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Biomedical subjects

K McIntyre

Publications and source records attributed to K McIntyre.

At least 19 recordsLinked to original sources

Substantial between-hospital variation in outcome following first emergency admission for heart failure.

BACKGROUND: Following hospitalization with a range of cardiovascular disorders, substantial variation has been noted in clinical outcome, both between and within countries. OBJECTIVES: To examine the variation, between hospitals, in the clinical outcomes of death and readmission following hospitalization with heart failure in Scotland. Setting All 29 acute hospitals in Scotland with more than 200 beds. PATIENTS: All 31 452 patients discharged from these hospitals between January 1990 and December 1995 with a first-ever, primary, diagnosis at discharge/death of heart failure. ANALYSIS: An analysis of the Scottish database of discharge summaries linking index admissions with subsequent admissions and deaths. Death rates and readmission rates were adjusted for baseline age, co-morbidity and socio-economic status and were calculated at different time periods (inpatient, 30 days, 1 year). Rates were calculated separately for large teaching hospitals (n=6, category A), large general hospitals with specialist units (n=8, category B) and medium sized general hospitals with limited specialist units (n=15 category C). RESULTS: A total of 31 452 patients were discharged between 1990-1995 - 10 219 (33%), 9735 (31%) and 11 498 (37%) to category A, B and C hospitals, respectively. The national, average, inpatient case fatality rate was 15.3%, ranging, in individual hospitals, from the lowest rate of 8.5% to the highest rate of 23.4%. The average 1 year case fatality rate was 42.4%, ranging between 35.3% and 50.8%. A similar two- to threefold variation was found in hospital readmission rates - thus the average 30 day readmission rate was 5.3% (lowest 3.3%, highest 7.3%). This variation, in both case-fatality and readmission rates, was apparent within all three groups of hospitals and persisted after adjustment for the baseline factors outlined above. CONCLUSIONS: A patient admitted to one Scottish hospital with heart failure may be two to three times more likely to die or be readmitted, both in the short and longer term, compared to a patient admitted to another hospital. Although we may not have accounted for some sources of variation, it is both surprising and disturbing that large, statistically significant, differences in adjusted death and readmission rates can apparently exist for such an important condition in a relatively small country with generally homogenous health care provision. Further, detailed investigation of this apparent variation is required.

Age Factors↗

The Saccharomyces cerevisiae MUM2 gene interacts with the DNA replication machinery and is required for meiotic levels of double strand breaks.

The Saccharomyces cerevisiae MUM2 gene is essential for meiotic, but not mitotic, DNA replication and thus sporulation. Genetic interactions between MUM2 and a component of the origin recognition complex and polymerase alpha-primase suggest that MUM2 influences the function of the DNA replication machinery. Early meiotic gene expression is induced to a much greater extent in mum2 cells than in meiotic cells treated with the DNA synthesis inhibitor hydroxyurea. This result indicates that the mum2 meiotic arrest is downstream of the arrest induced by hydroxyurea and suggests that DNA synthesis is initiated in the mutant. Genetic analyses indicate that the recombination that occurs in mum2 mutants is dependent on the normal recombination machinery and on synaptonemal complex components and therefore is not a consequence of lesions created by incompletely replicated DNA. Both meiotic ectopic and allelic recombination are similarly reduced in the mum2 mutant, and the levels are consistent with the levels of meiosis-specific DSBs that are generated. Cytological analyses of mum2 mutants show that chromosome pairing and synapsis occur, although at reduced levels compared to wild type. Given the near-wild-type levels of meiotic gene expression, pairing, and synapsis, we suggest that the reduction in DNA replication is directly responsible for the reduced level of DSBs and meiotic recombination.

Alleles↗

Autologous graft-versus-host disease induction in advanced breast cancer: role of peripheral blood progenitor cells.

The purpose of the present study was to investigate the impact of the use of peripheral blood progenitor cells (PBPCs) on the induction of autologous graft-versus-host disease (GVHD) in patients with advanced breast cancer. 14 women with stage IIIB and 36 women with stage IV breast cancer received cyclosporine (CsA) 2.5 mg kg-1 i.v. daily, d 0-28, and interferon-gamma (IFNg) 0.025 mg/m2 s.c. qod, d7-28, following PBPC-T +/- bone marrow transplantation (BMT). Preceding high-dose chemotherapy consisted of cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2. Histologically proven > or = grade II cutaneous GVHD was induced in18/50 (36%) of patients and was independent of the source of haematopoietic support. In vitro studies showed that post-transplant, 76% of patients had developed auto-cytotoxicity against their own pre-transplant PHA-lymphoblasts. A significant correlation between the occurrence of GVHD > or = grade II and cytolysis was observed in the NK cell-line K562 and the T47D breast cancer cell-line. With a median follow-up of 2(1/2) years, the overall survival (OS) is 58%, the disease-free survival (DFS) 26%, both independent of the development of GVHD and similar to what has been observed in other studies on high-dose chemotherapy in advanced breast cancer. It therefore remains unclear whether the induction of autologous GVHD with the occurrence of auto-cytotoxic lymphocytes can result in an anti-tumour effect in this group of patients.

Adult↗

Serum lysozyme activity can differentiate infection from rejection in organ transplant recipients.

BACKGROUND: The presentation of infection in immunocompromised patients can be subtle. Patients often undergo extensive testing and empiric treatment for rejection and infection while awaiting the results of the biopsy and culture results. Delay in diagnosis of either entity can result in a worse clinical outcome. Lysozyme activity has been found to be both a sensitive and a specific marker for infection in laboratory animals and trauma patients. Our goal was to determine whether lysozyme activity could serve as a reliable marker for infection in immunocompromised organ transplant recipients. METHODS: Transplant recipients from three clinical categories were enrolled in this study. Group 1 (n = 16) were patients hospitalized for sepsis (culture-positive), and Group 2 (n = 13) for biopsy-proven rejection. Group 3 (n = 51) were recipients who had routine blood sampling in the clinic. In Groups 1 and 2, blood was collected within 24 h of hospital admission and centrifuged, and serum samples were stored at 80 degrees C until processing. Lysozyme activity was assayed by turbidimetric measurement on a sample of a standard suspension (0.15 mg/ml) of Micrococcus lysodeikticus in buffer using a spectrophotometer to read the optical density at 450 nm. The lysozyme activity level was then determined by the measuring activity at 1 min subtracted from activity at 4 min. White blood cell count was determined by using a flow cytometer. Statistical comparisons between groups were made using paired Student's t test. RESULTS: Serum lysozyme was found to be significantly elevated in Group 1; the mean level of activity was 60.1 +/- 13 (P < 0.05) compared to the level of activity in Group 2, mean 41.1 +/- 11, and Group 3, mean 40.8 +/- 13. A level of 45 units of activity/ml of serum or above indicated infection and not rejection in the patients admitted to the hospital. CONCLUSIONS: These findings indicate that the lysozyme activity assay appears to be useful in differentiating infection from rejection in transplant recipients.

Adolescent↗

Evaluation of Simulated Presence: a personalized approach to enhance well-being in persons with Alzheimer's disease.

OBJECTIVE: To evaluate the efficacy of Simulated Presence, a personalized approach to enhance well-being among nursing home residents with Alzheimer's disease and related dementia's (ADRD). DESIGN: Latin-Square, double blinded, 3-factor design with restrictive randomization of three treatments (the study intervention, a placebo audio tape of a person reading the newspaper, and usual care). The three factors were treatment, time, and facility type. SETTING: Nine nursing homes in Eastern Massachusetts and Southern New Hampshire. PARTICIPANTS: Fifty-four subjects with documented ADRD who were aged 50 years or older, medically stable, had resided in their current nursing home for at least 3 months, and who had no planned discharge. All subjects had a history of agitated or withdrawn behaviors. INTERVENTION: The purpose of Simulated Presence is to provide a personalized intervention for persons with moderate to severe cognitive impairment. Through a unique testing process, some of the best loved memories of the ADRD person's lifetime are identified and then those memories are introduced to the patient in the format of a telephone conversation using a continuous play audio tape system. The intervention may be used for extended periods of time because each repetition is viewed as a fresh, live telephone call as a result of the short-term memory deficit of the person with ADRD. MEASUREMENTS: Direct observations of outcomes included using a newly developed scale, the Scale for the Observation of Agitation in Persons with Dementia, an agitation visual analog scale, the Positive Affect Rating Scale (mood and "interest"), a withdrawal visual analog scale, and facial diagrams of mood. Reported measures included daily staff observation logs of responses to interventions offered, and weekly staff surveys using the short-form Cohen-Mansfield Agitation Inventory and the Multidimensional Observation Scale for Elderly Subjects (mood and "interest"). Severity of dementia was assessed by the Mini-Mental State Exam, the Test for Severe Impairment, the Bedford Alzheimer's Nursing Scale, and the ADL Self-Performance Scale. RESULTS: Chi-square analysis of direct observations, using facial diagrams, revealed that Simulated Presence was equivalent to usual care (P = .141) and superior to placebo for producing a happy facial expression (P = .001). A positive effect was also documented in nursing staff observation logs using Analysis of Variance techniques (ANOVA) for subjects during Simulated Presence phases compared with the placebo phases (P < .001) and usual care phases (P < .001). According to ANOVA analyses of "interest" from weekly surveys, Simulated Presence was superior to both usual care (P = .001) and placebo (P = .008). We were unable to find evidence of significant differences (P < .05) among interventions for other direct observations and weekly reports of overall agitation or mood aspects of withdrawal. Subjects accepted the intervention most of the time, except for five subjects who refused it more than 50% of the time. CONCLUSION: This study provided evidence that Simulated Presence can be effective in enhancing well-being and decreasing problem behaviors in the nursing home setting as a substitute for or complement to usual care.

Aged↗

Randomized, double-blind, placebo-controlled trial to evaluate the hematopoietic growth factor PIXY321 after moderate-dose fluorouracil, doxorubicin, and cyclophosphamide in stage II and III breast cancer.

PURPOSE: To measure the effect of PIXY321 (granulocyte-macrophage colony-stimulating factor/interleukin-3 S. cerevisiae fusion protein) on the incidence, duration, and complications of neutropenia and thrombocytopenia after moderate-dose fluorouracil 600 mg/m(2), doxorubicin 60 mg/m(2), and cyclophosphamide 750 mg/m(2) (FAC) chemotherapy in patients with stage II and III breast cancer. PATIENTS AND METHODS: In this multicenter, randomized, double-blind placebo-controlled trial, 71 women were to receive four 21-day cycles of treatment with moderate-dose FAC chemotherapy by short intravenous infusion on day 1, followed by either placebo or PIXY321 (375 microg/m(2) subcutaneously twice a day) on days 3 to 15. All patients were to receive prophylactic oral ciprofloxacin when the absolute neutrophil count was less than 1,000/microL. RESULTS: PIXY321 significantly reduced the incidence and duration of grade 3 and grade 4 neutropenia in cycles 1 and 2 and the duration of grade 3 neutropenia in cycles 1 through 4. In cycles 3 and 4, grade 3 thrombocytopenia was significantly more common with PIXY321 (P <.05). Two patients, both in the PIXY321 group, required platelet transfusions. Fever and hospitalization for intravenous antibiotics were significantly more common in the PIXY321 group during cycle 1 only. More patients in the PIXY321 group achieved hematologic recovery by day 22 in cycles 1 through 3, and time to recovery was significantly shorter with PIXY321 in all cycles. FAC dose intensity was roughly 2% higher in the PIXY321 group (P = NS). Nonhematologic events of any intensity occurring with significantly greater overall frequency in the PIXY321 group included injection-site reactions, fever, chills, abdominal pain, and arthralgia. No patient died on study or within 30 days of her last dose of study drug. CONCLUSION: PIXY321 decreased the incidence and duration of FAC-induced grade 3 and 4 neutropenia in cycles 1 and 2 and significantly shortened the time to hematologic recovery in all cycles. However, it produced more systemic toxicity as well as thrombocytopenia in cycles 3 and 4.

Adenocarcinoma↗

Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection.

HIV-specific cytotoxic T lymphocytes (CTLs) play an important role in the immune response to HIV infection. Long-term nonprogressors (LTNPs) or slow progressors (SPs) in HIV infection may make qualitatively different CTL responses compared to those generated by seropositive individuals who progress to disease at a faster rate. The class I molecule HLA-B*57 has been identified as one restriction element overrepresented in SP groups studied, and, together with the closely related molecule HLA-B*58, occurs commonly in ethnic groups where HIV is most prevalent. In this study, we have identified five new HLA-B*57-restricted CTL epitopes recognized by SP donors, one of which is also HLA-B*5801 restricted. These HLA-B*57-restricted responses represent the dominant HIV-specific CTL response in each of the SP donors tested. These and other such epitopes may be an important component in future vaccine design.

Amino Acid Sequence↗

Endoscopic management of benign and malignant biliary strictures.

BACKGROUND: It is now possible to manage most extrahepatic bile duct strictures, benign or malignant, using endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic dilatation and stenting. METHODS: Over a 5-year period we treated 218 patients with strictures of extrahepatic bile ducts. Eighty-six patients had benign biliary stricture. Endoscopic treatment was performed in 67 (78%) of these patients. Open surgical biliary drainage was preferred in 12 patients (14%), and 7 patients (8%) were managed conservatively without stenting or surgery. One hundred and thirty-two patients had malignant biliary stricture. One hundred and one patients (77%) underwent endoscopic stent placement. Thirty-one patients (23%) underwent surgery for potential curative resection after diagnostic ERCP. The average life span in the malignant stricture group was 5 months (range 0.1 to 25 months) after the initial endoscopic procedure. RESULTS: Altogether 313 endoscopic procedures in 218 patients were performed for benign and malignant bile duct strictures. Complications included hemorrhage in 8 (3%), pancreatitis in 10 (3%), and suspected retroperitoneal perforation in 2 (0.6%). There were no ERCP related deaths; one patient died of uncontrolled bleeding from transhepatic stenting. In benign strictures, there has been no recurrence of strictures after the last stent removal with a mean followup of 21 months (range 0.1 to 31 months). All complications were successfully treated conservatively. CONCLUSIONS: Endoscopic management of benign and malignant biliary stricture is possible with minimal morbidity and mortality and should be considered an acceptable option to surgical management.

Bile Duct Diseases↗

Role of CD14 in hemorrhagic shock-induced alterations of the monocyte tumor necrosis factor response to endotoxin.

OBJECTIVE: To determine if the shock-induced alterations in whole blood monocyte tumor necrosis factor (TNF) response are mediated by the CD14 receptor. DESIGN: Prospective controlled animals experiments. MATERIALS AND METHODS: New Zealand White rabbits (n = 15) were subjected to hemorrhage and resuscitation. Blood samples obtained before shock and 24, 72, and 120 hours after shock were stimulated with lipopolysaccharide in the presence or absence of the anti-CD14 monoclonal antibody, 63D3. Tumor necrosis factor was assayed using L929 cells. MEASUREMENTS AND MAIN RESULTS: There are no detectable TNF activity in unstimulated blood. The CD14 inhibition resulted in a 55% reduction in baseline TNF activity. After shock, there was a marked increase in TNF activity with lipopolysaccharide stimulation. Addition of 63D3 resulted in a dose-dependent 95% reduction in TNF activity at 24 and 72 hours after shock, (p < 0.05). CONCLUSION: The enhanced whole blood monocyte TNF response after hemorrhage is CD14 dependent.

Animals↗

Reproduction in mice lacking a functional type 1 IL-1 receptor.

Growth factors and cytokines have been identified in having critical roles at mediating maternal-fetal interactions during pregnancy, with interleukin-1 being a recently implicated factor. Previous experiments indicated that repeated intraperitoneal injections of the Il-1 receptor antagonist (Il-1Ra), which inhibits binding of interleukin-1 (Il-1) to the type 1 Il-1 receptor (Il-1Rt1) blocks blastocyst implantation in superovulated mice. To gain a greater insight into the role of Il-1 receptor in implantation, we analyzed the reproduction of mice deficient for the Il-1Rt1. Our results show that mice lacking this receptor do not exhibit any profound alterations in their reproduction, apart from a slight reduction in mean litter size. Furthermore, repeated intraperitoneal injections of either IL-1Ra or the monoclonal antibody 35F5, which also blocks ligand binding to the Il-1Rt1, did not affect embryo implantation in either wild type and Il-1 receptor deficient mice.

Animals↗

X-ray structure analysis of the iron-dependent superoxide dismutase from Mycobacterium tuberculosis at 2.0 Angstroms resolution reveals novel dimer-dimer interactions.

The X-ray structure of the tetrameric iron-dependent superoxide dismutase from Mycobacterium tuberculosis has been refined to an R-factor of 0.167 and a correlation coefficient of 0.954 at 2.0 A resolution. The crystals are monoclinic P2(1) and have four subunits related by strong non-crystallographic 222 (or D2) symmetry in the asymmetric unit. 198 of the 207 amino acids of each subunit are defined by the electron density which shows that they adopt the conserved fold of other iron- or manganese-dependent SODs. The structure can be divided into two domains, the N-terminal domain involving an extended region followed by two projecting antiparallel alpha-helices, and the C-terminal domain containing four more helical segments with a three-stranded antiparallel beta-sheet inserted sequentially between the fourth and fifth helices. The catalytic iron is co-ordinated by five ligands: three histidines (residues 28, 76 and 164), one aspartate (160) and a solvent molecule. The inferred positions of protons at the active site are consistent with the solvent ligand being a hydroxide ion. This ligand interacts with His145 in the Mycobacterium tuberculosis SOD. In the highly homologous Mycobacterium leprae Mn-SOD, the histidine is replaced by glutamine, this being the only significant residue difference within 10 A of the Fe3+. The nature of the amino acid at this position may influence the metal ion specificity of these enzymes. The subunits of the Mycobacterium tuberculosis SOD associate by polar contacts to form dimers, which closely resemble those of other dimeric or tetrameric Fe- or Mn-SODs. However, the dimer-dimer interactions within the tetramer are novel, being dominated by dimerisation of the 144 to 152 loop regions which connect the outer two beta-strands of the three-membered beta-sheet. This contrasts strongly with the other tetrameric Fe- or Mn-SODs where the dimer-dimer association is dominated by the projecting alpha alpha-turn in the N-terminal domain.

Amino Acid Sequence↗

Liposomes modulate Kupffer cell endotoxin response.

OBJECTIVES: To test the hypothesis that pretreatment with liposomes enriched with the omega 3 fatty acid docosahexaenoic acid (22:6 omega 3) will alter the Kupffer's cell and systemic cytokine (tumor necrosis factor and interleukin-6) response to endotoxin challenge, and to demonstrate alterations in Kupffer's cell phospholipid fatty acid composition after in vivo liposome treatment. DESIGN: Nonrandomized controlled laboratory investigation in Wistar rats. INTERVENTIONS: Animals were assigned to three pretreatment groups: no liposomes; liposomes, 100 mg/kg; or liposomes, 400 mg/kg given by bolus intravenous injection with the animals under inhalation anesthesia. Eighteen hours after liposome treatment, each group was challenged with Escherichia coli lipopolysaccharide (3 mg/kg intraperitoneally in 10 mL of lactated Ringer's solution) or lactated Ringer's solution only. In a separate set of experiments, Kupffer's cells were obtained from animals pretreated with liposome, 400 mg/kg, or controls and challenged with lipopolysaccharide (1, 100, or 10(4) ng/mL) in vitro. OUTCOME MEASURES: Serum and Kupffer's cell supernatant tumor necrosis factor and interleukin-6 bioactivity, Kupffer's cell phospholipid fatty acid composition, survival, and liver histologic findings. RESULTS: In vivo liposome pretreatment (400 mg/kg) resulted in significant increases in serum tumor necrosis factor and interleukin-6 levels 90 minutes after intraperitoneal lipopolysaccharide challenge (P < .05 vs no liposomes). Kupffer's cells isolated from liposome-treated animals (400 mg/kg) compared with untreated controls release significantly more tumor necrosis factor and interleukin-6 after lipopolysaccharide stimulation in vitro in a dose-dependent response (P < .05). Liposome treatment increased total polyunsaturated fatty acid, total omega 3, and docosahexaenoic acid 22:6 omega 3 content in Kupffer's cell phospholipids compared with untreated controls. Survival 24 hours after lipopolysaccharide challenge was reduced by liposome (400 mg/kg) pretreatment (P < .05 by chi 2 test). Livers from each treatment group demonstrated focal areas of hepatocyte necrosis and inflammatory cells. CONCLUSION: Liposome pretreatment increases the circulating and Kupffer's cell cytokine response to endotoxemia, increases Kupffer's cell polyunsaturated fatty acid content, and is associated with reduced survival.

Animals↗

Differential TNF secretion by wound fibroblasts compared to normal fibroblasts in response to LPS.

Fibroblasts cultured from wound sites have been shown to have an altered phenotype compared to normal dermal fibroblasts and are generally regarded as target cells of the cytokine response at sites of injury. This study was undertaken to determine whether wound fibroblasts can contribute to proinflammatory cytokine production in wounds and, in particular, whether they are capable of secreting TNF. Wound fibroblasts were cultured from polyvinyl alcohol sponges implanted subcutaneously for 2 weeks in Balb/c mice. Fibroblasts harvested from the skin and subcutaneous tissue of untreated mice served as a control population of cells. All cells were passaged at least twice and then stimulated with a dose range of LPS. Supernatants were harvested 8 hr following stimulation and TNF was assayed using a standard L929 cell-killing assay. There was a significant TNF response to LPS by wound fibroblasts, evident as early as 4 hr following exposure to LPS and associated with an upregulation of TNF mRNA. Normal dermal fibroblasts did not secrete any measurable amounts of TNF in response to LPS. The results indicate that wound fibroblasts generate a brisk TNF response to stimulation with LPS, in contrast to normal subcutaneous fibroblasts. These data reveal an additional unique property of wound-harvested fibroblasts and suggest a possible contributing mechanism to disordered wound healing in the face of infection or conditions characterized by excessive fibrosis.

Animals↗

Acute-phase hepatocytes regulate liver sinusoidal cell mediator production.

BACKGROUND: Overproduction of liver sinusoidal cell (LCS) mediators in response to endotoxemia or gram-negative infection that follows tissue injury may contribute to hepatic dysfunction. OBJECTIVE: To better define the role of hepatocyte-derived acute-phase reactants in the regulation of sinusoidal cell mediator production following sequential insults, we tested the hypothesis that interleukin-6 (IL-6) prestimulation alters hepatocyte regulation of lipopolysaccharide (LPS)-stimulated sinusoidal cell tumor necrosis factor (TNF), IL-6, and nitric oxide production. METHODS: Hepatocytes and LSCs were isolated from Wistar rats, and in vitro responses were compared between LSCs alone and hepatocyte-LSC cocultures. Cocultures and LSCs alone were sequentially stimulated with IL-6 (5000 U/mL) then LPS (dose-response), and culture supernatants were analyzed for TNF (L929 cytolysis), IL-6 (7TD1 proliferation), and nitric oxide (Griess reaction). Induction of acute-phase protein synthesis by the stimulation of hepatocytes with IL-6 and dexamethasone (0.1 mumol/L) was assayed by methionine radiolabeling and SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Coculture levels of messenger RNA for TNF-alpha and IL-6 were examined by RNA extraction and reverse transcriptase polymerase chain reaction with specific primers. RESULTS: Interleukin-6 and dexamethasone signal hepatocyte acute-phase protein synthesis. Prestimulation of cocultures, but not of LSCs alone, with IL-6 inhibits LPS-stimulated IL-6 and nitric oxide production significantly. Bioactivity of TNF is reduced to a lesser extent. Polymerase chain reaction analysis demonstrated similar levels of TNF and IL-6 message following sequential stimulation. CONCLUSIONS: Interleukin-6-stimulated acute-phase hepatocytes limit LPS-stimulated coculture cytokine bioactivity and nitric oxide production. This hepatocyte response may provide a local counterregulatory mechanism to limit LSC-mediated injury.

Acute-Phase Proteins↗