Using GI-specific patient outcome measures in renal transplant patients: Validation of the GSRS and GIQLI

Introduction: Gastrointestinal (GI) side-effects occur frequently as a result of immunosuppressant regimens used in renal transplant patients. Little effort has been made to quantify the impact of these side-effects on patients’ health-related quality of life and symptom severity. Objective: To assess the psychometric characteristics of two GI-specific outcome instruments (the Gastrointestinal Rating Scale (GSRS) and the Gastrointestinal Quality of Life Index (GIQLI)) for use in post-renal transplant patients. Methods: Cross-sectional study conducted at 5 clinical centers in 4 countries. Patients were required to be on mycophenolate mofetil and a calcineurin inhibitor. Patients completed the GSRS, GIQLI and two generic instruments (the Psychological General Well-Being Index and the EQ-5D) at one timepoint. Reliability, construct and known groups validity were assessed. Results: In general the GSRS and the GIQLI demonstrated Cronbach’s alphas higher than 0.70. The GIQLI was moderately to highly correlated with the PGWB and EQ-5D. Correlations among the GSRS and generic instruments were slightly lower. The GSRS and GIQLI both distinguished between patients with and without GI complaints (all p<0.05). Conclusions: The GSRS and the GIQLI are appropriate for use in a post-renal transplant population. Scores on both instruments demonstrated significant differences between renal transplant patients with GI complications and without GI complications.     

A collaborative study to establish the 5th International Standard for Unfractionated Heparin

Twenty-four laboratories participated in a collaborative study to calibrate a replacement for the 4th International Standard for Unfractionated Heparin (82/502). Both candidate materials A and B, gave excellent intra- and inter-laboratory variations (majority of mean %gcv <10%) when assayed against the 4th International Standard. No major differences of potency estimates were found between methods, although the USP method generally gave lower potencies than the other methods and candidate B gave a greater variation between methods than A. Overall, this study showed that the differences between the candidates are marginal. Based on its narrower molecular weight profile, higher specific activity and slightly lower inter-method variation, candidate A, 97/578, was proposed and accepted in October, 1998, by the Expert Committee on Biological Standardisation of the World Health Organisation to be the 5th International Standard for Unfractionated Heparin with an assigned potency of 2031 IU/ampoule.     

Inter-species comparison of liver and small intestinal microsomal metabolism of fluoranthene.

The magnitude of susceptibility to toxicant exposure may depend on the ability of animals to metabolize the chemicals. The present study has been undertaken to see whether any differences exist among mammals in the metabolism of fluoranthene (FLA), a polycyclic aromatic hydrocarbon (PAH) compound. Microsomes were isolated from the small intestine and liver of rat, mouse, hamster, goat, sheep, pig, dog, cow, monkey, and humans (commercially procured), and incubated with FLA. Post-incubation, samples were extracted with ethyl acetate and analyzed for FLA/metabolites by reverse-phase HPLC with fluorescence detection. The metabolism of FLA in both liver and small intestine was in the order: human > monkey > cow > goat > sheep > dog > pig > hamster > rat > mouse under conditions of the test system used. The rate of metabolism (pmol of metabolite/min/mg protein) was found to be more in liver than in intestine in all the species studied. The FLA metabolites identified were FLA 2,3-diol, trans-2,3-dihydroxy-1,10b-epoxy-1,2,3,10beta tetrahydro FLA (2,3D FLA), 3-hydroxy FLA, and 8-hydroxy FLA. The rodent microsomes produced considerably higher proportion of FLA 2,3-diol, and 2,3D FLA than did pig, dog, and humans. On the other hand, microsomes from higher mammals converted a greater proportion of FLA to 3-hydroxy FLA, the detoxification product of FLA. Overall, our results revealed a great variation among species to metabolize FLA.     

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

Tardive dyskinesia (TD) is a common and potentially irreversible side effect associated with long-term treatment with typical antipsychotics. Approximately, 80% or more of patients with schizophrenia are smokers. Smoking is a potent inducer of the CYP1A2 enzyme, and is known to cause a significant decrease in plasma concentrations of some antipsychotics. Therefore, person-to-person differences in the extent of CYP1A2 induction by smoking may contribute to risk for the development of TD. Recently, a (C-->A) genetic polymorphism in the first intron of the CYP1A2 gene was found to be associated with variation in CYP1A2 inducibility in healthy volunteer smokers. The aim of this study was to test the clinical importance of the (C-->A) polymorphism in CYP1A2 in relation to TD severity. A total of 85 patients with schizophrenia were assessed for TD severity using the Abnormal Involuntary Movement Scale (AIMS), and were subsequently genotyped for the (C-->A) polymorphism in CYP1A2. The mean AIMS score in patients with the (C/C) genotype (associated with reduced CYP1A2 inducibility) was 2.7- and 3.4-fold greater than in those with the (A/C) or (A/A) genotype, respectively (F[2,82] = 7.4, P = 0.0007). Further, a subanalysis in the 44 known smokers in our sample, revealed a more pronounced effect. The means AIMS score in smokers was 5.4- and 4. 7-fold greater in (C/C) homozygotes when compared to heterozygotes and (A/A) homozygotes, respectively (F[2,41] = 3.7, P = 0.008). These data suggest that the (C-->A) genetic polymorphism in the CYP1A2 gene may serve as a genetic risk factor for the development of TD in patients with schizophrenia. Further studies in independent samples are warranted to evaluate the applicability of our findings to the general patient population receiving antipsychotic medications.     

Evaluation of the WHO clinical decision rule for streptococcal pharyngitis.

AIMS: To prospectively assess the WHO clinical decision rule (CDR) for group A beta haemolytic streptococcal (GABHS) pharyngitis in three countries. METHODS: A prospective, observational cohort study in urban outpatient clinics in Rio de Janeiro, Cairo, and Zagreb. There were 2225 children aged 2-12 years with cough, rhinorrhoea, red or sore throat; 1810 of these with sore throat were included in the analysis. RESULTS: The proportion of children presenting with sore throat and found to have GABHS pharyngitis ranged from 24.6% (Brazil) to 42.0% (Croatia). WHO CDR sensitivity was low for all sites in both age groups. In children age 5 or older, sensitivity ranged from 3.8% in Egypt to 10.8% in Brazil. In children under 5, sensitivity was low (0.0-4.6%) Specificity was high in both age groups in all countries (93.8-97.4%). CONCLUSIONS: In these populations, the current WHO CDR has high specificity, but low sensitivity; it did not detect up to 96.0% of children who have laboratory confirmed GABHS pharyngitis. A CDR with higher sensitivity should be developed for use in regions where rheumatic fever and rheumatic heart disease are still major health problems.     

Clinical evaluation of biomarkers in Gaucher disease

Novel or candidate biomarkers require thorough evaluation to establish their utility in a clinical setting. This paper describes an evaluation of several established enzyme markers of Gaucher disease and a newly-described chemokine, pulmonary and activation-regulated chemokine (PARC). The ability of the biomarkers to rank patients with Gaucher disease in order of disease severity and organ bulk, and to reflect changes in key clinical parameters in response to enzyme replacement therapy were evaluated. PARC concentrations were found to be reliably correlated with visceral disease and with key clinical responses to enzyme replacement in an unbiased manner. Unlike chitotriosidase and serum angiotensin-converting enzyme activity, genetic variation in serum PARC did not appear to influence its utility as a biomarker.
Conclusion: For each new candidate biomarker of lysosomal storage diseases, a similar clinical evaluation will be required, though the approach will need to be modified according to the clinical features and natural history of each disorder.     

Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia

BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.     

Smoking relapse during the first year after treatment for early-stage non-small-cell lung cancer.

BACKGROUND: Non-small-cell lung cancer patients who continue to smoke after cancer diagnosis are more likely to experience disease recurrence, decreased treatment efficacy, and treatment complications. Despite this, many continue to smoke, with estimates ranging from 13% to approximately 60%. METHODS: Participants were 154 early-stage, non-small-cell lung cancer patients who had smoked within 3 months before surgery. Patients were followed for 12 months after surgery to assess smoking status and duration of continuous abstinence after surgery. Predictors included medical, smoking history, psychosocial, and demographic characteristics. RESULTS: At some point after surgery, 42.9% of patients smoked; at 12 months after surgery, 36.9% were smoking. Sixty percent of patients who lapsed did so during the first 2 months after surgery. Smoking at follow-up was predicted by shorter quit duration before surgery, more intense Appetitive cravings (expectation of pleasure from smoking), lower income, and having a higher level of education. Time until the first smoking lapse was predicted by shorter quit duration before surgery, more intense Appetitive cravings to smoke, and lower income. Among those who lapsed, greater delay before the lapse was associated with abstinence at the 12-month follow-up assessment. CONCLUSIONS: Nearly half of non-small-cell lung cancer patients return to smoking after surgery if they have recent smoking histories. Most initial lapses happen within 2 months and occur in response to more recent smoking and more intense cravings. Findings suggest that interventions to prevent relapse should target those who wait until cancer surgery to quit smoking and should be started as soon as possible after treatment.     

Family history of cancer, oral contraceptive use, and ovarian cancer risk.

OBJECTIVE: The purpose of this study was to determine whether women with a family history of ovarian cancer are at reduced risk of ovarian cancer from the use of oral contraceptives and to compare their risk with that of women with no family history of ovarian cancer. STUDY DESIGN: A population-based case-controlled study was conducted from May 1994 through July 1998 in which 767 women aged 20 to 69 years with a diagnosis of epithelial ovarian cancer were ascertained from 39 hospitals in 3 northeastern states. Personal interviews with the women and 1367 control subjects provided data that allowed us to estimate the relative risk of ovarian cancer in relation to a family history of cancer and total duration of oral contraception. RESULTS: Among the 33 case patients and 24 control subjects with a first-degree family history of ovarian cancer, risk of ovarian cancer declined with increasing duration of oral contraception (P =.01). Risk reduction from short-term use of oral contraceptives (< or = 48 months) did not differ significantly by family history (combined estimate of odds ratio, 0.72; 90% CI, 0.59%-0.87%). Risk reduction from long-term use of oral contraceptives (>48 months) was greater in women with a positive family history of ovarian cancer (odds ratio, 0.12) than in women with a negative family history of ovarian cancer (odds ratio, 0.51; test of interaction, P =.04; 692 case patients, 1279 control subjects). CONCLUSION: Four to 8 years of oral contraception may substantially reduce the risk of ovarian cancer by age 70 years in women with a family history of the disease, from approximately 4 women per 100 women who did not use oral contraceptives to only 2 women per 100 women who did use oral contraceptives.     

Promising hypotensive effect of hawthorn extract: a randomized double-blind pilot study of mild, essential hypertension.

This pilot study was aimed at investigating the hypotensive potential of hawthorn extract and magnesium dietary supplements individually and in combination, compared with a placebo. Thirty-six mildly hypertensive subjects completed the study. At baseline, anthropometric and dietary assessment, as well as blood pressure measurements were taken at rest, after exercise and after a computer 'stress' test. Volunteers were then randomly assigned to a daily supplement for 10 weeks of either: (a) 600 mg Mg, (b) 500 mg hawthorn extract, (c) a combination of (a) and (b), (d) placebo. Measurements were repeated at 5 and 10 weeks of intervention. There was a decline in both systolic and diastolic blood pressure in all treatment groups, including placebo, but ANOVA provided no evidence of difference between treatments. However, factorial contrast analysis in ANOVA showed a promising reduction (p = 0.081) in the resting diastolic blood pressure at week 10 in the 19 subjects who were assigned to the hawthorn extract, compared with the other groups. Furthermore, a trend towards a reduction in anxiety (p = 0.094) was also observed in those taking hawthorn compared with the other groups. These findings warrant further study, particularly in view of the low dose of hawthorn extract used.