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Biomedical subjects

J Sargent

Publications and source records attributed to J Sargent.

At least 19 recordsLinked to original sources
PubMed2005

Potentiation of in vitro ara-C cytotoxicity by ribonucleotide reductase inhibitors, cyclin-dependent kinase modulators and the DNA repair inhibitor aphidicolin in paediatric acute myeloid leukaemia.

To modulate in vitro cytarabine (ara-C) resistance we combined ara-C with six potential resistance modifiers in 10 paediatric acute myeloid leukaemia (AML) patient samples (methyl thiazol tetrazolium assay). Drug interactions were determined by median drug effect analysis. Co-incubation of ara-C/aphidicolin showed strong synergism. The combinations of ara-C/cladribine and ara-C/gemcitabine were synergistic. Nearly additive and moderately synergistic interactions were observed between ara-C/flavopiridol and ara-C/UCN-01. The combination of ara-C/decitabine was antagonistic. In conclusion, favourable interactions were observed between ara-C and aphidicolin, cladribine, gemcitabine and also with flavopiridol and UCN-01, supporting the evaluation of these combinations in clinical trials with AML patients.

Antimetabolites, Antineoplastic↗
PubMed2004

The ADP ribosyltransferase domain of Pseudomonas aeruginosa ExoT contributes to its biological activities.

ExoT is a type III secreted effector protein found in almost all strains of Pseudomonas aeruginosa and is required for full virulence in an animal model of acute pneumonia. It is comprised of an N-terminal domain with GTPase activating protein (GAP) activity towards Rho family GTPases and a C-terminal ADP ribosyltransferase (ADPRT) domain with minimal activity towards a synthetic substrate in vitro. Consistent with its activity as a Rho family GTPase, ExoT has been shown to inhibit P. aeruginosa internalization into epithelial cells and macrophages, disrupt the actin cytoskeleton through a Rho-dependent pathway, and inhibit wound repair in a scrape model of injured epithelium. We have previously shown that mutation of the invariant arginine of the GAP domain to lysine (R149K) results in complete loss of GAP activity in vitro but only partially inhibits ExoT anti-internalization and cell rounding activity. We have constructed in-frame deletions and point mutations within the ADPRT domain in order to test whether this domain might account for the residual activity observed in ExoT GAP mutants. Deletion of a majority of the ADPRT domain (residues 234 to 438) or point mutations of the ADPRT catalytic site (residues 383 to 385) led to distinct changes in host cell morphology and substantially reduced the ability of ExoT to inhibit in vitro epithelial wound healing over a 24-h period. In contrast, only subtle effects on the efficiency of ExoT-induced bacterial internalization were observed in the ADPRT mutant forms. Expression of each domain individually in Saccharomyces cerevisiae was toxic, whereas expression of each of the catalytically inactive mutant domains was not. Collectively, these data demonstrate that the ADPRT domain of ExoT is active in vivo and contributes to the pathogenesis of P. aeruginosa infections.

ADP Ribose Transferases↗
PubMed2001

Primary ovarian carcinomas display multiple methylator phenotypes involving known tumor suppressor genes.

Mounting evidence suggests that aberrant methylation of CpG islands is a major pathway leading to the inactivation of tumor suppressor genes and the development of cancer. Recent studies on colorectal and gastric cancer have defined a CpG island methylator phenotype (CIMP), which involves the targeting of multiple genes by promoter hypermethylation. To determine the role of methylation in ovarian cancer, we have investigated the methylation status of 93 primary ovarian tumors at ten loci using methylation-specific polymerase chain reaction (MSP). Seven of the loci (BRCA1, HIC1, MINT25, MINT31, MLH1, p73 and hTR) were found to be methylated in a significant proportion of the ovarian tumors, and methylation of at least one of these was found in the majority (71%) of samples. Although concurrent methylation of multiple genes was commonly seen, this did not seem to be due to a single CIMP phenotype. Instead the results suggest the presence of at least three groups of tumors, two CIMP-positive groups, each susceptible to methylation of a different subset of genes, and a further group of tumors not susceptible to CpG island methylation, at least at the loci studied.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Maternal depressive symptoms and low literacy as potential barriers to employment in a sample of families receiving welfare: are there two-generational implications?

This study examines the role of maternal depressive symptoms and low maternal literacy in predicting outcomes in two generations in families receiving welfare: mothers' employment and children's development. The sample consists of 351 African-American families, each with a preschool-age child, in which the mother had applied for or was receiving welfare. Close to the start of the study, 52.6 percent of the mothers in the sample had scores indicating lower literacy, 39.5 percent reported moderate to high levels of depressive symptoms, and 24.6 percent had a co-occurrence of these. Using continuous scores, in multivariate analyses of variance, neither level of literacy, extent of depressive symptoms, nor the interaction of these, were found to predict two measures of subsequent employment (any employment across the two year follow-up period, and current employment at the time of the follow-up). However, when cut points were used (low literacy; moderate to high depressive symptoms), mothers with low literacy were found less often to be employed approximately two years later. Multivariate analyses of variance examining the set of child outcomes (cognitive school readiness and behavior problems) in light of mothers' depressive symptoms and literacy level found a statistically significant interaction of literacy level and extent of depressive symptoms: children of mothers with more depressive symptoms had less favorable developmental outcomes only in the presence of low maternal literacy. Structural equation models provide evidence that parenting behavior mediates the relationship between the predictor variables and child outcomes, and that the pathways from depressive symptoms through parenting to child outcomes are stronger when maternal depressive symptoms co-occur with low maternal literacy.

Adult↗
PubMed2001

Variations in family composition. Implications for family therapy.

The American family is truly diverse, with many forms and changes between and among forms common. Each variation in family composition presents its own unique challenges and possesses its own unique possibilities for success, building on its own unique strengths. Each family in trouble expects and demands respectful, patient, and committed assistance from the family therapist. The family therapist must appreciate the uniqueness of an individual family and the features that that family has in common with similar families and with all families. It is the commitment of parental figures to take responsibility for their children and participate actively with them in their development that creates successful family life. The family therapist's acceptance, curiosity, and respect for the family and its members encourages change and enlists strengths. This approach permits the family therapist to participate in meaningful and effective lives for each family.

Adolescent↗
PubMed2001

Child and adolescent mental health emergency services in Eastern European former Iron Curtain countries.

This paper describes the evolution of child and adolescent mental health emergency services in Eastern European countries over the past decade since the dissolution of the Iron Curtain. The process of helping countries to organize services, as facilitated by the authors through their training and mentoring of Eastern European mental health professionals, organized by the Children's Mental Health Alliance Foundation, with funding from the Soros Foundation, is described. This paper is a prelude to reports from six Eastern European countries which describe in more detail how child and adolescent mental health emergencies are evaluated and treated locally.

Adolescent↗
PubMed2001

Child and adolescent mental health emergency services in Macedonia.

This paper describes the development of child and adolescent mental health emergency services in Macedonia since 1993. The evolution of services through the Mental Crisis Centre for Children and Adolescents, funded by the Open Society Institute, and located in six cities is outlined. The paper also defines traditional services, the nature of child mental health emergencies, the evaluation process, follow-up care and training and supervision. It concludes with concern that the mental health emergency system is not sufficient to meet the needs of the child and adolescent population, particularly in the face of the Kosovar refugee crisis. Recommendations for the future are made.

Adolescent↗
PubMed2001

The impact of social change on child mental health in Eastern Europe.

The transition of the Eastern European countries in the past 12 years from totalitarian, communist societies to democratic societies has had a broad impact on children's mental health, both positively and negatively. This transition has not been without economic difficulties. All countries in the region experienced a significant deterioration of output that has affected the availability of commodities and services. Although recovery has been achieved in some Eastern European countries and is in progress in other countries, reversal of the cutbacks in allocations to necessary services that protect children and families may take longer to achieve. Movement toward a free market economy and greater individualism also has focused attention away from the role of society to protect and provide care for its citizens, especially the most vulnerable. On the positive side, mental health, as a concept for children and adults, comes to be appreciated only in a society that values and safeguards individual rights. Democratic process within the family, the depoliticization of mental illness, the passage of laws assuring basic children's rights, services for and public awareness about children abuse, reforms in education, the proliferation of mental health clinics and support centers, and the resumption of training of mental health professionals all set a tone to first consider, then assure, the positive development of children's mental health.

Adolescent↗
PubMed2000

The D(2) dopamine receptor A(1) allele and opioid dependence: association with heroin use and response to methadone treatment.

A total of 95 Caucasian opioid-dependent patients were followed over a one-year period in an outpatient methadone treatment program. The frequency of the TaqI A(1) allele of the D(2) dopamine receptor (DRD2) gene was 19.0% in these patients compared with 4.6% in controls free of past and current alcohol and other drug abuse and free of family history of alcohol and other drug abuse (p = 0.009). Twenty-two of these patients dropped out of the methadone program (Group A), 54 had a successful treatment (Group B), and 19 had a poor treatment (Group C) outcome. The frequency of the A(1) allele was highest in Group C (42.1%), followed by Group A (22.7%) and was lowest in Group B (9.3%). The more than fourfold higher frequency of the A(1) allele in the poor treatment outcome group compared with the successful treatment outcome group was significant (p = 0.00002). Moreover, the average use of heroin (grams/day) during the year prior to study entry was more than twice as great in patients with the A(1)(+) allele (A(1)/A(1) or A(1)/A(2) genotype) than those with the A(1)(-) allele (A(2)/A(2) genotype) (A(1)(+) allele = 0.55 +/- 0. 10, A(1)(-) allele = 0.25 +/- 0.05; p = 0.003). The results indicate that DRD2 variants are predictors of heroin use and subsequent methadone treatment outcome and suggest a pharmacogenetic approach to the treatment of opioid dependence.

Adult↗
PubMed2000

Developing child abuse prevention, identification, and treatment systems in Eastern Europe.

Although the dissolution of the Soviet Union in 1989 brought a welcome end to the Cold War, the subsequent reestablishment of independent Eastern European countries revealed a host of problems. Among these was frequent child abuse and neglect, although lack of epidemiological data precluded any accurate estimate of prevalence. In an effort to address the problem of child abuse within this rapidly changing sociopolitical environment, the Children's Mental Health Alliance and the Soros Foundation organized the Eastern European Child Abuse and Child Mental Health Project in 1995. The authors describe the development of this multidisciplinary initiative involving collaboration with professionals from 17 countries in Eastern Europe. They highlight the goals, principles, and major phases of the project, as well as some of the challenges involved in its implementation.

Child↗
PubMed1999

The How Are You? scale: a quality-of-life outcomes measure for routine practice.

The How Are You? scale, a quality-of-life outcomes self-report measure to be completed by patients, was developed to address the concerns of the mental health consumer movement. Specific concerns included using less technical language in assessing mental health problems and developing a collaborative dialogue between clinician and patient. The How Are You? scale is a user-friendly instrument that allows patients to be actively involved in their assessment and treatment process. To implement the How Are You? scale into a recording and measurement system, its psychometric properties were assessed using two samples: (1) An employee group from The Menninger Clinic was used to assess internal consistency and stability, and (2) a patient group from The Menninger Clinic was used to assess known-group and discriminant validity, as well as sensitivity to change. The How Are You? scale was found to have good internal consistency and stability and good known-group and discriminant validity. It was also found to be sensitive to change. Although data continue to be collected at The Menninger Clinic, initial indications are that the How Are You? scale is a psychometrically sound outcomes measurement tool.

Adolescent↗
PubMed1999

Which treatments help? The patient's perspective.

In an effort to determine which specific aspects of treatment might account for patient satisfaction, the authors developed the Components of Treatment Questionnaire. This measure, which was administered to 500 adult inpatients along with the Client Satisfaction Questionnaire (CSQ-8; Larsen, Attkisson, Hargreaves, and Nguyen, 1979), asked patients to assess the helpfulness of their treatment. Convinced that patient input is pertinent to program design, the authors later surveyed 46 patients on treatments that they perceived as helpful and would like to receive. Respondents identified individual relationships and problem-focused therapies as the most helpful aspects of treatment.

Adult↗
PubMed1998

Effects of feeding Lunaria oil rich in nervonic and erucic acids on the fatty acid compositions of sphingomyelins from erythrocytes, liver, and brain of the quaking mouse mutant.

Feeding an oil from Lunaria biennis rich in 22:1n-9 and 24:1n-9 to homozygous quaking (qk.qk) mice caused a large increase in the percentage of 24:1n-9 and corresponding decreases in the percentage of 24:0 and 22:0 in sphingomyelins from liver, erythrocytes, and milk. Brain sphingomyelin from 2-wk-old qk.qk pups born to qk.qk mothers maintained on the Lunaria oil had essentially normal percentage of 24:1n-9 and 18:0, in contrast to pups born to mothers maintained on a control oil rich in 18:1n-9 whose brain sphingomyelin had a markedly reduced percentage of 24:1n-9 and an increased percentage of 18:0. After 2 wk and up to and beyond weaning, the qk.qk pups from Lunaria-fed mothers weaned on to the Lunaria diet had a markedly decreased percentage of 24:1n-9 in their brain sphingomyelin, accompanied by an increased percentage of 18:0, as compared to heterozygous quaking mice. However, the percentage of 24:1n-9 in brain sphingomyelin in qk.qk pups weaned on to the Lunaria diet continued throughout this period (2-8 wk postbirth) to be significantly higher than in qk.qk pups weaned on to the control diet. We conclude that dietary 24:1n-9 influences the fatty acid composition of brain sphingomyelin in qk.qk mice, but only via the mother in pre- or early postnatal animals. We further consider that the dietary effects may be elicited mainly in the sphingomyelin of nonmyelinated brain cells, and that the nervonic acid in myelin sphingomyelin may be formed mainly by chain elongation in oligodendrocytes from shorter chain fatty acid precursors.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Double-blind, placebo-controlled, dose-finding study of rizatriptan (MK-462) in the acute treatment of migraine.

Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical efficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Patients with moderate or severe migraine (n = 417) were treated with placebo (n = 67), rizatriptan 2.5 mg (n = 75), 5 mg (n = 130), or rizatriptan 10 mg (n = 145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e., placebo initially-->rizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initially-->placebo as optional second dose). An upward dose-response relationship was observed among placebo, rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to "no pain or mild pain" at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for placebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2 h post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.

Acute Disease↗
PubMed1996

Severe cranial nerve involvement in longstanding demyelinating polyneuropathy: a clinicopathologic correlation.

Onion bulb formations involving cranial nerves are an unusual pathologic feature. We report the postmortem neuropathologic findings in a 69-year-old man with a longstanding neuropathy characterized by progressive muscle weakness, sensory ataxia and multiple cranial nerve abnormalities. Electrodiagnostic testing disclosed features of an acquired demyelinating polyneuropathy. Treatment with corticosteroids and plasmapheresis resulted in no change in his neurologic status, and the patient died after repeated episodes of pneumonia and sepsis. Autopsy showed widespread onion bulb formation in cranial nerves III, IV, V, VI, X, XI and XII, anterior and posterior spinal nerve roots, dorsal root ganglia and multiple peripheral nerves, some of which also had foci of epineurial perivascular inflammation. Muscle sections revealed severe neurogenic atrophy. This case demonstrates that, in longstanding acquired demyelinating neuropathy, the cranial nerves also undergo repetitive cycles of demyelination and remyelination resulting in severe weakness of the bulbar musculature and histologic features of hypertrophic neuropathy.

Aged↗