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Biomedical subjects

S Stephens

Publications and source records attributed to S Stephens.

At least 19 recordsLinked to original sources
PubMed1999

Tongue protrusion force and fatiguability in male and female subjects.

Limb and respiratory muscle (diaphragm) strength and fatiguability have been extensively studied in man and are known to vary with age and sex. However, in contrast to limb muscles and the diaphragm, force and fatiguability characteristics have not been studied in upper airway muscles. This study examines the hypotheses that tongue protrusion strength or fatiguability, determined by the properties of the intrinsic muscles and genioglossus, may change with age and may be reduced in males compared to females. A force transducer was used to compare maximal tongue protrusion force (Fmax) and fatiguability in 81 males and 86 females matched for age (mean+/-SD, 43+/-19 yrs, 42+/-19 yrs, respectively). Fatiguability indices were based on the time that subjects could maintain 50% of Fmax. Fmax declined with age in both males (r=-0.57, p<0.001) and females (r=-0.56, p<0.001). Fmax in males was greater than in females (males 26+/-8 N; females 20+/-7 N; p<0.001). However, after correction of Fmax for sex differences in total body muscle (fat-free mass) there was no significant difference between males and females (p=0.3). There was also no difference in fatiguability between males and females (p=0.5). In conclusion, tongue protrusion strength is greater in males compared to females, and decreases with age. If these differences also apply to patients with sleep apnoea, the reduction in maximal tongue protrusion force with age could be of relevance to the observed increase in prevalence and severity of sleep apnoea-hypopnoea syndrome in middle age, but would not explain the gender difference in prevalence.

Adult↗
PubMed1999

Therapeutic antibody fragments with prolonged in vivo half-lives.

Antibody fragments can be isolated rapidly using techniques such as phage display and can be expressed to high levels in microbial systems. However, to date such antibody fragments have been of limited use for many therapeutic applications because they are rapidly cleared from the body. We present a strategy for the site-specific chemical modification of antibody fragments with polyethylene glycol, which results in the production of antibody fragments with long in vivo half-lives and full retention of antigen-binding properties. This technology should allow more rapid and economical production of therapeutic antibodies for chronic disease therapy.

Animals↗
PubMed1999

Cystic kidney disease presenting in infancy.

AIM: The clinical, histological and imaging findings of 12 children with ultrasound features of severe renal cystic disease presenting in the first year of life were reviewed. METHODS AND RESULTS: Two children had cystic dysplasia and four had autosomal dominant polycystic disease. Two had a malformation syndrome, one a variant of Meckel syndrome and the other Bardet Biedl syndrome. One had autosomal recessive polycystic disease and in three there was no final diagnosis. Intravenous urography gave non-specific information. In six cases clinical findings combined with imaging established a diagnosis. Diagnosis was established by biopsy in two and gave supportive evidence in one. Outlook for renal function is variable. One child has had a transplant and one is on dialysis awaiting a transplant. Three have a degree of renal failure and one has died. Six have normal renal function. Renal cystic disease is the common pathway for a heterogeneous group of disorders as shown in these children. CONCLUSION: It is emphasized that a specific diagnosis could not be made from the renal sonographic appearances alone, nor could any prognostic implications for renal function be made. Contrast retention on intravenous urography was also insufficiently specific to be of value. Ultrasound of the parents was the most useful imaging procedure and should be done in all cases.

Adolescent↗
PubMed1999

Effect of Sch 55700, a humanized monoclonal antibody to human interleukin-5, on eosinophilic responses and bronchial hyperreactivity.

This report describes the development and the biology of Sch 55700, a humanized monoclonal antibody to human IL-5 (hIL-5). Sch 55700 was synthesized using CDR (complementarity determining regions) grafting technology by incorporating the antigen recognition sites for hIL-5 onto consensus regions of a human IgG4 framework. In vitro, Sch 55700 displays high affinity (Kd = 20 pmol/l) binding to hIL-5, inhibits the binding of hIL-5 to Ba/F3 cells (IC50 = 0.5 nmol/l) and blocks IL-5 mediated proliferation of human erythroleukemic TF-1 cells. In allergic mice, Sch 55700 (0.1-10 mg/kg, i.p. or i.m.) inhibits the influx of eosinophils in the lungs, demonstrates long duration of activity and the anti-inflammatory activity of this compound is additive with oral prednisolone. In allergic guinea pigs, Sch 55700 (0.03-30 mg/kg i.p.) inhibits both the pulmonary eosinophilia and airway hyperresponsiveness and at 30 mg/kg, i.p. inhibited allergic, but not histamine-induced bronchoconstriction. In allergic rabbits, Sch 55700 blocks cutaneous eosinophilia. Sch 55700 (0.1-1 mg/kg i.p.) also blocks the pulmonary eosinophilia and neutrophilia caused by tracheal injection of hIL-5 in guinea pigs. In allergic cynomolgus monkeys, a single dose of Sch 55700 (0.3 mg/kg i.v.) blocks the pulmonary eosinophilia caused by antigen challenge for up to six months. Sch 55700 is, therefore, a potent antibody against IL-5 in vitro and in a variety of species in vivo that could be used to establish the role of IL-5 in human eosinophilic diseases such as asthma.

Animals↗
PubMed1998

Dorsal horn spatial representation of simple cutaneous stimuli.

A model of lamina III-IV dorsal horn cell receptive fields (RFs) has been developed to visualize the spatial patterns of cells activated by light touch stimuli. Low-threshold mechanoreceptive fields (RFs) of 551 dorsal horn neurons recorded in anesthetized cats were characterized by location of RF center in cylindrical coordinates, area, length/width ratio, and orientation of long axis. Best-fitting ellipses overlapped actual RFs by 90%. Exponentially smoothed mean and variance surfaces were estimated for these five variables, on a grid of 40 points mediolaterally by 20/segment rostrocaudally in dorsal horn segments L4-S1. The variations of model RF location, area, and length/width ratio with map location were all similar to previous observations. When elliptical RFs were simulated at the locations of the original cells, the RFs of real and simulated cells overlapped by 64%. The densities of cell representations of skin points on the hindlimb were represented as pseudocolor contour plots on dorsal view maps, and segmental representations were plotted on the standard views of the leg. Overlap of modeled and real segmental representations was at the 84% level. Simulated and observed RFs had similar relations between area and length/width ratio and location on the hindlimb: r(A) = 0.52; r(L/W) = 0.56. Although the representation of simple stimuli was orderly, and there was clearly only one somatotopic map of the skin, the representation of a single point often was not a single cluster of active neurons. When two-point stimuli were simulated, there usually was no fractionation of response zones or addition of new zones. Variation of stimulus size (area of skin contacted) produced less variation of representation size (number of cells responding) than movement of stimuli from one location to another. We conclude that stimulus features are preserved poorly in their dorsal horn spatial representation and that discrimination mechanisms that depend on detection of such features in the spatial representation would be unreliable.

Animals↗
PubMed1997

Improving blood availability in a district hospital, Bo, Sierra Leone. The Bo PMM Team.

PRELIMINARY STUDIES: A situation analysis of Bo Government Hospital found there was no functioning blood bank. Focus group discussions revealed negative perceptions of community members regarding donation and transfusion of blood. INTERVENTIONS: In late 1992, the hospital laboratory was refurbished: a refrigerator, freezer, reagents and other equipment and supplies were provided and technicians were trained. Consequently, small quantities of blood could be stored and rapidly transfused. Other improvements to obstetric services in the hospital were undertaken at the same time. Afterwards, community education to encourage blood donation was done. RESULTS: The number of units of blood drawn increased from 304 to 501 (65%) from 1992 to 1993 (the first intervention year); the number actually transfused increased from 296 to 452 (53%). By the third intervention year (1995), the annual numbers of units drawn and transfused were 469 and 422, respectively. Case fatality rates for major obstetric complications were lower in all post-intervention years (10% in 1993, 7% in 1994, 10% in 1995) as compared to 1992 (13%). COSTS: Cost of improvements to blood services in the hospital was nearly US $10,000, of which 77% was used to purchase supplies and equipment. CONCLUSIONS: Even in settings with irregular electrical supply, storage of small quantities of blood is possible. Ready availability of blood may contribute to improved quality of obstetric care and improved survival among patients.

Blood Banks↗
PubMed1997

The in vivo and in vitro characterisation of an engineered human antibody to E-selectin.

BACKGROUND: E-selectin is an endothelial cell specific adhesion molecule that is believed to play an important role in the early stages of leukocyte extravasation. OBJECTIVES: Here we describe the construction and evaluation of an engineered human monoclonal antibody that blocks E-selectin function. RESULTS: SPLAT-1 is an engineered human monoclonal antibody that has a very similar affinity for E-selectin as its murine parent antibody. In vitro SPLAT-1 blocks the binding of human leukocytes to E-selectin and does not mediate antibody-dependent cellular cytotoxicity (ADCC) or complement-mediated lysis of endothelial cells. In vivo, SPLAT-1 inhibits the recruitment of leukocytes to cytokine-inflamed human skin grafted on to SCID mice and has a long circulating half-life in primates. It does not appear to provoke an immune response in primates even on repeat administration. CONCLUSIONS: SPLAT-1 has the characteristics of a antibody suitable for human therapy studies.

Animals↗
PubMed1997

Treatment of ulcerative colitis with an engineered human anti-TNFalpha antibody CDP571.

BACKGROUND: Tumour Necrosis Factor-alpha (TNFalpha) is a pro-inflammatory cytokine whose expression is increased in the colonic mucosa of patients with active ulcerative colitis. TNFalpha antibodies have been shown to be beneficial in animal models of bowel inflammation and in Crohn's disease but have not previously been studied in ulcerative colitis. METHODS: Patients with mild/moderate ulcerative colitis were treated openly with a single intravenous infusion of 5 mg/kg of an engineered human IgGgamma4 antibody CDP571 and monitored for 8 weeks. RESULTS: Fifteen patients entered the study, eight males and seven females, with a mean age of 44 years. Eleven had left-sided disease, four extensive disease and six patients were steroid-unresponsive. The treatment was well tolerated and plasma half-life of CDP571 was approximately 7 days. There was a significant reduction from 6.7 to 4.6 (P = 0.023) in the mean Powell-Tuck score by 1 week post-infusion and a reduction to 5.5 was seen at 2 weeks (P = 0.218). Significant but modest reductions also occurred in erythrocyte sedimentation rate and serum C reactive protein in the first 2 weeks. Mean Interleukin-6 plasma concentrations fell from 6.9 to 5.4 pg/mL by week 1, and to 6.1 pg/mL by week 2 (NS). Reductions in sigmoidoscopic score and number of liquid stools were noted but failed to reach statistical significance. CONCLUSION: A consistent improvement in disease activity was seen in the initial 2 weeks after infusion and the treatment was well tolerated. These promising results support the testing of CDP571 in a larger controlled trial.

Adult↗
PubMed1997

Treatment of ulcerative colitis in the cottontop tamarin using antibody to tumour necrosis factor alpha.

BACKGROUND: The aetiology and pathophysiology of ulcerative colitis remains unclear; however, there is increasing recognition of the critical role of inflammatory cytokines in the pathogenesis of this disease. Among these, tumour necrosis factor alpha (TNF alpha) seems to play an important role. AIM: To study the effects of an engineered human monoclonal antibody to TNF alpha (CDP571) in the treatment of idiopathic ulcerative colitis in the cottontop tamarin. METHODS: Six cottontop tamarins with confirmed ulcerative colitis received repeated doses of CDP571. Progression of disease was assessed by measuring both body weight and rectal biopsy pathology. RESULTS: All animals showed a rapid improvement in clinical condition and rectal biopsy pathology that was maintained following completion of the therapy. CONCLUSION: These studies indicate the efficacy of selective antibody therapy to TNF alpha for the treatment of ulcerative colitis in a primate and suggest that similar therapy in human could be of value.

Animals↗
PubMed1996

Differentiating benign from malignant lung lesions using "quantitative" parameters of FDG PET images.

UNLABELLED: Fluorine-18 labeled deoxyglucose positron-emission tomography (FDG-PET) applications in oncology include the differential diagnosis of chest masses and single pulmonary nodules. However, FDG is not tumor-specific; rather, it also accumulates in inflammatory processes. This study was performed to identify image parameters that would improve the specificity of PET. METHODS: Twenty-six patients who had benign and malignant lung lesions were examined retrospectively. Positron-emission tomography data were acquired in dynamic scanning mode after intravenous bolus of 250-402 MBq of FDG. Standardized uptake values (SUVs) were calculated and Patlak analyses were performed in selected regions of interest in the PET images. Positron-emission tomography results were related to histological diagnosis (N = 49) or clinical follow-up (N = 3). RESULTS: The specificity and sensitivity of the original PET scan reports, which was based on visual image interpretation and loosely applied SUVs, was 100% and 73%, respectively. Using the SUVs with a cut-off value of 3.8 and Kpat value with a cut-off at 0.025 min-1 improved the specificity to 81% and 85%. CONCLUSION: FDG-PET image interpretation can be facilitated by using SUV information or the accumulation rate of the radiotracer (Patlak). With additional validation, this method could have a significant cost-effective impact on the medical/surgical management of chest masses.

Adult↗
PubMed1996

Arthroscopic Bankart repair using a degradable tack. A followup study using optimized indications.

Arthroscopic Bankart repair using degradable polymers is a relatively new procedure. Initial reports describing results among the first patients treated for instability of the shoulder using degradable tacks found rates of recurrent instability significantly higher than those for open repair procedures. A 21% postoperative recurrence rate was reported in the initial group of 62 patients studied. Modifications of the operative procedure and, more importantly, the indications for the procedure have led to substantially improved results. Using the following indications, a 2-year followup group of patients was found to have a 10% recurrence of instability rate: (1) traumatic instability, which primarily was anterior, unidirectional; (2) presence of a Bankart lesion; (3) presence of a robust inferior glenohumeral ligament; and (4) minimal to mild amount of bony erosions present at the glenoid. It is concluded that with more precise patient selection, arthroscopic stabilization using a degradable polymeric tack can provide high levels of patient satisfaction with low rates of recurrence.

Adult↗
PubMed1996

Resistance to antidepressant medications and short-term clinical response to ECT.

OBJECTIVE: Traditionally, it has been widely assumed that the likelihood of response to ECT is independent of the adequacy of previous treatment with antidepressant medications. However, recent research has raised the possibility that medication-resistant patients with depression have a poorer clinical ECT outcome than patients who have not failed previous adequate medication trials. METHOD: Medication resistance of 100 patients with primary, unipolar, nonpsychotic major depression was evaluated during the index episode with the Antidepressant Treatment History Form. Patients were recruited and treated with ECT at three sites; standardized ECT and clinical assessment procedures were used. Clinical outcome was assessed immediately and 1 week after completion of the ECT course. RESULTS: Patients who previously had failed one or more adequate antidepressant medication trials were less likely to respond to subsequent ECT than patients not known to be medication resistant. This finding held within each study site, whether clinical response was assessed categorically or in terms of the magnitude of symptomatic improvement and after the authors accounted for other potential predictors of clinical outcome. Resistance to heterocyclic antidepressants predicted poorer outcome after ECT, while resistance to selective serotonin reuptake inhibitors and monoamine oxidase inhibitors did not show significant predictive relations. CONCLUSIONS: While a substantial percentage of medication-resistant patients respond to ECT, clinical outcome in this group is inferior to that of patients without established medication resistance. The predictive power of medication resistance is generalizable across diverse clinical settings, particularly for heterocyclic antidepressants, which perhaps suggests an overlap in the mechanisms of actions of ECT and this medication class.

Aged↗
PubMed1995

CDP571, a humanized antibody to human tumor necrosis factor-alpha: safety, pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in patients with septic shock. CPD571 Sepsis Study Group.

OBJECTIVES: To determine the safety of a "humanized" antibody to human anti-tumor necrosis factor-alpha (TNF-alpha) in patients with septic shock, and to examine the pharmacokinetics, immune response, and influence of the antibody on cytokine concentrations in this patient group. DESIGN: Prospective, randomized, placebo-controlled, phase II multicenter clinical trial, with escalating doses of a fully humanized anti-TNF-alpha antibody (CDP571). SETTING: Seven academic intensive care units in Europe. PATIENTS: Forty-two patients with rapidly evolving septic shock who received CDP571 in addition to standard supportive care. INTERVENTIONS: Patients received intravenously either placebo or one of four single doses of CDP571: 0.1, 0.3, 1.0, or 3.0 mg/kg. MEASUREMENTS AND MAIN RESULTS: The humanized anti-TNF-alpha antibody was well tolerated. The overall all-cause 28-day mortality rate was 62%. Mortality rate was similar in the placebo and treatment groups, except that all six patients who received 0.3 mg/kg of CDP571 died within 7 days. This outcome, which was not dose-related, is consistent with the poorer prognostic characteristics of this group at baseline. The peak CDP571 concentrations and area under the curve increased proportionately with the dose. The low level of the immune response detected had little effect on the ability of circulating CDP571 to bind TNF-alpha and on the pharmacokinetics of the antibody. An abrupt reduction in circulating TNF-alpha concentration was observed 30 mins after CDP571 administration at all active dosage levels. While interleukin-1 beta and interleukin-6 plasma concentrations decreased with time in all dosage groups, these cytokine concentrations decreased more rapidly during the initial 24 hrs in the treatment groups than in the placebo group. CONCLUSIONS: The humanized anti-TNF-alpha antibody, CDP571, is well tolerated and able to cause a dose-dependent reduction in circulating TNF-alpha concentrations in patients with septic shock. Further studies are needed to determine the efficacy of this antibody to improve the survival rates of critically ill patients with severe sepsis.

APACHE↗
PubMed1995

Role of TNF alpha in the induction of antigen induced arthritis in the rabbit and the anti-arthritic effect of species specific TNF alpha neutralising monoclonal antibodies.

OBJECTIVE: To investigate the role of tumour necrosis factor alpha (TNF alpha) in the development of antigen induced arthritis (AIA) in rabbits. METHODS: Monoclonal antibodies to rabbit TNF alpha were developed in rats and were used to detect TNF alpha in synovial fluid by enzyme linked immunosorbent assay and to localise it in tissue sections of synovium and cartilage from rabbits up to 21 days after induction of AIA. An antibody which neutralised TNF alpha activity in vitro was injected into rabbits to block TNF alpha action in vivo in AIA. Joint swelling, leucocyte infiltration into synovium and proteoglycan loss from cartilage were measured and compared with a control group, which were injected with sterile saline. RESULTS: Monoclonal antibodies to purified rabbit TNF alpha were prepared in rats and two were selected which were able to neutralise rabbit TNF alpha in a cytotoxicity bioassay. TNF alpha was detected in significant concentrations (21.7 (SE 0.5) pg/ml) in the arthritic joint fluid of rabbits with AIA only at one day after induction and it was then also sparsely localised in cells of the synovium, but from day 3 onwards it was localised more strongly in the deep zone of articular cartilage. Injection of anti-TNF monoclonal antibody R6 over three days into rabbits with AIA reduced joint swelling and leucocyte infiltration into joint fluid and decreased the expression of CD11b and CD18 on cells in the joint fluid. However, there was no significant reduction in the loss of proteoglycan from articular cartilage, although the joint fluid at three days contained a lower glycosaminoglycan content. The antibody R6 gave most effect at a dose of 0.6 mg/kg and there was no increase in its effectiveness at a fivefold greater dose (3.0 mg/kg). Treatment over 10 days gave a more complete suppression of joint swelling, but did not result in any less proteoglycan loss from cartilage. Treatment for five days with a 16 day follow up gave a significant reduction in swelling for several days beyond the treatment, but the swelling then slowly returned, until by day 21 there was no significant difference in joint swelling and there was also no recovery of cartilage proteoglycan content. A rabbit anti-rat immunoglobulin response was detected at 21 days, which may have limited the long term effectiveness of the antibody. CONCLUSIONS: In AIA in rabbits, TNF alpha was only detected in synovial fluid at one day after induction and there was only limited cellular localisation of TNF alpha in synovium and cartilage from three days. However, neutralising TNF alpha with a monoclonal antibody was effective in suppressing inflammatory changes in the joint during the acute onset of AIA, but it had little effect on the loss of proteoglycan from cartilage. The results suggest that blocking inflammation and synovitis with anti-TNF alpha may be more easily achieved than preventing damage to articular cartilage.

Animals↗
PubMed1995

Significance of systemic endotoxaemia in inflammatory bowel disease.

Quantitative and qualitative disturbances in faecal flora suggest a role for enteric bacteria and their products in the pathogenesis of inflammatory bowel disease (IBD). This study investigated the hypothesis that systemically circulating endotoxins are of pathogenic significance in IBD by measuring antibody, cytokine, and acute phase protein responses. Systemic endotoxaemia was found in 88% patients with ulcerative colitis (n = 25) and 94% with Crohn's disease (n = 31) during clinical relapse. Systemic endotoxaemia correlated positively with anatomic extent and clinical activity of ulcerative colitis. Circulating tumour necrosis factor (TNF) was detected in 40% of patients with ulcerative colitis and 45% with Crohn's disease. Plasma TNF concentrations correlated with clinical and laboratory measures of disease activity and were associated with a surgical outcome to the disease episode. Plasma soluble TNF receptor p55 concentration correlated positively with disease activity and endotoxin core antibody concentrations. Plasma IgG endotoxin core antibody concentrations were significantly increased in patients with Crohn's disease and correlated with systemic endotoxaemia. The presence of systemic endotoxaemia, its correlation with disease activity, disease extent, and endotoxin core antibody concentration and the detection of circulating TNF and soluble TNF receptors all support a pathogenic role for endotoxins in IBD.

Adolescent↗
PubMed1995

Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses.

A murine antibody to human tumour necrosis factor-alpha (TNF-alpha) (CB0010) was complementarity-determining region (CDR)-grafted using human IgG4 heavy and kappa light chain constant regions. In cynomolgus monkeys, the grafted antibody (CDP571) was eliminated with a half-life of 40-90 hr, two to three times longer than CB0010, and immunogenicity was reduced by > 90%. Responses to the constant regions were almost entirely eliminated and responses to the CDR loop (anti-idiotype) were lowered. CDP571 was given to 24 human volunteers in doses from 0.1 to 10.0 mg/kg. It was well tolerated, with a half-life of approximately 13 days. Anti-CDP571 antibodies were low or undetectable at higher doses. At lower doses, anti-CDP571 peaked at 2 weeks and then declined. The response was primarily IgM (in contrast to the cynomolgus monkey, where by 5 weeks IgG predominated) and was against a conformational epitope comprising heavy and light chain CDR loops. No antibodies were detected against the gamma 4/kappa domains or frameworks. The response had little or no effect on CDP571 binding to TNF-alpha or on plasma clearance.

Amino Acid Sequence↗
PubMed1994

Differential effect of isotype on efficacy of anti-tumor necrosis factor alpha chimeric antibodies in experimental septic shock.

Immune complexes containing human gamma (g)1 or murine g2a antibodies generate secondary effector mechanisms via Fc receptor binding or complement activation, whereas those containing human g4 or murine g1 antibodies generally do not. Therefore, isotype selection of therapeutic antibodies may have important clinical consequences. In a rabbit model of human tumor necrosis factor (rhuTNF)-induced pyrexia, a murine/human chimeric g4 anti-human TNF-alpha monoclonal antibody (mAb) (cCB0011) showed a dose-dependent inhibition of pyrexia, whereas a g1 isotype variant of the same mAb gave a marked pyrexia that was seen at all doses indicative of an immune complex-mediated response. To investigate whether isotype difference could influence mAb efficacy in pathological disease states, hamster/murine chimeric g1 and g2a anti-murine TNF-alpha mAbs (TN3g1, TN3g2a) were studied in experimental shock in mice and rats. In lipopolysaccharide-induced shock in mice, treatment with TN3g1 mAb at 30 and 3 mg/kg resulted in 90% survival by 72 h (p < or = 0.004), and prolonged survival to 45 h (p < or = 0.05), respectively, compared with 100% mortality by 27 h in controls. In contrast, a g2a isotype variant of the same mAb (30 mg/kg) resulted in only 10% survival by 72 h (p < or = 0.05). In a neutropenic sepsis model in rats there was greater survival in animals receiving the g1 isotype of TN3 compared with g2a isotype variant (70 vs. 27%; p < or = 0.005) with 100% mortality in the controls. These differences were not due to the pharmacokinetic profiles of the mAbs. In models of experimental shock antibody isotype can affect outcome with inactive isotypes (human g4 and murine g1) being more efficacious than active isotypes (human g1 and murine g2a).

Animals↗