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Biomedical subjects

A Nicholls

Publications and source records attributed to A Nicholls.

At least 19 recordsLinked to original sources
PubMed1999

A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.

BACKGROUND: T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS: A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS: There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION: Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.

Acute Disease↗
PubMed1999

Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44.

The Muckle-Wells syndrome (MWS) is a hereditary inflammatory disorder characterized by acute febrile inflammatory episodes comprising abdominal pain, arthritis, and urticaria. Progressive nerve deafness develops subsequently, and, after several years, the disease is complicated by multiorgan AA-type amyloidosis (i.e., amyloidosis derived from the inflammatory serum amyloid-associated protein) (MIM 191900) with renal involvement and end-stage renal failure. The mode of inheritance is autosomal dominant, but some sporadic cases have also been described. No specific laboratory findings have been reported. The genetic basis of MWS is unknown. Using a genomewide search strategy in three families, we identified the locus responsible for MWS, at chromosome 1q44. Our results indicate that the gene is located within a 13.9-cM region between markers D1S2811 and D1S2882, with a maximum two-point LOD score of 4. 66 (recombination fraction.00) at D1S2836 when full penetrance is assumed. Further identification of the specific gene that is responsible for MWS will therefore provide the first biological element for characterizing MWS, other than doing so on the basis of its variable clinical expression.

Abdominal Pain↗
PubMed1999

Determinants of the first decade of bone loss after menopause at spine, hip and radius.

This study documented bone loss at three different sites in the early postmenopausal period, and examined potential predictors. Forty-three women underwent repeated measurements of bone density at the lumbar spine, proximal femur and distal radius for up to 14 years. Individual rates of bone loss were calculated for the spine and hip; for radial trabecular bone, rates were calculated separately for two time periods, earlier and later after menopause. In the spine and radius, initially high rates of loss diminished with time after menopause. No positive correlations for bone loss were found between the three sites, suggesting that faster than average bone loss was specific to individual bones. High body mass index (BMI) was significantly protective against fast bone loss at the spine and radius; in the spine, each unit increase in BMI was associated with a approximately 5% reduction in the rate of bone loss. Of the other variables measured (maximum oxygen consumption, lean body mass, fat mass, mean psoas muscle area at the L3 level, hand grip strength as well as anthropometry) only bone densitometry was sufficiently predictive to help guidance on hormone replacement or other prophylactic therapy. The data suggest that the known relationship between excessive leanness and risk of osteoporosis and vertebral fracture after menopause might in part be due to fast post-menopausal bone loss. Because bulk of psoas muscle was associated with low spine loss rates, the data also support a role for applied muscular loading in local maintenance of bone density.

Adult↗
PubMed1998

Genetic studies into inherited and sporadic hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) in adults carries a high morbidity and mortality, and its cause remains unknown despite many theories. Although familial HUS is rare, it affords a unique opportunity to elucidate underlying mechanisms that may have relevance to acquired HUS. We have undertaken a genetic linkage study based on a candidate gene approach. A common area bounded by the markers D1S212 and D1S306, a distance of 26 cM located at 1q32 segregated with the disease (Z max 3.94). We demonstrate that the gene for factor H lies within the region. Subsequent mutation analysis of the factor H gene has revealed two mutations in patients with HUS. In an individual with the sporadic/relapsing form of the disease we have found a mutation comprising a deletion, subsequent frame shift and premature stop codon leading to half normal levels of serum factor H. In one of the three families there is a point mutation in exon 20 causing an arginine to glycine change, which is likely to alter structure and hence function of the factor H protein. Factor H is a major plasma protein that plays a critical regulatory role in the alternative pathway of complement activation. In light of these findings and previous reports of HUS in patients with factor H deficiency, we postulate that abnormalities of factor H may be involved in the etiology of HUS.

Adult↗
PubMed1996

Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration.

A randomized, crossover study of 12 healthy volunteers was conducted with single, 1.5-g doses of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. During the intravenous infusion, phase systemic plasma clearance of MMF was approximately 10 L/min and the half-life (t1/2) was a few minutes. After oral administration, however, plasma MMF was below quantitation limits at all times. The plasma MPA profile of oral MMF showed a sharp peak at approximately 1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t1/2 of MPA was similar for both routes (approximately 17 hours). The area under the concentration-time curve (AUC) from time 0 to 24 hours was statistically higher for intravenous than for oral administration, but total AUC showed statistical equivalence (80-120 rule), with mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route. Total plasma AUC of mycophenolic acid glucuronide (MPAG), the sole metabolite of MPA, was four- to five-fold higher than MPA. Total 48-hour MPAG recovery in urine was statistically equivalent for the two routes and represented a mean of 70% of administered drug; corresponding MPA recovery was less than 1%. Renal clearance (ClR) values required transport mechanisms for MPAG, but not for MPA. The ClR of MPAG was statistically higher after intravenous administration than oral administration. MMF administered orally undergoes rapid, complete absorption and essentially complete presystemic deesterification. There was presystemic removal of MPA, but enterohepatic circulation compensated for the first pass loss. Renal metabolism of MPA also may have occurred.

Administration, Oral↗
PubMed1996

Free-energy determinants of alpha-helix insertion into lipid bilayers.

A detailed treatment is provided of the various free-energy terms that contribute to the transfer of a polyalanine alpha-helix from the aqueous phase into lipid bilayers. In agreement with previous work, the hydrophobic effect is found to provide the major driving force for helix insertion. However, an opposing effect of comparable magnitude is also identified and is attributed to the large free-energy penalty associated with the desolvation of peptide hydrogen bonds on transfer to the low dielectric environment of the bilayer. Lipid perturbation effects as well as the entropy loss associated with helix immobilization in the bilayer are also evaluated. Two configurations of a membrane-bound 25mer polyalanine helix were found to be lower in free energy than the isolated helix in the aqueous phase. The first corresponds to the case of vertical insertion, in which a helix terminus protrudes from each side of the bilayer. The second minimum is for the case of horizontal insertion, for which the helix is adsorbed upon the surface of the bilayer. The calculated free-energy minima are found to be in good agreement with recent measurements of related systems. Large free-energy barriers resulting from desolvation of unsatisfied hydrogen-bonding groups at the helix termini are obtained for both insertion processes. The barriers for insertion are significantly reduced if the helix termini are assumed to be "capped" through the formation of hydrogen bonds with polar sidechains. For uncapped helices, our results support recently proposed models in which helices are inserted by first adsorbing on the membrane surface and then having one terminus "swing around" so as to penetrate the bilayer.

Biophysical Phenomena↗
PubMed1996

Pharmacokinetics of mycophenolate mofetil (RS61443): a short review.

Overall, the PK of MMF is reasonably straightforward and relatively unaffected by the complex pathophysiological changes involved in the management of renal transplant recipients. The ability to relate plasma MPA concentrations to efficacy through the PK/PD correlation implies that, unlike for many other drugs, plasma PK has direct relevance to the clinical outcome. These features should not only greatly help the exploration of immunosuppressive regiments using MMF but also the development of clinical use of MMF in situations other than renal transplantation.

Body Weight↗
PubMed1995

Classical electrostatics in biology and chemistry.

A major revival in the use of classical electrostatics as an approach to the study of charged and polar molecules in aqueous solution has been made possible through the development of fast numerical and computational methods to solve the Poisson-Boltzmann equation for solute molecules that have complex shapes and charge distributions. Graphical visualization of the calculated electrostatic potentials generated by proteins and nucleic acids has revealed insights into the role of electrostatic interactions in a wide range of biological phenomena. Classical electrostatics has also proved to be successful quantitative tool yielding accurate descriptions of electrical potentials, diffusion limited processes, pH-dependent properties of proteins, ionic strength-dependent phenomena, and the solvation free energies of organic molecules.

Biochemistry↗
PubMed1995

Elective ventilation of potential organ donors.

Elective ventilation describes the procedure of transferring selected patients dying from rapidly progressive intracranial haemorrhage from general medical wards to intensive care units for a brief period of ventilation before confirmation of brain stem death and harvesting of organs. This approach in Exeter has led to a rate of kidney retrieval and transplant higher than has been achieved elsewhere in the United Kingdom, with a stabilisation of numbers on patients on dialysis. Recently doubt has been cast on the legality of our practice of elective ventilation on the grounds that relatives are not permitted to consent to treatment of an incompetent person when that treatment is not in the patient's best interests. We are thus faced with the dilemma of a protocol that is ethical, practical, and operates for the greater good but which may be illegal. This article explores various objections to the protocol and calls for public, medical, and legal debate on the issues.

Brain Death↗
PubMed1995

Evolution of spinal bone loss and biochemical markers of bone remodeling after menopause in normal women.

The main objective of this study was to describe longitudinal patterns of spinal bone loss in normal women who undergo a natural menopause. The second objective was to determine if a proportion of women suffer excessively rapid postmenopausal bone loss from the spine. If this was the case it was the aim to devise a means of predicting the woman at excess risk; but if all women lost bone at similar rates, the aim was to document changing loss rates over the first 5-8 postmenopausal years. Responding women in six suburban general practices recalled for cervical smears who had their last menstrual period 9- 36 months previously were invited to participate in a longitudinal study of bone loss and the biochemical markers plasma osteocalcin and urinary hydroxyproline. Sixty-four subjects agreed to participate, a response rate of 80%. In the ensuing 5 years, six received hormone replacement therapy and are not reported on. The main outcome measures were rates of spinal bone loss over 5 years, measured by dual photon absorptiometry, and radial bone loss over the first 2 years measured to quantitative computed tomography. Spinal bone loss was similar between individuals, with 94% of the variability in the data being accounted for by a statistical model that assumed parallel rates of bone loss. A less restrictive model allowing women to have different rates of spinal bone loss accounted for 12% more of the remaining variance in the data than the previous model. However, rates of radial bone loss were more dissimilar between women than rates of spinal loss. The results of the biochemical data collected serially showed that the plasma osteocalcin rose slowly to a plateau at 5 years postmenopause; in contrast, the hydroxyproline fell progressively with time over the whole period of study. These results were interpreted as being consistent with diminishing rates of bone destruction which gradually reequilibrated with bone formation as time passed after menopause.

Absorptiometry, Photon↗
PubMed1995

Ocular and renal sarcoidosis.

Sarcoidosis commonly presents in young adults with bilateral hilar lymphadenopathy, lung parenchymal disease and/or skin lesions. Ocular symptoms are the presenting feature in up to 10% of cases, but eye involvement can be demonstrated in around a quarter of all patients. Renal disease is much rarer, and may manifest with hypercalcaemic nephropathy, granulomatous interstitial nephritis, tubular dysfunction or glomerulonephritis. Eye and renal involvement are rarely found together, and may be confused with Wegener's granulomatosis or polyarteritis. We report a case of a young man who developed renal failure due to sarcoidosis soon after presenting with uveitis. The case illustrates an unusual combination of systemic features that may not be widely recognized.

Acute Kidney Injury↗
PubMed1994

The arthropathy of the Muckle-Wells syndrome.

Muckle-Wells syndrome (MWS) is a rare condition characterized by urticaria, arthralgias, deafness and amyloid nephropathy. The arthropathy is poorly documented. We describe the arthropathy occurring in four cases of MWS and discuss the management. Each patient developed recurrent bouts of transient synovitis. One patient developed a persistent sterile pyoarthrosis.

Adult↗