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Biomedical subjects

A Morris

Publications and source records attributed to A Morris.

At least 55 records · Page 3Linked to original sources
PubMed2001

Successful allogeneic engraftment of mismatched unrelated cord blood following a nonmyeloablative preparative regimen.

Reduction in the toxicity of allogeneic transplantation with nonmyeloablative induction regimens has expanded the scope of practice to older and more debilitated patients. However, the limited availability of matched sibling donors requires that alternative donor sources be investigated. Reported here are 2 cases of patients with advanced hematologic malignancies without matched siblings, partially matched family members, or matched unrelated donors who successfully underwent nonmyeloablative conditioning therapy followed by infusion of partially matched, unrelated-donor cord blood cells. The patients are in remission and remain 100% donor as assessed by short tandem repeat analysis of the marrow 6 and 12 months following transplantation.

Adult↗
PubMed2001

Consequence of beta 16 and beta 112 replacements on the kinetics of hemoglobin assembly.

The rates of alpha/beta monomer combination of four beta(A) variants (beta 112C --> S, beta 112C --> D, beta 112C --> T, and beta 112C --> V) in the presence and absence of beta 16G --> D (beta(J)) were measured in an attempt to assess the consequences of amino acid substitution at both a surface (beta 16) and an alpha(1)beta(1) interface (beta 112) residue on oxyhemoglobin assembly. Rates of alpha/beta monomer combination determined spectrally in 0.1 M Tris-HCl, 0.1 M NaCl, 1 mM EDTA, pH 7.4, at 21.5 degrees C differed by over 40-fold (22 +/- 2.0 to 0.49 +/- 0.1 x 10(5) M(-1) s(-1)), and were in the order: HbA beta 112S = HbJ beta 16D, beta 112S > HbA beta 112D = HbJ beta 16D, beta 112D > HbA > Hb J > HbA beta 112T = HbJ beta 16D, beta 112T > HbJ beta 16D, beta 112V > HbA beta 112V. This extensive kinetic investigation of single/double amino acid-substituted recombinant hemoglobin molecules, in conjunction with molecular modeling studies, has allowed examination of an array of unique alpha/beta subunit interactions and assembly processes.

Amino Acid Substitution↗
PubMed2001

Has misdiagnosis of appendicitis decreased over time? A population-based analysis.

CONTEXT: Misdiagnosis of presumed appendicitis is an adverse outcome that leads to unnecessary surgery. Computed tomography, ultrasonography, and laparoscopy have been suggested for use in patients with equivocal signs of appendicitis to decrease unnecessary surgery. OBJECTIVE: To determine if frequency of misdiagnosis preceding appendectomy has decreased with increased availability of computed tomography, ultrasonography, and laparoscopy. DESIGN, SETTING, AND PATIENTS: Retrospective, population-based cohort study of data from a Washington State hospital discharge database for 85 790 residents assigned International Classification of Diseases, Ninth Revision procedure codes for appendectomy, and United States Census Bureau data for 1987-1998. MAIN OUTCOME MEASURE: Population-based age- and sex-standardized incidence of appendectomy with acute appendicitis (perforated or not) or with a normal appendix. RESULTS: Among 63 707 nonincidental appendectomy patients, 84.5% had appendicitis (25.8% with perforation) and 15.5% had no associated diagnosis of appendicitis. After adjusting for age and sex, the population-based incidence of unnecessary appendectomy and of appendicitis with perforation did not change significantly over time. Among women of reproductive age, the population-based incidence of misdiagnosis increased 1% per year (P =.005). The incidence of misdiagnosis increased 8% yearly in patients older than 65 years (P<.001) but did not change significantly in children younger than 5 years (P =.17). The proportion of patients undergoing laparoscopic appendectomy who were misdiagnosed was significantly higher than that of open appendectomy patients (19.6% vs 15.5%; P<.001). CONCLUSION: Contrary to expectation, the frequency of misdiagnosis leading to unnecessary appendectomy has not changed with the introduction of computed tomography, ultrasonography, and laparoscopy, nor has the frequency of perforation decreased. These data suggest that on a population level, diagnosis of appendicitis has not improved with the availability of advanced diagnostic testing.

Adolescent↗
PubMed2001

A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect.

Dominant optic atrophy (DOA) is a hereditary optic neuropathy characterised by decreased visual acuity, colour vision deficits, centro-coecal scotoma and optic nerve pallor. The gene OPA1, encoding a dynamin-related GTPase, has recently been identified within the genetic linkage interval for the major locus for DOA on chromosome 3q28 and shown to harbour genetic aberrations segregating with disease in DOA families. The prevalence of the disorder in Denmark is reported to be the highest of any geographical location, suggestive of a founder effect. In order to establish the genetic basis of disease in a sample of 33 apparently unrelated Danish families, we screened DNA from affected members for OPA1 gene mutations by heteroduplex analysis and direct sequencing. A novel identical mutation in exon 28 (2826delT) was associated with DOA in 14 pedigrees and led to a frameshift and abnormal OPA1 protein -COOH terminus. Haplotype analysis of a region of approximately 1 Mb flanking the OPA1 gene using eight polymorphic markers revealed a common haplotype shared by all 14 patients; this haplotype was markedly over-represented compared with ethnically matched controls. Statistical analysis confirmed significant linkage disequilibrium with DOA over approximately 600 kb encompassing the disease mutation. We have therefore demonstrated that the relatively high frequency of DOA in Denmark is attributable to a founder mutation responsible for approximately 42% of the examined families and suggest that presymptomatic screening for the (2826delT) mutation may facilitate diagnosis and genetic counselling in a significant proportion of DOA patients of Danish ancestry.

Alleles↗
PubMed2001

Neonatal screening for medium-chain acyl-CoA dehydrogenase deficiency.

Neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency has not yet been introduced in the UK, primarily because of uncertainty about the natural history of the disorder and concerns about the specificity of the screening test. To obtain data on these issues, we did a retrospective study in which we analysed the concentrations of acylcarnitines in stored neonatal blood spots, and reviewed patients with high octanoylcarnitine concentrations at age 7-9 years. The high morbidity and mortality associated with the disorder, and the specificity of acylcarnitine analysis seen in our study support the introduction of screening for MCAD deficiency.

Acyl-CoA Dehydrogenase↗
PubMed2001

Activation of ATP-ubiquitin-dependent proteolysis in skeletal muscle in vivo and murine myoblasts in vitro by a proteolysis-inducing factor (PIF).

Loss of skeletal muscle is a major factor in the poor survival of patients with cancer cachexia. This study examines the mechanism of catabolism of skeletal muscle by a tumour product, proteolysis-inducing factor (PIF). Intravenous administration of PIF to normal mice produced a rapid decrease in body weight (1.55 +/- 0.12 g in 24 h) that was accompanied by increased mRNA levels for ubiquitin, the Mr 14 000 ubiquitin carrier-protein, E2, and the C9 proteasome subunit in gastrocnemius muscle. There was also increased protein levels of the 20S proteasome core and 19S regulatory subunit, detectable by immunoblotting, suggesting activation of the ATP-ubiquitin-dependent proteolytic pathway. An increased protein catabolism was also seen in C(2)C(12)myoblasts within 24 h of PIF addition with a bell-shaped dose-response curve and a maximal effect at 2-4 nM. The enhanced protein degradation was attenuated by anti-PIF antibody and by the proteasome inhibitors MG115 and lactacystin. Glycerol gradient analysis of proteasomes from PIF-treated cells showed an elevation in chymotrypsin-like activity, while Western analysis showed a dose-related increase in expression of MSSI, an ATPase that is a regulatory subunit of the proteasome, with a dose-response curve similar to that for protein degradation. These results confirm that PIF acts directly to stimulate the proteasome pathway in muscle cells and may play a pivotal role in protein catabolism in cancer cachexia.

Adenosine Triphosphate↗
PubMed2001

Pertussis is a frequent cause of prolonged cough illness in adults and adolescents.

Although pertussis is increasingly recognized as a cause of prolonged cough illness in adolescents and adults, its prevalence is not well established. We evaluated pertussis infection in 442 adolescents and adults > or = 12 years old (mean age, 41.3 years) who had a cough-related illness of 7--56 days' duration. For 4 patients (0.9%), results of nasopharyngeal culture or PCR were positive for Bordetella pertussis; for 10 patients (2.3%), either results of culture or PCR were positive or pertussis antibody titers increased 4-fold. Eighty-eight patients (19.9%) had either laboratory-confirmed pertussis or laboratory evidence of pertussis. These patients had significantly longer duration of cough than did patients without laboratory evidence of pertussis (56 days vs. 46 days), and more of them had vomiting with cough (45.5% vs. 28.5%, respectively). Pertussis is a common cause of prolonged cough illness in adolescents and adults and is frequently associated with other symptoms of whooping cough.

Adolescent↗
PubMed2001

Usefulness of the triple test score for palpable breast masses; discussion 1012-3.

HYPOTHESIS: The triple test score (TTS) is useful and accurate for evaluating palpable breast masses. DESIGN: Diagnostic test study. SETTING: University hospital multidisciplinary breast clinic. PATIENTS: Four hundred seventy-nine women with 484 palpable breast lesions evaluated by TTS from 1991 through July 2000. MAIN OUTCOME MEASURES: Physical examination, mammography, and fine-needle aspiration were each assigned a score of 1, 2, or 3 for benign, suspicious, or malignant results; the TTS is the sum of these scores. The TTS has a minimum score of 3 (concordant benign) and a maximum score of 9 (concordant malignant). The TTS was correlated with subsequent histopathologic analysis or follow-up. INTERVENTIONS: The TTS was prospectively calculated for each mass. Lesions with a TTS greater than or equal to 5 were excised for histologic confirmation, whereas lesions with scores less than or equal to 4 were either excised (n = 60) or followed clinically (n = 255). RESULTS: All lesions with TTS less than or equal to 4 were benign on clinical follow-up, including 8 for which the fine-needle aspiration was the suspicious component. Of the 60 biopsied lesions, 51 were normal breast tissue, 4 showed fibrocystic change, 1 was a papilloma, and 4 were atypical hyperplasia. All lesions with a TTS greater than or equal to 6 (n = 130) were confirmed to be malignant on biopsy. Thus, a TTS less than or equal to 4 has a specificity of 100% and a TTS greater than or equal to 6 has a sensitivity of 100%. Of the 39 lesions (8%) with scores of 5, 19 (49%) were malignant, and 20 (51%) were benign. CONCLUSIONS: The TTS reliably guides evaluation and treatment of palpable breast masses. Masses scoring 3 or 4 are always benign. Masses with scores greater than or equal to 6 are malignant and should be treated accordingly. Confirmatory biopsy is required only for the 8% of the masses that receive a TTS of 5.

Biopsy, Needle↗
PubMed2001

Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo.

The OX-40 receptor (OX-40R) is a member of the tumor necrosis factor receptor (TNF-R) superfamily that is expressed on activated CD4+ T cells. The OX-40R is a costimulatory molecule that induces CD4+ T cell activation when engaged by its ligand (OX-40 L; found on antigen presenting cells). In human and murine tumors, we have shown upregulation of the OX-40R on CD4+ T cells from tumor-infiltrating lymphocytes (TIL) and tumor-draining lymph node cells (TDLNC) but not on systemic CD4+ T cells, such as peripheral blood lymphocytes (PBL) or splenocytes. In order to examine potentially heightened anti-tumor immunity through enhanced costimulation when engaging OX-40R in vivo, we inoculated mice with a murine mammary cancer cell line (SM1) and then treated with a soluble form of the OX-40 L. Mice injected with a lethal inoculum of SM1 cells were given two intraperitoneal injections (days 3 and 7 post-inoculation) of 100 microg soluble OX-40 L. Seven of 28 treated mice survived the lethal tumor inoculum, as compared to one of 28 control mice, demonstrating a significant survival benefit with treatment (p = 0.0136, log rank analysis). Mice that did not develop tumor by day 90 were rechallenged; all remained tumor-free. Mice were also injected with a second mammary tumor line (4T1) and treated with OX-40L:Ig with similar therapeutic results. Activation of OX-40R+ CD4+ T cells during mammary cancer priming stimulated an antitumor immune response resulting in enhanced survival and protective anti-tumor immunity. These results should have practical applications for treatment modalities for patients with breast cancer.

Animals↗
PubMed2001

Carboxyl-terminal modification alters the subunit interactions and assembly pathways of normal and sickle hemoglobins.

Parallel isofocusing studies established that carboxypeptidase A removal of the His-146 (HC3) and Tyr-145 (HC2) residues of beta heme subunits affected the assembly properties of both Des beta(A) and Des beta(S) with alpha heme chains, albeit to differing degrees. Indeed, the rate of Des beta(A) oligomer dissociation (k1), as determined by visible spectroscopy, was 4.3-fold faster than that of its native beta(A) counterpart. Furthermore, Soret spectral studies have affirmed distinct rates of normal (HbA), sickle (HbS), and Des HbA hemoglobin assembly (k'2) from their alpha and beta [Des beta(A)] heme-containing monomers. Matching kinetic analysis of Des beta(A) and Des beta(S) chain assembly (with an identical a chain) revealed 4.6- and 7.8-fold faster combination rates than those seen for beta(A) and beta(S) chains, respectively. This 3-fold disparity in rates strongly supports the critical role of the beta-6 (A3) residue, and its amino-terminal region, in a chain partner recognition and subsequent human hemoglobin assembly.

Carboxypeptidases↗
PubMed2001

SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis.

BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.

Adolescent↗
PubMed2001

Interaction of cytokines and growth factor in the regulation of verotoxin-induced apoptosis in cultured human endothelial cells.

The role of CD77, inflammatory cytokines and endothelial cell growth factor (ECGF) in verotoxin (VT)-induced apoptosis in human umbilical vein endothelial cells (HUVECs) was studied. Apoptosis was detected using annexin V and propidium iodide staining. The expression of CD77 antigen was measured on a FACStar flow cytometer using specific monoclonal antibodies. Our experiments showed that HUVECs had very low initial levels of CD77 and were resistant to VT. Treatment with tumour necrosis factor alpha (TNF-alpha) resulted in a significant upregulation of CD77 expression and sensitized endothelial cells to VT-mediated apoptosis. HUVECs incubated with a combination of cytokines [TNF-alpha and interferon gamma (IFN-gamma), both 500 U/ml] showed more pronounced upregulation of CD77 expression (> sixfold at 48 h) and underwent apoptosis, suggesting that TNF-alpha and IFN-gamma have a synergistic effect on CD77 expression in HUVECs and can induce apoptosis without VT. Cells pretreated with TNF-alpha and IFN-gamma and incubated with VT showed the most pronounced (14-fold) increase in CD77 expression. ECGF had a partial protective effect against cytokine- and VT-induced apoptosis. Taken together, our data suggest that CD77 antigen is involved in the regulation of endothelial cell apoptosis.

Apoptosis↗
PubMed2001

Characterization of an antibody to the human melatonin mt1 receptor.

Melatonin acts via high affinity, G-protein coupled, seven transmembrane domain receptors. To precisely localize these receptors, antibodies were raised in chickens against a 15 amino acid fragment at the intracellular C-terminal region of the human melatonin receptor subtype mt1 (DSSNDVADRVKWKPS, mt(1338-352)). A chimeric form of the receptor with a hydrophilic Flag peptide (DYKDDDDK) in sequence with the extracellular N-terminus (Flag-mt1) was generated by polymerase chain reaction and expressed in mammalian cell lines. An IgY antibody (Y31), which gave high antibody titres by enzyme-linked immunosorbent assay, was used to localize Flag-mt1 in stably transfected cells by immunofluoresence. Flag-mt1 localization with Y31 was identical to that obtained with the M5 antibody directed against the Flag epitope and was mainly localized to the Golgi apparatus with some staining at the cell surface. No staining was seen in untransfected cells with either antibody. Y31 staining was abolished using antibody preabsorbed with peptide antigen. Y31 immunofluorescence in fetal human kidney sections was restricted to nephrogenic regions and matched that of 2-((125)I)iodomelatonin binding and mt1 gene expression by in situ hybridization. Y31 was used to immunoprecipitate biotinylated membrane proteins from Flag-mt1 stably transfected and untransfected CHO cells. Western blotting of immunoprecipitated proteins revealed two major bands specific to stably transfected cells, one at 63 kDa and one at 86 kDa. The first band almost certainly corresponds to the glycosylated form of Flag-mt1 and the second band to receptor dimers. Thus, Y31 antibody is suitable for use in detecting the human mt1 receptor subtype in tissues and in transfected cells.

Amino Acid Sequence↗
PubMed2001

The role of n-6 polyunsaturated fat in stable asthmatics.

We investigated in a clinical setting whether increased intake of linoleic acid alters respiratory function in 26 mild asthmatics. Subjects completed a 16-week-dietary intervention comprising 8 weeks eating an enriched n-6 polyunsaturated fat diet (9.2% energy from linoleic acid) and consuming either a high monounsaturated or saturated fat diet in a random cross-over resign for 8 weeks. Neither FEV1 nor PC20 values changed significantly after increased linoleic acid consumption when compared with the other diets. Increased consumption of linoleic acid caused a 20% rise (p < or = 0.01) in plasma linoleic acid, a 38% decrease (p < or = 0.01) in plasma eicosapentaenoic acid, but no change in arachidonic acid. There were no changes in symptom scores or bronchodilator use.

Asthma↗