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Biomedical subjects

L White

Publications and source records attributed to L White.

At least 73 records · Page 4Linked to original sources
PubMed1998

Phase I and pharmacokinetic study of GI147211, a water-soluble camptothecin analogue, administered for five consecutive days every three weeks.

GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.

Adult↗
PubMed1997

The association between adaptive and cognitive deficits in geriatric chronic schizophrenic patients.

Cognitive impairments have been shown to predict impairments in adaptive functioning in patients with chronic schizophrenia and to be more predictive of overall outcome than positive or negative symptoms of the illness. Both adaptive and cognitive impairments are multidimensional, and it is possible that correlations between these domains may be limited to certain aspects of these functions. In this study, 208 geriatric patients with chronic schizophrenia were examined with a cognitive battery and assessed with a structured scale to determine the extent of their adaptive functions. Instrumental and social skills deficits were more strongly correlated with cognitive impairments than with the severity of undercontrolled behavior. Each of the cognitive measures was correlated with global social-adaptive deficits, with minimal variation in the magnitude of correlations. These results suggest that interventions should be individually targeted to cognitive-adaptive impairments and undercontrolled behavior.

Age Factors↗
PubMed1997

A dose-intensive, cyclophosphamide-based regimen for the treatment of recurrent/progressive or advanced solid tumors of childhood: a report from the Australia and New Zealand Children's Cancer Study Group.

BACKGROUND: Children with solid tumors that progress or recur after conventional multimodality therapies have a very poor prognosis. In a pilot study, vincristine, etoposide, and dose-escalated cyclophosphamide (VETOPEC) was shown to be a promising salvage regimen. Continued accrual of patients and increased duration of follow-up has resulted in substantial experience with VETOPEC. METHODS: Between May 1991 and March 1994, 56 pediatric patients from 6 centers were enrolled in this study; 44 had recurrent or progressive tumors (Group A) and 12 had newly diagnosed, advanced tumors with a very poor prognosis (Group B). The VETOPEC regimen was comprised of vincristine, 0.05 mg/kg, on Days 1 and 14; etoposide, 2.5 mg/kg, on Days 1, 2, and 3; and fractionated, dose-escalated cyclophosphamide on Days 1, 2, and 3. The initial cyclophosphamide dose was 90 mg/kg (2.7 g/m2)/cycle with an escalation of 15 mg/kg/cycle in each subsequent cycle, to a maximum (over 6 cycles) of 165 mg/kg (5.0 g/m2)/cycle. Tumor response was evaluated every two to three cycles and included central review of imaging. RESULTS: The combined and partial response rates for Groups A and B were 66% (25 of 38 patients) and 91% (10 of 11 patients), respectively. In Group A, best evaluable responses and event free (EF) survivors were observed with: brain tumors (7 of 9 patients; 2 EF at 39 and 45 months [mos], respectively), Wilms' tumor (6 of 7 patients; 3 EF at 37-49 mos), and lymphoma (4 of 4 patients; 2 EF at 52 and 59 mos, respectively); in Group B best evaluable responses and EF were observed with: neuroblastoma (5 of 6 patients; 1 disease free at 57 mos) and rhabdomyosarcoma (4 of 4 patients; no survivors). Hematologic toxicity was limiting despite support with myeloid growth factors in 33 patients. Four deaths in Group A and one in Group B were directly associated with this toxicity. Specifically, no cases of drug-related myocardial toxicity or pneumonitis were observed. CONCLUSIONS: This chemotherapy regimen with its intense scheduling produced a high response rate and appreciable survival in patients with a variety of recurrent, progressive, or advanced solid tumors of childhood.

Adolescent↗
PubMed1997

CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion.

BACKGROUND: Adhesion of leukocytes to the extracellular matrix and to other cells is mediated by members of the integrin family of adhesion molecules. Src family kinases are activated upon integrin-mediated adhesion. In lymphocytes, CD45 is a leukocyte-specific transmembrane protein tyrosine phosphatase that activates Src family kinases associated with B-cell and T-cell antigen receptor signaling by constitutive dephosphorylation of the inhibitory carboxy-terminal tyrosine phosphorylation site. Here, we show that CD45 is also important in downregulating the kinase activity of Src family members during integrin-mediated adhesion in macrophages. RESULTS: We found that CD45 colocalized with beta2 integrin and the Src family kinase p53/56(lyn) to adhesion sites in bone marrow-derived macrophages. Macrophages from CD45(-/-) mice were unable to maintain integrin-mediated adhesion. In adherent macrophages, absence of CD45 led to the hyperphosphorylation and hyperactivation of p56/59(hck) and p53/56(lyn), but not of p58(c-fgr). CD45 directly inactivated p59(hck) but not p56(lck) in transient transfection assays. Furthermore, coexpression of CD45 with p59(hck) or p56(lyn) containing a tyrosine to phenylalanine mutation at the carboxy-terminal negative regulatory site resulted in decreased tyrosine phosphorylation of the Src family member kinases due to dephosphorylation of the potentiating tyrosine phosphorylation site within the kinase domain. CONCLUSIONS: Using primary bone marrow macrophages, these studies demonstrate that CD45 regulates Src family kinases and is required to maintain macrophage adhesion. CD45 decreases Src family kinase activity by dephosphorylating the tyrosine residue located within the kinase domain.

Animals↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor in association with high-dose chemotherapy (VETOPEC) for childhood solid tumors: a report from the Australia and New Zealand Children's Cancer Study Group.

PURPOSE: Combination chemotherapy with vincristine, etoposide, and high-dose, escalating cyclophosphamide (VETOPEC) is an effective regimen in pediatric patients with high-risk solid tumors. The toxicity of the regimen is predominantly haematologic. This study addressed the role of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) following each cycle of chemotherapy in decreasing neutropaenia, incidence of fever/ hospitalization, and/or increasing chemotherapy dose-intensity. PATIENTS AND METHODS: Twenty-nine children with recurrent solid tumors were treated with the VETOPEC regimen. Sequential cohorts of patients received no GM-CSF (Group I), or GM-CSF in a dosage of 5 micrograms/kg/day (Group II) or 10 micrograms/kg/day (Group III) on days 4-18 of each chemotherapy cycle. Up to four cycles of chemotherapy were analysed with respect to haematopoietic recovery, clinical parameters, and dose intensity. RESULTS: Neutrophil recovery was significantly more rapid in patients treated with GM-CSF. Time to achieving an absolute neutrophil count (ANC) over 0.5 x 10(9)/L in Groups I, II, and III were 21, 18, and 16 days, respectively (P < 0.0001). Time to achieving an absolute neutrophil count (ANC) over 1.0 x 10(9)/L in Groups I, II, and III were 24, 19, and 17 days, respectively (P < 0.0001). There was no significant difference in the incidence of febrile neutropaenia between the three groups. Febrile neutropaenia occurred following 42, 68, and 62% of chemotherapy cycles in Groups I, II, and III, respectively (P = 0.27). Chemotherapy dose intensity was not different between the three groups. GM-CSF was associated with pericarditis and myalgias in one patient, and transient hypoxia/hypotension in another. CONCLUSION: GM-CSF led to significantly more rapid neutrophil recovery following VETOPEC chemotherapy, but did not lead to any demonstrable clinical benefit, either in reducing febrile events, or in increasing chemotherapy dose intensity.

Adolescent↗
PubMed1997

Characteristics of elderly psychiatric patients retained in a state hospital during downsizing: a prospective study with replication.

OBJECTIVE: This study examined the clinical characteristics of elderly inpatients associated with retention in a large state hospital during a period of rapid reduction in the inpatient census. DESIGN: During the first year of the study all inpatients age 65 or greater were individually evaluated. Patients remaining in the hospital during the second year were reevaluated and followed for an additional year. Separate statistical analysis of the data allowed for replication of findings. SETTING: The study was conducted at Pilgrim Psychiatric Center, the largest state hospital in New York State. PARTICIPANTS: The entire inpatient population over the age of 65 were included in the study (N = 806). The average age of the sample was 76 years and 70% were assigned a lifetime research diagnosis of schizophrenia. The majority of patients were hospitalized for long periods (mean = 33.9 years) and had significant cognitive impairment. MAIN OUTCOME MEASURES: Cognitive functioning was assessed on the Clinical Dementia Rating Scale. Severity of psychiatric symptoms was evaluated on the PANSS. Occurrence of dangerous behavior and medical and psychiatric treatment were obtained from the patients' medical histories. MAIN RESULTS: The findings, replicated across assessments, were that patients retained had more severe symptoms of excitement, hostility and impulsive behavior than those discharged, while uncooperativeness, delusions, grandiosity and suspiciousness were also more severe in those retained than those discharged. CONCLUSIONS: Elderly patients who are very difficult to place are so characterized because of behavior disorders that are difficult to manage rather than psychotic symptoms, cognitive impairment or medical disorders.

Aged↗
PubMed1997

Restoration of thymocyte development and function in zap-70-/- mice by the Syk protein tyrosine kinase.

The Syk family of protein tyrosine kinases, consisting of ZAP-70 and Syk, associate with the pre- and alphabeta T cell antigen receptors (TCRs) and undergo tyrosine phosphorylation and activation following receptor engagement. Thymocyte development in zap-70-/- mice is blocked at the CD4+CD8+ TCR(lo) stage. The presence of Syk in the thymus has raised the possibility that Syk may be able to mediate TCR function. To determine if Syk can play a role in thymocyte development, we generated zap-70-/- mice expressing a human syk cDNA. Syk expression restored both thymocyte development and function. In addition, Syk function required the CD45 transmembrane protein tyrosine phosphatase. Hence, ZAP-70 and Syk can play overlapping functions and exhibit similar regulatory mechanisms in mediating alphabeta T cell development.

Animals↗
PubMed1997

Adapting instruments for caregiver research in elderly Japanese American women.

Accounting for cultural differences in caregiver research is now widely recognized. However, adapting instruments to assure reliable and valid data across cultures has been neglected, leading to concerns about information obtained in cross cultural research. This paper discusses instrumentation issues which influence the assessment of information in elderly women of Japanese descent who are caregivers to persons with dementia. Data from interviews in the Honolulu Aging and Caregiver Study focus on semantic, content, technical, criterion and conceptual equivalence.

Journal Article↗
PubMed1997

Delivery of oligoribonucleotides to human hepatoma cells using cationic lipid particles conjugated to ferric protoporphyrin IX (heme).

The receptor-ligand interaction between hepatocyte heme receptors and heme was evaluated as a basis for developing a targeted cationic lipid delivery reagent for nucleic acids. Heme (ferric protoporphyrin IX) was conjugated to the aminolipid dioleoyl phosphatidylethanolamine (DOPE) and used to form cationic lipid particles with dioleoyl trimethylammonium propane (DOTAP). These lipids particles (DDH) protect oligoribonucleotides from degradation in human serum and increase oligoribonucleotide uptake into 2.2.15 human hepatoma cells (to a level of 50-60 ng oligo/10(4) cells) when compared with the same lipid particles (DD) prepared identically without heme. The DDH heme level that was optimal for oligoribonucleotide delivery was also optimal for maximum expression of plasmid-encoded luciferase. The enhancing effect of heme was evident only at net particle negative charge. Fluorescence microscopy showed that DDH delivered oligoribonucleotides into both the 2.2.15 cell cytoplasm and nucleus. DDH may thus be a potentially useful delivery vehicle for oligonucleotide-based therapeutics and transgenes, appropriate for use in such liver diseases as viral hepatitis, hepatoma, and hypercholesterolemia.

Animals↗
PubMed1997

External quality assessment of the serum bactericidal test: results of a methodology/interpretation questionnaire.

Two hundred microbiology laboratories in the UK took part in two separate experimental external quality assessment distributions related to the serum bactericidal test (SBT). In the first, Staphylococcus aureus NCTC 6571 (vancomycin MIC 1 mg/L), was tested against a human serum containing vancomycin 38 mg/L plus gentamicin 0.5 mg/L. In the second, Streptococcus oralis PAJ 112/4183 (penicillin MBC < or = 0.03 mg/L) and Streptococcus sanguis PAJ 107/4184 (penicillin MBC = 128 mg/L) were tested against human serum containing penicillin 15 mg/L. Respondents returned their laboratory results and a questionnaire on clinical interpretation and technical aspects. Most laboratories (194/199, 97.5%) recommend the use of the SBT in the management of infective endocarditis but only 48 (25.2%) often or always change therapy on the basis of the result. A wide range of interpretative criteria, definitions of bactericidal endpoints and methodologies are used. Performance in the first distribution was acceptable for 75% of laboratories but in the second only 34% could identify penicillin tolerance; 34 respondents reported an SBT result of < or = 2 for the tolerant strain, 81 laboratories reported one of > or = 16. Technical factors related to acceptable performance were: sonication of broth before counting the inoculum; knowing the inoculum size in cfu/mL; use of a 4-8 h broth culture to make the inoculum; incubation of recovery plates for > 36 h; use of a calibrated pipette to sample for surviving bacteria; use of measured volumes to add the inoculum. Use of uncalibrated pipettes or standard loops to recover survivors was related to poor performance. Microbiology departments in the UK should review the clinical need to perform the SBT in the light of their local circumstances and if they elect to continue to offer this test, revise their methodologies which could be producing misleading results when testing alpha-haemolytic streptococci.

Bacteriological Techniques↗
PubMed1997

Prevalence of hypertension among Navajo Indians: findings from the Navajo Health and Nutrition Survey.

Hypertension and other chronic diseases are becoming increasingly important health problems for many Native American people, including the Navajo. A community-based survey that included three standardized measurements of blood pressures, was conducted during 1991-92 on the Navajo Reservation. Among the 780 adults examined, the overall age-standardized prevalence of hypertension, defined as an elevated systolic (> or = 140 mm Hg) or diastolic (> or = 90 mm Hg) blood pressure, or possession of prescription antihypertensive medications, was 19% (24% among men and 15% among women). The prevalence of hypertension increased with age and relative weight, and among men, was associated with diabetes mellitus. Among women, hypertension was associated with a central distribution of body fat, cigarette smoking, self-reported diabetes mellitus and impaired glucose tolerance. Although only 50% of the persons found to have elevated blood pressure at the examination reported they had been previously told that they had hypertension, persons who had been previously diagnosed with hypertension had a slightly higher rate (approximately 60%) of blood pressure control than that seen in the general U.S. population. On the basis of these results, the prevalence of hypertension among the Navajo appears to have substantially increased since the 1930s. Improved prevention and management of hypertension, especially for overweight and diabetic individuals, may reduce morbidity and mortality from cardiovascular and renal disease.

Adult↗
PubMed1997

Obesity, levels of lipids and glucose, and smoking among Navajo adolescents.

Although there is a high prevalence of overweight among Navajo children and adolescents, other risk factors for chronic disease in this population have received little attention. We therefore examined the distribution and interrelationships of overweight, cigarette smoking, blood pressure and plasma levels of lipids and glucose among 160 Navajo 12- to 19-y-olds. In agreement with previous reports, participants were approximately 2 kg/m2 heavier than adolescents in the general U.S. population, and the prevalence of overweight (> 85th percentile) was 35-40%. Levels of total cholesterol and blood pressure were similar to those in the general U.S. population, but Navajo adolescents had a 5-10 mg/dL lower median level of HDL cholesterol, and a 30 mg/dL higher median triglyceride level. Eight percent of the adolescents examined had either impaired glucose tolerance or diabetes mellitus as assessed through an oral glucose tolerance test (n = 10) or self-report (n = 1). Relative weight (kg/m2) was associated with adverse levels of lipids, lipoproteins and glucose, with overweight adolescents having a fivefold greater risk for elevated triglyceride levels than other adolescents. Tobacco use was fairly prevalent among boys (24% cigarettes, 23% smokeless tobacco), but not girls (9% cigarettes, 3% smokeless tobacco). Because of its associations with other risk factors and with various chronic diseases in later life, it may be beneficial to focus on the primary prevention of obesity among Navajo children and adolescents.

Adolescent↗
PubMed1997

The health of Navajo women: findings from the Navajo Health and Nutrition Survey, 1991-1992.

Cancer-screening behaviors, reproductive history, risk behaviors during pregnancy and chronic disease risk factors were examined in a representative sample of 566 Navajo women residing on the Navajo Reservation in 1991-1992. Among all women 15 y and older, 59% were overweight, 4% were current smokers, 10% currently used smokeless tobacco and 12% were anemic. Seventy-one percent of Navajo women aged 18 and older reported ever having had a Pap smear, but only 35% of women aged 50 and over reported ever having had a mammogram. Among parous women, the prevalence of having received no prenatal care for any pregnancy declined from 60% among women 60 and older to 13% among women 20-29 y of age, and the prevalence of ever having had a child born at home declined from 82 to 2%. These data suggest marked secular improvement in these pregnancy-related risk behaviors. However, data on cancer-screening behaviors indicate opportunities to improve health of Navajo women by increasing their use of mammography and Pap smear screening services.

Adolescent↗
PubMed1997

Social-Adaptive Functioning Evaluation (SAFE): a rating scale for geriatric psychiatric patients.

Geriatric chronic psychiatric inpatients often remain in a chronic psychiatric hospital because of serious deficits in adaptive life functions. Because the additional complications and adaptive changes associated with aging have not been considered in previous scales, the Social-Adaptive Functioning Evaluation (SAFE) was developed. The items in the scale measure social-interpersonal, instrumental, and life skills functioning and are designed to be rated by observation, caregiver contact, and interaction with the subject if possible. Interrater and test-retest reliability were examined (n = 60) and convergent and discriminant validity were rated against other relevant measures (n = 50) in separate studies, with all being found adequate. The factor structure of the scale was examined with exploratory factor analysis, revealing a three-factor structure. Finally, predictive validity was examined in a preliminary study of 140 patients, 45 of whom were discharged after the assessment. The results indicate that patients who remained hospitalized could be discriminated from those who were sent to nursing homes or community care on the basis of certain SAFE items and subscales. These results support the use of this instrument in later studies of geriatric psychiatric patients.

Activities of Daily Living↗
PubMed1997

Empirical assessment of the factorial structure of clinical symptoms in schizophrenia. A multisite, multimodel evaluation of the factorial structure of the Positive and Negative Syndrome Scale. The PANSS Study Group.

The Positive and Negative Syndrome Scale (PANSS) is widely used as a method for the assessment of symptoms of schizophrenia but the most complete model of how symptoms are structured has not been determined. Using the methods of confirmatory factor analysis with a large sample of 1,233 of schizophrenic subjects this study examined the goodness of fit of 20 previously proposed models. None of these proposed models met criteria for adequate fit to the empirical data. The sample was then stratified and half of the data was used to calibrate a new model. The model was validated in the second half of the data. The new pentagonal model uses 25 of the 30 items of the PANSS in 5 factors: positive, negative, dysphoric mood, activation, and and autistic preoccupation. Patients who varied widely in age, severity, and chronicity of illness did not differ in their overall symptom structure. The results of this study also implicated some problems in the validity of the PANSS as currently configured when used to assess symptoms of schizophrenia.

Adult↗
PubMed1997

Age-related differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross-sectional study across nine decades.

OBJECTIVE: This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan. METHOD: Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed. RESULTS: Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced. CONCLUSIONS: Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.

Adult↗
PubMed1997

Verbal fluency deficits in geriatric and nongeriatric chronic schizophrenic patients.

This study examined age-related differences and correlates of deficits on phonological and category fluency tasks performed by schizophrenic patients. Equal numbers (n = 41) of geriatric (age > 64) and nongeriatric chronically hospitalized schizophrenic patients were examined with tests of phonological and category fluency, verbal learning and delayed recall, confrontation naming, and reading, as well as overall estimates of cognitive impairment. Both types of fluency tests were performed very poorly by both groups. Age-related differences were found to be statistically significant. In both groups, category fluency impairments were correlated with deficits in naming, while phonological fluency deficits were best predicted by memory impairments. These data suggest that category fluency impairments are part of a general profile of impaired semantic functioning, whereas phonological fluency deficits may be induced by alterations in information processing capacity.

Aged↗