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Biomedical subjects

John Scott

Publications and source records attributed to John Scott.

At least 19 recordsLinked to original sources
PubMed2006

Use of OSWALD for analyzing longitudinal data with informative dropout.

OSWALD (Object-oriented Software for the Analysis of Longitudinal Data) is flexible and powerful software written for S-PLUS for the analysis of longitudinal data with dropout for which there is little other software available in the public domain. The implementation of OSWALD is described through analysis of a psychiatric clinical trial that compares antidepressant effects in an elderly depressed sample and a simulation study. In the simulation study, three different dropout mechanisms: completely random dropout (CRD), random dropout (RD) and informative dropout (ID), are considered and the results from using OSWALD are compared across mechanisms. The parameter estimates for ID-simulated data show less bias with OSWALD under the ID missing data assumption than under the CRD or RD assumptions. Under an ID mechanism, OSWALD does not provide standard error estimates. We supplement OSWALD with a bootstrap procedure to derive the standard errors. This report illustrates the usage of OSWALD for analyzing longitudinal data with dropouts and how to draw appropriate conclusions based on the analytic results under different assumptions regarding the dropout mechanism.

Humans↗
PubMed2006

Statistical analysis of longitudinal psychiatric data with dropouts.

Longitudinal studies are used in psychiatric research to address outcome changes over time within and between individuals. However, because participants may drop out of a study prematurely, ignoring the nature of dropout often leads to biased inference, and in turn, wrongful conclusions. The purpose of the present paper is: (1) to review several dropout processes, corresponding inferential issues and recent methodological advances; (2) to evaluate the impact of assumptions regarding the dropout processes on inference by simulation studies and an illustrative example using psychiatric data; and (3) to provide a general strategy for practitioners to perform analyses of longitudinal data with dropouts, using software available commercially or in the public domain. The statistical methods used in this paper are maximum likelihood, multiple imputation and semi-parametric regression methods for inference, as well as Little's test and index of sensitivity to nonignorability (ISNI) for assessing statistical dropout mechanisms. We show that accounting for the nature of the dropout process influences results and that sensitivity analysis is useful in assessing the robustness of parameter estimates and related uncertainties. We conclude that recording the causes of dropouts should be an integral part of any statistical analysis with longitudinal psychiatric data, and we recommend performing a sensitivity analysis when the exact nature of the dropout process cannot be discerned.

Antidepressive Agents↗
PubMed2006

Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study.

BACKGROUND: low vitamin B12 concentrations are common in older people, but the clinical relevance of biochemical evidence of vitamin B12 deficiency in the absence of anaemia is uncertain. OBJECTIVE: to examine associations of cognitive impairment, depression and neuropathy with blood measurements of vitamin B12 and folate status in older people. DESIGN: cross-sectional study in general practice in Banbury, England. PARTICIPANTS: a total of 1,000 individuals aged 75 years or older living in the community. RESULTS: low vitamin B12 concentrations were identified in 13% of older people and were associated with memory impairment and depression. After adjustment for age, sex and smoking, individuals with vitamin B12 or holotranscobalamin (holoTC) in the bottom compared with top quartiles had a 2-fold risk (OR = 2.17; 95% CI 1.11-4.27) and a 3-fold risk (OR = 3.02; 95% CI 1.31-6.98) of cognitive impairment, respectively. Low vitamin B12 status was also associated with missing ankle tendon jerks but not with depression. Treatment with vitamin B12 for 3 months corrected the biochemical abnormalities but had no effect on any of the clinical measurements. CONCLUSIONS: low vitamin B12 concentrations are associated with cognitive impairment and missing ankle tendon jerks in older people in the absence of anaemia. Large-scale trials of vitamin B12 supplementation are required to assess the clinical significance of these associations.

Aged↗
PubMed2006

An open-label trial of enhanced brief interpersonal psychotherapy in depressed mothers whose children are receiving psychiatric treatment.

Major depression affects one out of five women during her lifetime. Depressed mothers with psychiatrically ill children represent an especially vulnerable population. Challenged by the demands of caring for ill children, these mothers often put their own needs last; consequently, their depressions remain untreated. This population is especially difficult to engage in treatment. We have developed a nine-session intervention, an engagement session followed by eight sessions of brief interpersonal psychotherapy designed to increase maternal participation in their own psychotherapy, resolve symptoms of maternal depression, and enhance relationships (IPT-MOMS). This open-label trial assesses the feasibility and acceptability of providing this treatment to depressed mothers. Thirteen mothers meeting DSM-IV criteria for major depression were recruited from a pediatric mental health clinic where their school-age children were receiving psychiatric treatment. Subjects (mothers) were treated openly with IPT-MOMS. Eighty-five percent (11/13) completed the study. Subjects were evaluated with the Hamilton Rating Scale for Depression, and completed self-report measures of quality of life and functioning at three time points: baseline, after treatment completion, and 6-months posttreatment. A signed rank test was used to compare measurement changes between assessment time points. Subjects showed significant improvement from baseline to posttreatment on measures of maternal symptoms and functioning. These gains were maintained at 6-month follow-up. Therapy was well tolerated and accepted by depressed mothers, who are typically difficult to engage in treatment. A high proportion of subjects completed treatment and experienced improvements in functioning. Future randomized clinical trials are needed to establish the efficacy of this approach.

Adolescent↗
PubMed2006

Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation.

There is increasing evidence to suggest that reduced folate status may be a causative factor in carcinogenesis, particularly colorectal carcinogenesis. Folate is essential for the synthesis of S-adenosylmethionine, the methyl donor required for all methylation reactions in the cell, including the methylation of DNA. Global DNA hypomethylation appears to be an early, and consistent, molecular event in carcinogenesis. We have examined the effects of folate depletion on human-derived cultured colon carcinoma cells using 2 novel modifications to the Comet (single cell gel electrophoresis) assay to detect global DNA hypomethylation and gene region-specific DNA hypomethylation. Colon cells cultured in folate-free medium for 14 d showed a significant increase in global DNA hypomethylation compared with cells grown in medium containing 3 micromol/L folic acid. This was also true at a gene level, with folate-deprived cells showing significantly more DNA hypomethylation in the region of the p53 gene. In both cases, the effects of folate depletion were completely reversed by the reintroduction of folic acid to the cells. These results confirm that decreased folate levels are capable of inducing DNA hypomethylation in colon cells and particularly in the region of the p53 gene, suggesting that a more optimal folate status in vivo may normalize any DNA hypomethylation, offering potential protective effects against carcinogenesis. This study also introduces 2 novel functional biomarkers of DNA hypomethylation and demonstrates their suitability to detect folate depletion-induced molecular changes.

Azacitidine↗
PubMed2005

Histological and histochemical observations on salivary microliths in ferret.

The fortuitous observation of salivary microliths in ferret was pursued in the present investigation. Major salivary glands obtained post-mortem from mature ferrets of either sex were examined with the use of histology and light microscopical histochemistry for calcium, protein, amino acids, mucosubstances and hydrolytic enzymes. Microliths were detected in most parotids, but were absent from submandibular and sublingual glands. The microliths were usually seen in lumens, and occasionally in parenchyma and interstices. They were variably stained for calcium, tryptophan, and neutral and acidic mucosubstances, similarly to acinar or ductal secretory granules. Unlike secretory granules, microliths showed autofluorescence, high levels of tyrosine and a low concentration of -SS- groups. Acid phosphatase and beta-glucuronidase reaction surrounded non-luminal microliths. The present data establish ferret as a new model for the investigation of salivary microliths and do not support the notion of microliths being almost absent from the parotid. Probably there is secretory inactivity in ferret parotid and this fosters the formation and accumulation of microliths containing calcium and disintegrated secretory material.

Acid Phosphatase↗
PubMed2005

Organic secretory products, adaptive responses and innervation in the parotid gland of ferret: a histochemical study.

To qualify cellular events of possible pathophysiological significance in the parotid of ferret, tissue obtained post-mortem from mature animals of either sex was examined by light microscopical histochemistry for calcium, protein, amino acids, mucosubstances and hydrolases, and by neurohistology. Calcium was localised in acinar cells replete with granules containing protein, disulphides and usually carboxylated mucosubstances. Acid phosphatase activity was basally concentrated in the acinar cells. The granular luminal region of striated ductal cells showed protein, tryptophan, disulphides, neutral mucosubstances, and E600-sensitive esterase and Naphthol AS-D chloroacetate esterase activities, whereas their basal region showed acid phosphatase activity. Strong periluminal activity of acid phosphatase and E600-resistant esterase characterised the collecting ducts. Cholinesterase activity was associated with an extensive network of nerve fibres embracing parenchyma. Catecholamine fluorescence was not seen. beta-glucuronidase reactive macrophages abounded in the interstices. The results suggest that while the acini in the parotid of ferret secrete polyionic glycoproteins, shielded by calcium, the striated ducts secrete tryptophan-rich products comprising neutral glycoproteins and showing proteolytic activity. Innervation is of the cholinergic type and parenchymal lysosomal activity, possibly related to autophagy of stored secretory products and heterophagy of luminal material, is brisk. Macrophages contribute to maintaining the glandular microenvironment, wherein secretory activity appears to be lethargic.

Acid Phosphatase↗
PubMed2005

Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder.

CONTEXT: Numerous studies have pointed to the failure of prophylaxis with pharmacotherapy alone in the treatment of bipolar I disorder. Recent investigations have demonstrated benefits from the addition of psychoeducation or psychotherapy to pharmacotherapy in this population. OBJECTIVE: To compare 2 psychosocial interventions: interpersonal and social rhythm therapy (IPSRT) and an intensive clinical management (ICM) approach in the treatment of bipolar I disorder. DESIGN: Randomized controlled trial involving 4 treatment strategies: acute and maintenance IPSRT (IPSRT/IPSRT), acute and maintenance ICM (ICM/ICM), acute IPSRT followed by maintenance ICM (IPSRT/ICM), or acute ICM followed by maintenance IPSRT (ICM/IPSRT). The preventive maintenance phase lasted 2 years. SETTING: Research clinic in a university medical center. PARTICIPANTS: One hundred seventy-five acutely ill individuals with bipolar I disorder recruited from inpatient and outpatient settings, clinical referral, public presentations about bipolar disorder, and other public information activities. INTERVENTIONS: Interpersonal and social rhythm therapy, an adaptation of Klerman and Weissman's interpersonal psychotherapy to which a social rhythm regulation component has been added, and ICM. MAIN OUTCOME MEASURES: Time to stabilization in the acute phase and time to recurrence in the maintenance phase. RESULTS: We observed no difference between the treatment strategies in time to stabilization. After controlling for covariates of survival time, we found that participants assigned to IPSRT in the acute treatment phase survived longer without a new affective episode (P = .01), irrespective of maintenance treatment assignment. Participants in the IPSRT group had higher regularity of social rhythms at the end of acute treatment (P<.001). Ability to increase regularity of social rhythms during acute treatment was associated with reduced likelihood of recurrence during the maintenance phase (P = .05). CONCLUSION: Interpersonal and social rhythm therapy appears to add to the clinical armamentarium for the management of bipolar I disorder, particularly with respect to prophylaxis of new episodes.

Adult↗
PubMed2005

Homocysteine and folic acid: implications for pregnancy.

The role of folic acid and homocysteine in pregnancy is becoming clearer. The efforts of many countries to prevent neural tube defects through public awareness of folic acid have been disappointing, but evidence is now emerging that the food fortification programs in the United States and Canada are effective in reducing the numbers of neural tube defects, and there may be additional benefits in terms of other congenital defects such as oral-facial clefts and congenital heart disease. Homocysteine has a significant association with vascular disease in later life, is elevated in preeclampsia, and has been associated with other pregnancy complications such as early pregnancy loss. The data from cohorts of women with a history of preeclampsia during pregnancy indicate that they are at increased risk for cardiovascular and cerebrovascular disease in later life. Elevated homocysteine concentrations may be a common link that accounts for these associations.

Canada↗
PubMed2005

Acute treatment outcomes in patients with bipolar I disorder and co-morbid borderline personality disorder receiving medication and psychotherapy.

OBJECTIVE: Patients suffering from both bipolar I disorder and borderline personality disorder (BPD) pose unique treatment challenges. The purpose of this matched case-control study was to compare acute treatment outcomes of a sample of patients who met standardized diagnostic criteria for both bipolar I disorder and BPD (n = 12) to those who met criteria for bipolar I disorder only (n = 58). METHOD: Subjects meeting criteria for an acute affective episode were treated with a combination of algorithm-driven pharmacotherapy and weekly psychotherapy until stabilization (defined as four consecutive weeks with a calculated average of the 17-item version of the Hamilton Rating Scale for Depression and Bech-Rafaelsen Mania scale totaling < or = 7). RESULTS: Only three of 12 (25%) bipolar-BPD patients achieved stabilization, compared with 43 of 58 (74%) bipolar-only patients. Two of the three bipolar-BPD patients who did stabilize took over 95 weeks to do so, compared with a median time-to-stabilization of 35 weeks in the bipolar-only group. The bipolar-BPD group received significantly more atypical mood-stabilizing medications per year than the bipolar-only group (Z = 4.3, p < 0.0001). Dropout rates in the comorbid group were high. CONCLUSIONS: This quasi-experimental study suggests that treatment course may be longer in patients suffering from both bipolar I disorder and BPD. Some patients improved substantially with pharmacotherapy and psychotherapy, suggesting that this approach is worthy of further investigation.

Adult↗
PubMed2005

Understanding the new context of the male sex work industry.

The article reviews past and recent research on male sex work to offer a context to understand violence in the industry. It provides a critical review of research to show, first, the assumptions made about male sex workers and violence and, second, how such discourses have shaped thinking on the topic. The article presents a case study and original findings from two studies conducted by the authors in Australia and Argentina on violence in the male sex industry. Finally, the article reviews examples of legislative reforms to show how the sex industry is being regulated.

Homosexuality, Male↗
PubMed2005

Pain predicts longer time to remission during treatment of recurrent depression.

INTRODUCTION: Pain and depression are mutually exacerbating. We know that both of these syndromes predict the future occurrence of the other. It has not been shown, however, whether the presence of pain slows the effect of treatment for depression. We hypothesized that greater pain and somatic scores prior to treatment with imipramine and interpersonal psychotherapy would predict a slowed time to remission from depression. METHOD: We performed secondary data analyses of an archived study. Subjects (N = 230) were between 21 and 65 years of age and were enrolled in a study of maintenance treatment for recurrent unipolar depression. Patients had to meet Research Diagnostic Criteria (RDC) for a major depressive episode and historical requirements for at least 3 prior episodes and clear remissions (according to RDC). Patients were also required to have a minimum Hamilton Rating Scale for Depression score of 15 and a minimum score of 7 on the Raskin Severity of Depression Scale. This report describes the acute treatment phase, during which all subjects received combination therapy consisting of imipramine hydrochloride (150 to 300 mg) and interpersonal psychotherapy. Pain and somatization were measured with the Hopkins Symptom Checklist. RESULTS: Higher levels of both pain and somatization predicted a longer time to remission. After controlling for baseline severity of depression, only pain was still significant in predicting a longer time to remission. Headache and muscle soreness were the 2 variables from the pain index whose presence independently predicted a slower remission. Both pain and somatization improved during acute treatment. Subjects with more pain and somatization, after controlling for severity of depression, reported more suicidality. Women reported more pain than men. CONCLUSIONS: Pain, but not somatization, predicted a longer time to remission and may be a marker of a more difficult-to-treat depression. Adults with recurrent depression should be screened for the presence of pain prior to treatment, as the presence of these symptoms may require more aggressive treatment or may be a marker for suicidality or the use of dual-mechanism antidepressants.

Antidepressive Agents, Tricyclic↗
PubMed2004

Studies on pyrrolopyrimidines as selective inhibitors of multidrug-resistance-associated protein in multidrug resistance.

Multidrug resistance mediated by P-glycoprotein (Pgp) or multidrug-resistance-associated protein (MRP) remains a major obstacle for successful treatment of cancer. Inhibition of Pgp and MRP transport is important for high efficacy of anticancer drugs. While several Pgp inhibitors have entered clinical trials, the development of specific MRP1 inhibitors is still in its infancy. In our screening program, we have identified a pyrrolopyrimidine (4) as a novel and selective MRP1 inhibitor. Subsequent SAR work on the 4-position of the template revealed the phenethylpiperazine side chain as a potent replacement of the benzylthio group of the lead molecule. Introduction of groups at the 2-position seems to have no detrimental effect on activity. Modifications to the nitrile group at the 7-position resulted in the identification of analogues with groups, such as amides, with superior pharmacokinetic profiles. In vivo efficacy has been demonstrated by xenograft studies on selected compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Design and synthesis of new templates derived from pyrrolopyrimidine as selective multidrug-resistance-associated protein inhibitors in multidrug resistance.

In our continued effort to identify selective MRP1 modulators, we have developed two novel templates, 3 and 4, through rational drug design by identifying the key pharmacophore interaction at the 7-position of the pyrrolopyrimidine template 1. Further synthesis and SAR work on these novel templates gave a number of potent MRP1 modulators with great selectivity against Pgp. Additional studies to reduce the CYP3A4 inhibition are also reported. Several compounds of these classes were subjected to in vivo xenograft studies and in vivo efficacies were demonstrated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗