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Biomedical subjects

J Murray

Publications and source records attributed to J Murray.

At least 109 records · Page 6Linked to original sources
PubMed2000

Phase I clinical trial of the chimeric monoclonal antibody (c30.6) in patients with metastatic colorectal cancer.

The murine antibody 30.6 recognizes an antigen that is expressed on a high proportion of colorectal carcinomas and their metastases. We report the results of single-dose escalation studies of the chimeric 30.6 (c30.6) monoclonal antibody in metastatic colorectal cancer, to evaluate its safety, pharmacokinetics, and biodistribution. Recombinant c30.6 (IgG1kappa) antibody was secreted from Chinese hamster ovary cells and purified by a multistep chromatography process. Seventeen patients with metastatic colorectal cancer were enrolled in this dose escalation study. The first four patients were treated with 3 mg of 123I-labeled c30.6, whereas the next 13 received a single dose of unlabeled antibody (maximum dose, 50 mg/m2). The most frequent side effect was a novel syndrome of severe burning and erythema of the face, chest, neck, ears, palms, soles, and genitalia. The frequency of this syndrome was markedly reduced in those patients premedicated with high doses of histamine receptor 1 and histamine receptor 2 blockers. Other side effects were mild and predictable. Biodistribution studies showed a rapid and intensive hepatic uptake. At the 50 mg/m2 level the half-life and maximum serum concentration were 81 +/- 15 h and 7.9 microg/ml, respectively. One patient developed a low-level human anti-c30.6 response. Tumor response was assessed by computed tomography, positron emission tomography scanning, and serial carcinoembryonic antigen measurements. There were no partial responses, although positron emission tomography scanning demonstrated some reduction in tumor activity in three individuals. The chimerized c30.6 antibody is not immunogenic in humans and appears worthy of further study. It does, however, produce a unique profile of side effects that can be well controlled with premedication.

Adult↗
PubMed1999

The adhesive binding site of cadherins revisited.

Cadherins are single-pass transmembrane proteins that, through their homophilic specificity, function in selective cell adhesion and sorting. They have a modular structure that includes an ectodomain composed of tandem 'cadherin domains,' which have a beta-sandwich topology similar to that of immunoglobulin domains. Some early experiments suggest that, for the 'classical' cadherins, the adhesive specificity is encoded in the membrane-distal amino-terminal cadherin domain. Here, we review these data, and present new data that supports this idea.

Animals↗
PubMed1999

The gammaepsilon-c subunit interface in the ATP synthase of Escherichia coli. cross-linking of the epsilon subunit to the c subunit ring does not impair enzyme function, that of gamma to c subunits leads to uncoupling.

Mutants with a cysteine residue in the gamma subunit at position 207 and the epsilon subunit at position 31 were expressed in combination with a c-dimer construct, which contains a single cysteine at position 42 of the second c subunit. These mutants are called gammaY207C/cc'Q42C and epsilonE31C/cc'Q42C, respectively. Cross-linking of epsilon to the c subunit ring was obtained almost to completion without significant effect on any enzyme function, i.e. ATP hydrolysis, ATP synthesis, and ATP hydrolysis-driven proton translocation were all close to that of wild type. The gamma subunit could also be linked to the c subunit ring in more than 90% yield, but this affected coupling. Thus, ATP hydrolysis was increased 2. 5-fold, ATP synthesis was dramatically decreased, and ATP hydrolysis-driven proton translocation was abolished, as measured by the 9-amino-6-chloro-2-methoxyacridinequenching method. These results for epsilonE31C/cc'Q42C indicate that the c subunit ring rotates with the central stalk element. That the gamma-epsilon cross-linked enzyme retains ATPase activity also argues for a gammaepsilon-c subunit rotor. However, the uncoupling induced by cross-linking of gamma to the c subunit ring points to important conformational changes taking place in the gammaepsilon-c subunit interface during this. Blocking these structural changes by cross-linking leads to a proton leak within the F(0).

Amino Acid Substitution↗
PubMed1999

Helical interactions and membrane disposition of the 16-kDa proteolipid subunit of the vacuolar H(+)-ATPase analyzed by cysteine replacement mutagenesis.

Theoretical mechanisms of proton translocation by the vacuolar H(+)-ATPase require that a transmembrane acidic residue of the multicopy 16-kDa proteolipid subunit be exposed at the exterior surface of the membrane sector of the enzyme, contacting the lipid phase. However, structural support for this theoretical mechanism is lacking. To address this, we have used cysteine mutagenesis to produce a molecular model of the 16-kDa proteolipid complex. Transmembrane helical contacts were determined using oxidative cysteine cross-linking, and accessibility of cysteines to the lipid phase was determined by their reactivity to the lipid-soluble probe N-(1-pyrenyl)maleimide. A single model for organization of the four helices of each monomeric proteolipid was the best fit to the experimental data, with helix 1 lining a central pore and helix 2 and helix 3 immediately external to it and forming the principal intermolecular contacts. Helix 4, containing the crucial acidic residue, is peripheral to the complex. The model is consistent not only with theoretical proton transport mechanisms, but has structural similarity to the dodecameric ring complex formed by the related 8-kDa proteolipid of the F(1)F(0)-ATPase. This suggests some commonality between the proton translocating mechanisms of the vacuolar and F(1)F(0)-ATPases.

Cell Membrane↗
PubMed1999

Identification of a novel substitution in the constant region of a gene coding for an amyloidogenic kappa1 light chain.

Current concepts regarding the association between immunoglobulin (Ig) light chain structure and AL amyloidosis (AL) emphasize Ig variable region amino acid substitutions because the majority of light chain amyloid fibrils that have been sequenced contain amino termini of the variable region with only small amounts of the constant region. In this report, we describe a patient with rapidly progressive AL whose amyloid deposits contained primarily monoclonal kappa light chain constant region fragments. We sequenced and analyzed this AL protein, determining that it was an O18-O8 kappa1 variant and that the constant region possessed an unusual Ser-->Asn substitution at position 177. Using pre-mortem bone marrow cells, we cloned and sequenced the cDNA for this AL protein (HCAK1) and, using DNA from post-mortem somatic tissue, we cloned and sequenced the patient's kappa germline O18-O8 donor and kappa constant region (Ckappa) gene segments. The cDNA that coded for HCAK1 contained a variable region that was derived from O18-O8, showing 96.1% homology to germline, and a Ckappa that had a nucleotide substitution (AGC to AAC), resulting in the 177Ser-->Asn replacement. Two Ckappa genes were cloned from somatic tissue DNA, one identical to a known Ckappa sequence and another containing this substitution which likely is a new Ckappa allotype. Our findings indicate that further investigation is warranted into the contributions genetic polymorphisms and light chain constant regions may make to amyloidogenesis.

Amino Acid Sequence↗
PubMed1999

Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia.

BACKGROUND: Patients with the inherited disorder ataxia telangiectasia (A-T) have an increased susceptibility to lymphoid malignancies. In these patients mutations affect both alleles of the A-T gene (ATM). We have looked for mutations in the ATM gene in sporadic cases of B-cell chronic lymphocytic leukaemia (B-CLL). METHODS: 32 cases of B-CLL were analysed by restriction endonuclease fingerprinting to detect mutations within ATM. In six of the cases in which mutations were detected in tumour samples, germline DNA was screened to assess ATM carrier status. The samples in 20 cases were also studied by western blot for abnormal expression of ATM protein. FINDINGS: Expression of the ATM protein was impaired in eight (40%) of the 20 tumours analysed, being absent in three and decreased in five. Mutations within ATM were detected in six (18%) of the 32 patients. These point mutations, deletions, and one insertion were distributed across the coding sequence of ATM. Germline mutations, which indicate ATM carrier status, were found in two of these six patients compared with a frequency within the general population of below 1 in 200. INTERPRETATION: Abnormal expression of ATM protein is a frequent finding in B-CLL. Although the precise function of this protein is unknown, it is thought to have a role in programmed cell death, a deficiency of which would fit with the characteristic phenotype of prolonged cell survival seen in B-CLL tumour cells. Our results also suggest that carriers of ATM mutations may be at a particular risk for the development of B-CLL and this may partly explain the known genetic susceptibility to this disease.

Alleles↗
PubMed1999

Risk factors for hearing loss from meningitis in children: the Children's Hospital experience.

OBJECTIVES: To identify statistically significant risk factors for hearing loss in children with meningitis, determine the overall incidence of hearing loss in a large group of children with confirmed meningitis, and quantify the percentage of children with progressive or fluctuating hearing loss after meningitis. DESIGN: Retrospective analysis. PATIENTS AND OTHER PARTICIPANTS: Four hundred thirty-two children admitted to the Children's Hospital, Birmingham, Ala, from January 1, 1985, to December 31, 1995, with the diagnosis of meningitis. RESULTS: Of 432 children with meningitis, 59 (13.7%) had the development of hearing loss. Of these 59 children, 46 (78.0%) had stable sensorineural hearing loss and 13 (22.0%) had either progressive or fluctuating hearing loss. Of the variables examined using multiple logistic regression backward-elimination modeling, only 5 appeared to be significantly associated with the development of hearing loss: computed tomographic scan evidence of increased intracranial pressure (estimated odds ratio [OR] = 2.3), male sex (OR= 1.9), the common logarithm of glucose levels in the cerebrospinal fluid (OR = 0.58), Streptococcus pneumoniae as the causative organism (OR= 2.1), and the presence of nuchal rigidity (OR = 1.9). In the children with progressive hearing loss, the time for progression varied from 3 months to 4 years before hearing stabilized. CONCLUSIONS: In this study of children diagnosed as having meningitis, hearing loss developed in 59 (13.7%). Forty-six (78.0%) of these children with hearing loss had stable auditory thresholds over time, and 13 (22.0%) exhibited deterioration or fluctuation of acuity over time. Evidence of increased intracranial pressure by computed tomographic scan, male sex, low glucose levels in the patients' cerebrospinal fluid, S pneumoniae as the causative organism, and the presence of nuchal rigidity appear to be significant predictors for future hearing loss.

Child, Preschool↗
PubMed1999

EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: II--A qualitative analysis of the experience of caregiving.

BACKGROUND: Spouses caring for a partner with dementia are subject to physical, psychological and social stresses. In view of the part played by spouse carers in preventing admission to institutional care, a fuller understanding of the subjective experience of caring is an important area of enquiry. Qualitative analysis of their accounts of the difficulties and rewards in looking after their partners may indicate strategies to support them and to alleviate the stresses that they experience. METHOD: Twenty co-resident spouses of people with NINCDS-ADRDA probable dementia of the Alzheimer's type, who had been diagnosed as such within the past 12-36 months, were recruited from service contacts in each of 14 out of the 15 countries of the EU. All completed a semi-structured interview that included open-ended questions about the experience of caring. RESULTS: Overall, the most commonly expressed difficulties reflected: loss of companionship through diminished quality of communication; loss of reciprocity as carers experienced their partners' growing dependency; and deterioration in their partners' social behaviour. Satisfaction from caring stemmed from: a feeling of job satisfaction; continued reciprocity and mutual affection; companionship; and the fulfillment of a sense of duty. CONCLUSION: Spouse carers in the 14 countries described the difficulties and rewards of caring in similar terms. This suggests commonality of experience, in spite of diversity in informal and statutory provision of care for older people between different countries.

Aged↗
PubMed1999

Traumatic injury to the superior mesenteric artery.

BACKGROUND: Superior mesenteric artery (SMA) injuries are rare and devastating injuries incurring very high mortality rates. It is the purpose of this study to review our experience with these injuries, to analyze Fullen's classification based on anatomical zone and injury grade for its predictive value, and to correlate the American Association for the Surgery of Trauma-Organ Injury Scale (AAST-OIS) for abdominal vascular injury with mortality. METHODS: Retrospective study was made over a 65-month period of all patients sustaining SMA injuries in an urban level I trauma center. RESULTS: Thirty-five patients, mean age 31, had a mean Revised Trauma Score of 5.86 and a mean Injurity Severity Score of 23. Mechanisms of injury were penetrating 27 (77%) and blunt 8 (23%). Mean admission systolic blood pressure was 85 mm Hg. Mean estimated blood loss was 8,500 mL and mean total fluid replacement 17,000 mL. Operating room findings were retroperitoneal hematoma in 34 (97%) and "black bowel" in 2 (6%). Number of associated injuries was nonvascular, mean 4.2, and vascular, mean 1.5. Surgical management consisted of ligation in 18 (51%), primary repair in 14 (40%), and interposition graft in 2 (6%). Overall mortality was 19 of 35 (54%). Mortality versus Fullen's zones was zone I, 100%, zone II, 43%, and zones III and IV, 25%. Mortality versus Fullen's ischemia grade was grade 1, 89%, grade 2, 58%, grade 3, 100%, and grade 4, 19%. Mortality versus AAST-OIS: was grade 1, 0%, grade II, 20%, grade III, 0%, grade IV, 59%, and grade V, 88%. CONCLUSIONS: SMA injuries are highly lethal. Most deaths are due to exsanguination. A higher number of associated vascular injuries increases mortality. "Black bowel" is an uncommon finding. Both Fullen's anatomical zones and the AAST-OIS for abdominal vascular injuries correlate with mortality. Fullen's ischemia grade does not.

Adult↗
PubMed1999

Involvement of mitogen-activated protein kinase homologues in the regulation of lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide synthase in RAW 264.7 macrophages.

In RAW 264.7 macrophages lipopolysaccharide (LPS) stimulated the activation of p42 and p44 MAP kinases and their upstream activator mitogen-activated protein (MAP) kinase kinase (MAPKK), and induced the 69-kDa isoform of cyclo-oxygenase-2 (COX-2) and the 130-kDa isoform of nitric oxide synthase (iNOS). PD 098059, a specific inhibitor of the activation of MAPKK, prevented LPS-mediated activation of MAPKK (IC50 = 3.0 +/- 0.1 microM, n = 3) and p42/44 MAP kinases and substantially reduced the induction of COX-2 by approximately 40%-70%, but was without effect upon the induction of iNOS. In parallel, LPS also stimulated the activation of p38 MAP kinase and the MAPKAP kinase-2, a downstream target of p38 MAP kinase. SB 203580, a specific inhibitor of p38 MAP kinase prevented the activation of p38 MAP kinase (IC50 = 3.3 +/- 1.4 microM, n = 3) and MAPKAP kinase-2 by LPS and reduced the induction of COX-2 by approximately 50-90%, with no significant effect upon iNOS expression. These studies indicate the involvement of both the classical p42/44 MAP kinases and p38 MAP kinase in the regulation of COX-2 but not iNOS induction following exposure to LPS.

Animals↗
PubMed1999

Penetrating injuries to the subclavian and axillary vessels.

BACKGROUND: Subclavian and axillary vascular injuries are notorious for their mortality and their difficult surgical exposure. In the present study we analyze our experience with 79 patients and describe the techniques used for surgical access to these vessels. STUDY DESIGN: Retrospective review of the medical records of all patients with penetrating injuries to the subclavian or axillary vessels who had been admitted to 2 Los Angeles trauma centers during a 4-year, 3-month period. RESULTS: Seventy-nine patients were admitted during the study period January 1993 to March 1997 (58 gunshot injuries, 21 other penetrating injuries). The artery was injured in 59 patients and the vein in 40 (20 patients had both arterial and venous injuries). Eighteen patients (23%) were admitted with no signs of life or were in extremis and underwent an emergency room thoracotomy without any survivors. Fifty-eight patients underwent exploration in the operating room, 1 patient with an arteriovenous subclavian fistula was successfully managed with a radiologically placed endovascular stent, and 2 patients with minimal subclavian artery injuries were managed nonoperatively. Overall mortality was 34.2%. Excluding the ER thoracotomies the overall mortality was 14.8%. The mortality for isolated arterial injuries was 20.5%, for isolated venous injuries 50%, and for both vessels 45.0%. The mortality in venous injuries was significantly higher than in arterial injuries (p < 0.05). The standard clavicular incision provided adequate exposure in 32 (50.0%) of the operating room cases. In the other 50% of operating room cases a combination of a clavicular incision with a median sternotomy or thoracotomy was necessary. Proximal subclavian injuries may be accessed through a clavicular incision combined with a median sternotomy irrespective of left or right site location. CONCLUSIONS: Subclavian and axillary vascular injuries remain lethal. A clavicular incision provides satisfactory surgical exposure in about half the patients. In patients with proximal injuries addition of a median sternotomy provides adequate surgical access in both right and left subclavian vessels.

Adult↗
PubMed1999

Gunshot injuries to the liver: the role of selective nonoperative management.

BACKGROUND: Selective nonoperative management of blunt liver injuries has become standard practice in most trauma centers. We evaluated the role of selective nonoperative management of gunshot wounds to the liver. STUDY DESIGN: This was a retrospective review of gunshot wounds to the liver treated in a level I trauma center. Patients with peritoneal signs or hemodynamic instability were operated on without delay. Patients with a soft, nontender abdomen and no signs of heavy bleeding were selected for nonoperative management. Liver injury was diagnosed by CT scan. If peritonitis or signs of substantial internal bleeding developed, an operation was performed; otherwise the patient was discharged within a few days of admission. Analysis was restricted to the group of patients with isolated liver injuries. RESULTS: During a 42-month period, 928 patients were admitted with abdominal gunshot injuries, 152 of whom (16%) had a liver injury. In 52 patients (34% of all liver injuries), the liver was the only injured intraabdominal organ (4 patients had associated kidney or splenic injuries that did not require surgical repair). Thirty-six of the patients (69%) with isolated liver injuries had an emergent operation because of signs of peritonitis or hemodynamic instability. The remaining 16 patients (31%) were selected for nonoperative management (3 patients had associated right kidney injury). Five patients in the observed group required delayed operation because of development of signs of peritonitis (4 patients) or abdominal compartment syndrome (1 patient). The remaining 11 patients (7% of all liver injuries or 21% of isolated liver injuries) were managed successfully without operation. One patient with delayed operation developed multiple complications from abdominal compartment syndrome, and 1 patient in the nonoperative group had a biloma, which was treated with percutaneous drainage. CONCLUSIONS: Selected patients with isolated grades I and II gunshot wounds to the liver can be managed nonoperatively.

Humans↗
PubMed1999

Remodeling of an acellular collagen graft into a physiologically responsive neovessel.

Surgical treatment of vascular disease has become common, creating the need for a readily available, small-diameter vascular graft. However, the use of synthetic materials is limited to grafts larger than 5-6 mm because of the frequency of occlusion observed with smaller-diameter prosthetics. An alternative to synthetic materials would be a biomaterial that could be used in the design of a tissue-engineered graft. We demonstrate that a small-diameter (4 mm) graft constructed from a collagen biomaterial derived from the submucosa of the small intestine and type I bovine collagen has the potential to integrate into the host tissue and provide a scaffold for remodeling into a functional blood vessel. The results obtained using a rabbit arterial bypass model have shown excellent hemostasis and patency. Furthermore, within three months after implantation, the collagen grafts were remodeled into cellularized vessels that exhibited physiological activity in response to vasoactive agents.

Animals↗
PubMed1999

Report of the International Equine Gene Mapping Workshop: male linkage map.

The goal of the First International Equine Gene Mapping Workshop, held in 1995, was the construction of a low density, male linkage map for the horse. For this purpose, the International Horse Reference Family Panel (IHRFP) was established, consisting of 12 paternal half-sib families with 448 half-sib offspring provided by 10 laboratories. Blood samples were collected and DNA extracted in each laboratory and sent to the Lexington laboratory (KY, USA) for dispatch in aliquots to 14 typing laboratories. In total, 161 markers (144 microsatellites, seven blood groups and 10 proteins) were tested for all families for which the sire was heterozygous. Genealogies and typing data were sent for analysis to the INRA laboratory (Jouy-en-Josas, France) according to a specific format and entered into a database with input verification and output processes. Linkage analysis was performed with the CRIMAP program. Significant linkage was detected for 124 loci, of which 95 were unambiguously ordered using a multipoint analysis with an average spacing of 14.2 CM. These loci were distributed among 29 linkage groups. A more comprehensive analysis including synteny group data and FISH data suggested that 26 autosomes out of 31 are covered. The complete map spans 936 CM.

Animals↗
PubMed1999

Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation.

AL (primary or immunoglobulin light chain) amyloidosis (AL) differs from myeloma per se in that tissue deposits of amyloid are found, typically in association with small numbers of clonal plasma cells producing lambda light chains, and also in that AL patients typically present with a predominantly dysfunctional organ-system. This constellation of features - fibrillar deposits comprised of light chains, lambda light chain predominance, and organ-system tropism and dysfunction - remains unexplained. Select patients with AL respond to haemopoietic stem cell transplantation (SCT) with clinical improvement and extended survival, particularly those who do not have cardiac involvement. In order to ascertain whether the organ-system tropism of AL was associated with immunoglublin light chain variable region (Ig VL) germline gene utilization, we attempted to clone, sequence and assign germline donors to the clonal Ig VL genes of 62 AL patients, all of whom were treated with SCT. We succeeded in 39 cases, identifying clonal AL genes derived from donors of the lambdaI (n = 10), lambdaII (n = 5), lambdaIII (n = 6), lambdaVI (n = 11) and KI (n = 7) subtypes. The majority of the donors (IGLV6S1, DPL5, DPL2, DPL23 and LFVK431) were genes that appear in the expressed repertoire <5% of the time, suggesting an intrinsic propensity to form amyloid under certain conditions. Patients whose clones derived from the lambdaVI IGLV6S1 donor uniformly presented with dominant renal involvement while those with other Vlambda or unknown donors often had dominant cardiac or other organ involvement, particularly patients whose clones derived from the lambdaI DPL2 donor. In addition, both early (<3 months) and overall post-SCT survival were significantly better in lambdaVI IGLV6S1 patients compared to patients with other Vlambda donors. These findings indicate that there are important associations in AL amyloidosis among Ig VL gene utilization, organ-system tropism and post-SCT survival.

Adult↗
PubMed1999

Unusual distributions of body fat in AIDS patients: a review of adverse events reported to the Food and Drug Administration.

This report summarizes postmarketing adverse events reported to the Food and Drug Administration (FDA) that describe unusual or abnormal fat distribution in association with anti-retroviral therapies. Reports associated will protease inhibitors were compared to those associated with non-protease inhibitor antiretroviral therapies. The Spontaneous Reporting System (SRS) and Adverse Event Reporting System (AERS) of the FDA MEDWATCH post-marketing surveillance system served as the database. Four protease inhibitors (saquinavir, indinavir, nelfinavir, and ritonavir) and seven nonprotease inhibitors (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, nevirapine, and delavirdine) were searched for reports relating to: weight increase, unusual fat deposition, Cushing's syndrome, or Cushingoid appearance. Each drug was searched for its "life" from time of initial approval through a uniform database cutoff of March 18, 1998. A total of 62 cases of abnormal fat accumulation were reported in association with one or several of the four approved protease inhibitors compared to three cases reported in association with the seven non-protease inhibitor based therapies. Case descriptions varied, and included abdominal fat accumulation, breast enlargement, thick necks, buffalo humps, multiple lipomatous growths, Cushingoid features, centralized fat redistribution, and mesenteric, omental, and retroperitoneal fat accumulation. Some subjects switched or stopped their antiretroviral therapy, others underwent surgery to remove the fat, and many considered their symptoms disabling. The pathophysiologic mechanism for these events remains unclear and a causal link to a specific drug or drug class is uncertain. Patients and clinicians reporting to the MEDWATCH system, however, have clearly associated the development of abnormal body fat with protease inhibitors as opposed to other antiretroviral therapies.

Acquired Immunodeficiency Syndrome↗