central cell-binding domain of fibronectin requires both the Arg-Gly-Asp (RGD) sequence (in the tenth type III repeat) and a second site Pro-His-Ser-Arg-Asn (PHSRN) in the adjacent ninth type III repeat, which synergizes with RGD. Arg-Arg-Glu-Thr-Ala-Trp-Ala (RRETAWA) is a novel peptidic ligand for alpha5beta1, identified by phage display, which blocks alpha5beta1-mediated cell adhesion to fibronectin. A key question is the location of the binding sites for these ligand sequences within the integrin. In this study we have identified residues that form part of the epitopes of three inhibitory anti-alpha5 monoclonal antibodies (mAbs): 16, P1D6 and SNAKA52. These mAbs have distinct functional properties. mAb 16 blocks the recognition of RGD and RRETAWA, whereas P1D6 blocks binding to the synergy sequence. The binding of SNAKA52 is inhibited by anti-beta1 mAbs, indicating that its epitope is close to the interface between the alpha and beta subunits. Residues in human alpha5 were replaced with the corresponding residues in mouse alpha5 by site-directed mutagenesis; wild-type or mutant human alpha5 was expressed on the surface of alpha5-deficient Chinese hamster ovary cells. mAb binding was assessed by flow cytometry and by adhesion to the central cell-binding domain of fibronectin or RRETAWA by cell attachment assay. All three epitopes were located to different putative loops in the N-terminal domain of alpha5. As expected, disruption of these epitopes had no effect on ligand recognition by alpha5beta1. The locations of these epitopes are consistent with the beta-propeller model for integrin alpha-subunit structure and allow us to propose a topological image of the integrin-ligand complex.

Amino Acid Sequence↗
PubMed1999

Anatomy of pelvic arteries adjacent to the sacrospinous ligament: importance of the coccygeal branch of the inferior gluteal artery.

OBJECTIVE: To describe the arterial vascular anatomy in the area of the sacrospinous ligament. METHODS: Cadaver pelvises were dissected to reveal the anatomy of the sacrospinous ligament with emphasis on vascular and neuroanatomy. Flexible rulers were used to measure the coccygeal branch in five hemipelvises. RESULTS: The pudendal vessels and nerve pass immediately medial and inferior to the ischial spine (within 0.5 cm of the spine) and behind the sacrospinous ligament. The pudendal artery lies anterior to the sacrotuberous ligament, which passes behind the ischial spine to its attachment at the posterior ischial tuberosity. The inferior gluteal artery originates from the posterior or the anterior branch of the internal iliac artery to pass behind the sciatic nerve and the sacrospinous ligament. There is a 3- to 5-mm window in which the inferior gluteal vessel is left uncovered above the top of the sacrospinous ligament and below the lower edge of the main body of the sciatic nerve plexus. The coccygeal branch of the inferior gluteal artery passes immediately behind the midportion of the sacrospinous ligament and pierces the sacrotuberous ligament in multiple sites. The main body of the inferior gluteal artery leaves the pelvis by passing posterior to the upper edge of the sacrospinous ligament and following the inferior portion of the sciatic nerve out of the greater sciatic foramen. CONCLUSION: Sutures placed through the sacrospinous ligament at least 2.5 cm from the ischial spine along the superior border of the sacrospinous ligament and without transgressing the entire thickness are in an area generally free of arterial vessels.

Arteries↗
PubMed1999

The combined impact of donor age and acute rejection on long-term cadaver renal allograft survival.

BACKGROUND: Acute rejection (AR) is an important risk factor for long-term renal graft loss. Furthermore, donor age is also associated with graft outcome. We analyzed the combined effects of cadaver donor age and AR on long-term graft survival. METHODS: A retrospective review was made of 112 cadaver renal transplants at a single center. Only grafts functioning at least 3 months were included in this analysis. RESULTS: The 3-year survival of AR-free grafts was superior to that of grafts with AR (98% vs 67%, P < .001). Within the AR cohort donor age > 50 years (P < .05) had an additional negative impact on graft survival. The 3-year survival of an older donor graft with AR was 33% versus 82% for a younger donor graft with AR. CONCLUSIONS: AR was a significant predictor of long-term graft loss. Older donor kidneys with AR had poorer graft survival than did younger donor kidneys with AR.

Acute Disease↗
PubMed1999

'Tis better to receive than to give: the relative failure of the African American community to provide organs for transplantation.

There is a serious, continuous and increasing shortfall of organs, especially kidneys, for the purpose of transplantation. This shortfall is especially remarkable in African American populations. Because the incidence of hypertension (HTN) and associated end-stage renal diseases (ESRD) is 17 times greater in African Americans, this minority group, which comprises only 12% of the U.S. population, represents 34% of the dialysis population and 30% of the national kidney waiting list. Furthermore, while black individuals comprise 22-24% of kidney recipients, they comprise only 8-11% of donors. Because of the histocompatibility differences between the races and because tissue matching is part of the United Network for Organ Sharing (UNOS) allocation formula, African Americans wait twice as long for kidneys as Caucasians. Also, because they get more poorly matched organs, their kidney transplant graft survival is 10-20% lower than that for other racial groups. The African American community is unaware of the special needs in members of their own race. Steps must be taken to increase minority awareness of the need for well-matched transplant organs and their involvement in the donation process.

Adult↗
PubMed1998

Evaluating sensory conflict and postural instability. Theories of motion sickness.

Two experiments were carried out to evaluate the sensory conflict and the postural instability theories of motion sickness. The central hypothesis of sensory conflict theory is that motion sickness is caused by conflict between the current pattern of sensory inputs about self-movement and the pattern that is expected on the basis of previous experience. A subsidiary hypothesis is that the degree of motion sickness is proportional to the magnitude of sensory conflict. The central hypothesis of postural instability theory is that motion sickness is caused by loss of postural control. A subsidiary hypothesis is that the degree of motion sickness is proportional to amount of postural instability, which can be manipulated by physical restraint. In both experiments there were two levels of sensory conflict and two levels of postural restraint. Dependent variables were latency of onset and severity of motion sickness. The widespread occurrence of motion sickness in both experiments clearly confirmed the main hypothesis of sensory conflict theory. The results from Experiment 1, that there was significantly more motion sickness in the restrained condition, and from Experiment 2, that there was no significant difference in symptoms between the two restraint conditions, provide no support for the subsidiary hypothesis of postural instability theory. Evidence relating to the subsidiary proposition of sensory conflict theory was inconsistent.

Adolescent↗
PubMed1998

Identification of amino acid residues that form part of the ligand-binding pocket of integrin alpha5 beta1.

Arg-Arg-Glu-Thr-Ala-Trp-Ala (RRETAWA) is a novel ligand peptide for integrin alpha5 beta1, which blocks alpha5 beta1-mediated cell adhesion to fibronectin (Koivunen, E., Wang, B., and Ruoslahti, E. (1994) J. Cell Biol. 124, 373-380). Here we have localized the binding site for RRETAWA on alpha5 beta1 using inhibitory monoclonal antibodies (mAbs) and site-directed mutagenesis. A cyclic peptide containing this sequence (*CRRETAWAC*) had little effect on the binding of most anti-alpha5 and anti-beta1 mAbs to alpha5 beta1 but completely blocked binding of the anti-alpha5 mAb 16 in a directly competitive manner. Hence, the binding site of RRETAWA appears to closely overlap with the epitope of mAb 16. *CRRETAWAC* also acted as a direct competitive inhibitor of the binding of Arg-Gly-Asp (RGD)-containing fibronectin fragments to alpha5 beta1, suggesting that the binding site for RRETAWA is also closely overlapping with that for RGD. However, differences between the binding sites of RRETAWA and RGD were apparent in that (i) RGD peptides allosterically inhibited the binding of mAb 16 to alpha5 beta1, and (ii) several mAbs that perturbed binding of alpha5 beta1 to RGD had little effect on binding of alpha5 beta1 to RRETAWA. A double mutation in alpha5 (S156G/W157S) blocked the interaction of both RRETAWA and mAb 16 with alpha5 beta1 but had no effect on fibronectin binding or on the binding of other anti-alpha5 mAbs. Ser156-Trp157 is located near the apex of a putative loop region on the upper surface of a predicted beta-propeller structure formed by the NH2-terminal repeats of alpha5. Our findings suggest that this sequence forms part of the ligand-binding pocket of alpha5 beta1. Furthermore, as Ser156-Trp157 is unique to the alpha5 subunit, it may be responsible for the specific recognition of RRETAWA by alpha5 beta1.

Amino Acid Sequence↗
PubMed1998

Regulation of the extracellular ligand binding activity of integrins.

Integrins are a large heterodimeric family of cell surface adhesion receptors that bind extracellular matrix and cell surface ligands. The extracellular ligand binding activity of integrins is a dynamic and highly regulated event involving the induction of conformational changes within the integrin structure. The adhesive properties of integrins can be controlled by altering the activation state of the integrin, either through conformational change or receptor clustering, using mechanisms that are regulated by intracellular proteins. In this review, we will discuss what is currently known about integrin structure and the ligand binding sites present within the receptor. In addition, the mechanisms by which the ligand binding event is regulated through conformational change will be addressed, and the potential role of intracellular cytoplasmic proteins will be discussed.

Animals↗
PubMed1998

Transient hypoadrenalism during surgical critical illness.

OBJECTIVE: To report the cortisol levels in 6 patients during and after severe inflammation. DESIGN: Patients with severe inflammatory disease had basal and stimulated (cosyntropin) serum cortisol levels determined at the time of severe and less severe inflammation. SETTING: Intensive care unit and wards of a tertiary care center. PATIENTS: Six patients with continued evidence of severe inflammation, despite aggressive management of the underlying inflammatory disease. INTERVENTIONS: Five of 6 patients received hydrocortisone at "physiologic" doses. MAIN OUTCOME MEASURES: Basal and stimulated serum cortisol levels. RESULTS: The mean+/-SD cortisol data for these patients were as follows: baseline cortisol level during inflammation, 350+/-121 nmol/L (n=6); stimulated cortisol level during inflammation, 571+/-326 nmol/L (n=6); baseline cortisol level with less inflammation, 833+/-339 nmol/L (P=.03 vs baseline level during inflammation) (n=5); and stimulated cortisol level with less inflammation, 1090+/-295 nmol/L (P=.03 vs stimulated level during inflammation) (n=4). Manifestations of inflammation decreased with hydrocortisone administration. CONCLUSIONS: Severe inflammation may result in lower-than-expected serum cortisol levels, which then increase significantly as the inflammation decreases. Transient hypoadrenalism may aggravate the adverse effects of severe inflammation. These effects may be ameliorated by administering physiologic rather than pharmacologic doses of hydrocortisone.

Adrenal Insufficiency↗
PubMed1997

Selective binding of N-acetylglucosamine to the chicken hepatic lectin.

Among Ca2+-dependent (C-type) animal lectins, the chicken hepatic lectin (CHL) is unique in displaying almost complete selectivity for N-acetylglucosamine over other monosaccharide ligands. The crystal structures of the carbohydrate-recognition domain (CRD) from serum mannose-binding protein (MBP) and of a complex between the CRD from liver MBP and the methyl glycoside of N-acetylglucosamine were used to model the binding site in CHL. Substitution of portions of CHL into the MBP framework did not substantially increase selectivity. A bacterial expression system for the CRD of CHL was developed so that specific residues predicted to be near the 2-acetamido substituent of N-acetylglucosamine could be altered by site-directed mutagenesis. The results indicate that the ligand is bound to CHL in the same orientation as it binds to liver MBP. A tyrosine and a valine residue that probably contact the the N-acetyl group have been identified. These results, together with studies of ligand-binding selectivity, suggest that these residues form part of a binding pocket for the N-acetyl group, which confers selective binding of N-acetylglucosamine.

Acetylglucosamine↗
PubMed1997

The effect of pregnancy on cyclosporine levels in renal allograft patients.

OBJECTIVE: To assess the effects of pregnancy on cyclosporine levels in six renal allograft patients. METHODS: Maternal demographic, laboratory, clinical, and perinatal outcome data were recorded in six pregnant women with previous renal allografts receiving cyclosporine immunosuppression. The cyclosporine and serum creatinine levels were measured before pregnancy, during each trimester, and postpartum. RESULTS: The mean (standard deviation [SD]) maternal age was 29.1 (3.8) years. Parity ranged from 0 to 3. Mean serum creatinine levels tended to be lower during pregnancy than before or after, as did the mean cyclosporine levels. After adjusting for dose, five of six patients had declines in cyclosporine level during pregnancy. The mean (SD) gestational age at delivery was 37.5 (2.8) weeks with a mean (SD) birth weight of 2837 (538) g. CONCLUSION: Pregnancy in patients with renal allografts can lead to a substantial decline in cyclosporine levels.

Adult↗