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PubMed2004

Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke.

CONTEXT: The presence of antiphospholipid antibodies (aPL) has been associated with vascular occlusive events. However, the role of aPL in predicting ischemic events, particularly recurrent ischemic stroke, is controversial. OBJECTIVE: To evaluate the effect of baseline aPL positivity (ie, positivity for anticardiolipin antibodies [aCL], lupus anticoagulant antibodies [LA], or both) on subsequent thrombo-occlusive events, including recurrent stroke. DESIGN, SETTING, AND PARTICIPANTS: The Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study within the Warfarin vs Aspirin Recurrent Stroke Study (WARSS), a randomized double-blind trial (N = 2206) conducted at multiple US clinical sites from June 1993 through June 2000 and comparing adjusted-dose warfarin (target international normalized ratio, 1.4-2.8) and aspirin (325 mg/d) for prevention of recurrent stroke or death. APASS participants were 1770 (80%) WARSS participants who consented to enroll in the APASS, with usable baseline blood samples drawn prior to randomization to the WARSS and analyzed for aPL status within 90 days of index stroke by a central independent laboratory. Quality assurance was performed on approximately 10% of samples by a second independent laboratory. MAIN OUTCOME MEASURE: Two-year rate of the composite end point of death from any cause, ischemic stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis, pulmonary embolism, and other systemic thrombo-occlusive events. The primary analysis assessed the outcome associated with aPL positivity within each WARSS treatment group separately, after risk-factor adjustment (since these aPL-positive vs aPL-negative comparisons were not randomized). RESULTS: Of the 1770 APASS patients, 720 (41%) were classified as aPL-positive and 1050 (59%) as aPL-negative. There was no increased risk of thrombo-occlusive events associated with baseline aPL status in patients treated with either warfarin (relative risk [RR], 0.99; 95% confidence interval [CI], 0.75-1.31; P =.94), or aspirin (RR, 0.94; 95% CI, 0.70-1.28; P =.71). The overall event rate was 22.2% among aPL-positive and 21.8% among aPL-negative patients. There was no treatment x aPL interaction (P =.91). Patients with baseline positivity for both LA and aCL antibodies tended to have a higher event rate (31.7%) than did patients who tested negative for both antibodies (24.0%) (unadjusted RR, 1.36; 95% CI, 0.97-1.92; P =.07). Classification and regression tree analyses did not identify a specific LA test or aCL isotype or titer that was associated with increased risk of thrombo-occlusive event. CONCLUSIONS: The presence of aPL (either LA or aCL) among patients with ischemic stroke does not predict either increased risk for subsequent vascular occlusive events over 2 years or a differential response to aspirin or warfarin therapy. Routine screening for aPL in patients with ischemic stroke does not appear warranted.

Aged↗
PubMed1996

Effect of aluminium on expression and processing of amyloid precursor protein.

The environmental agent aluminium has been extensively investigated for a potential role in the aetiology of Alzheimer's disease. Despite many investigations there is at present no definite proof for any involvement. If aluminium is involved it is possible that its action is mediated through interaction with the synthesis or processing of amyloid precursor protein (APP). The present study compared aluminium loaded IMR-32 neuroblastoma cells and rat brains with control cells and brains to determine if aluminium affected APP expression and/or processing. In the IMR-32 model system aluminium had no effect on steady-state APP mRNA levels or on the ratio of individual isoforms. It also had no quantitative or qualitative effect on APP-immunoreactive bands detected in protein extracts from conditioned medium of these cells. In total cell extracts, aluminium reduced the intensity of APP-immunoreactive bands between 120-105 kDa but had no effect on a 9 kDa band. In rat brains, aluminium had no effect on APP-immunoreactive bands from soluble or insoluble-membranous extracts. The results, in general, provide no evidence for any effect of aluminium on APP expression or processing.

Aluminum↗
PubMed2000

Ordered structure acquisition by the N- and C-terminal domains of the small proline-rich 3 protein.

The cell envelope (CE) is a vital structure for barrier function in terminally differentiated dead stratified squamous epithelia. It is assembled by transglutaminase (TGase) cross-linking of several proteins, including hSPR3 in certain specialized epithelia normally subjected to mechanical trauma. Biochemical studies show that hSPR3 serves as a complete substrate for TGase1, TGase2, and TGase3. Multiple adjacent glutamines and lysines of only head-and-tail domain sequences are used by each enzyme for cross-linking. Structural data suggest that the hSPR3 central repeats, as well as hSPR1 and hSPR 2, are highly flexible and mobile; thus, the TGases might not be able to recognize the residues localized on the repeats as adequate substrate. To investigate this hypothesis further and to complete the structural investigation of hSPR3, we performed circular dichroism (CD) studies on peptides corresponding to the N- and C-terminal domain. CD spectra have also been carried out in the presence of different concentrations of the structure-promoting agent cosolvent trifluoroethanol (TFE), which mimics a partial hydrophobic environment found in vivo in or next to the membrane. In fact, this agent increases the dielectric constant of water proportionally, depending on its concentration, and confers structuring properties to the solution, to peptides and proteins that have a structuring propensity. The results indicate that in both the N-terminal and C-terminal, peptides acquire a more ordered structure as a function of the TFE concentration in water. This ability of both N- and C-terminal domain to acquire a more stable ordered conformation might be relevant for SPR3 to act as substrate of TGases. Indeed, only the N- and C-terminus is cross-linked by TGase1 and 3.

Amino Acid Sequence↗
PubMed2000

Gemcitabine plus vinorelbine as first-line chemotherapy in advanced nonsmall cell lung carcinoma a phase II trial.

BACKGROUND: Response and survival in patients with advanced or metastatic nonsmall cell lung carcinoma (NSCLC) remain poor. As single agents, the nucleoside analog gemcitabine, and the semisynthetic vinca alkaloid vinorelbine, have been shown to be effective in NSCLC and to have a low toxicity profile. METHODS: Fifty-four chemotherapy-naive patients with NSCLC Stage IIIB (any TN3M0 or T4 any NM0) or IV (any T any NM1) were enrolled in this single-institution Phase II study. Gemcitabine 1250 mg/m(2) and vinorelbine 25 mg/m(2) were both administered on Days 1 and 8 every 3 weeks for up to 9 courses unless disease progression or severe toxicity required their discontinuation. RESULTS: Partial tumor regression was observed in 16 patients, for an overall response rate of 30% (95% confidence interval, 18.4-46.7%) on an intent-to-treat basis. The median time to progression was 5 months (range, 3-20). The median survival was 12 months (range, 5-42+); 1-year and 2-year survival rates were 49.1% and 17%, respectively. Hematologic toxicity was mild with only 11% of the patients developing Grade 3 neutropenia. None of the patients developed any Grade 4 toxicity. CONCLUSIONS: The combination of gemcitabine plus vinorelbine is feasible on an outpatient basis. The good activity and tolerability of the regimen make it a suitable candidate for further trials, using platinum-based regimens as comparators and possibly selecting elderly and less fit patients.

Adult↗
PubMed2006

Steroids for symptom control in infectious mononucleosis.

BACKGROUND: Glandular fever (infectious mononucleosis) is associated with fatigue, fever, sore throat and swollen lymph nodes. The severity of symptoms can vary. In extreme cases, breathing difficulties because of swelling in the throat and other complications can require hospitalization. The duration of symptoms is also variable; in some instances they can last for months. There are few treatments available. There are no universal criteria for using steroids in glandular fever. While their use is generally reserved for severe complications, there are reports of practitioners treating most symptomatic people with steroids. As glandular fever often affects young people at a time in their studies where they need to be continually productive, the potential duration of the condition is perhaps a key factor in prescribing such a potent drug for symptom control. OBJECTIVES: To determine the efficacy and safety of steroid therapy for symptom control in glandular fever. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2005); MEDLINE (January 1966 to November 2005); EMBASE (January 1974 to November 2005); and the UK National Research Register (November 2005). SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared the effectiveness for symptom control of a steroid to placebo or to another intervention for people of any age with documented glandular fever were included. DATA COLLECTION AND ANALYSIS: Authors independently assessed trial inclusion according to predetermined criteria. Results are presented separately for each symptom and, where possible, it was intended to combine results in a meta-analysis. MAIN RESULTS: Seven trials were included. The diagnosis, steroid regime, outcomes and methodological quality varied between trials. The sample size ranged from 24 to 94. For sore throat the results of two studies suggest a benefit at 12 hours of steroid therapy over placebo; however this benefit was not maintained. The evidence from one trial suggests a longer benefit when the steroid is combined with an antiviral drug. There was evidence from one trial that steroids may improve resolution of fatigue around four weeks; however it is unclear if this is only in combination with an antiviral. Two trials reported severe complications in participants in the steroid group. AUTHORS' CONCLUSIONS: There is insufficient evidence - the trials were few, heterogeneous and some were of poor quality, to recommend steroid treatment for symptom control in glandular fever. There is also a lack of research on the side effects, potential adverse effects or complications, particularly in the long term.

Adrenal Cortex Hormones↗
PubMed1986

Aluminosilicates and the ageing brain: implications for the pathogenesis of Alzheimer's disease.

Senile plaques are a neuropathological feature of the ageing brain and consist of abnormal neuritic and glial processes surrounding an extracellular core of material with fibrillary ultrastructure. Present at low densities in the cerebral cortex of most aged individuals, they occur in large numbers in Alzheimer's disease, the major form of senile dementia. Energy-dispersive X-ray microprobe analysis of isolated cores and plaques in situ from patients with Alzheimer's disease or Down's syndrome and from normal controls has shown co-localization of high concentrations of aluminium (4-19%) and silicon (6-24%) at the centre of the core. The presence of these elements as aluminosilicates has been confirmed using solid-state 27Al nuclear magnetic resonance. These findings provide a link with the other major neuropathological feature of Alzheimer's disease, the neurofibrillary tangle-bearing neurons, where high intracellular levels of Al and Si have also been reported. The focal deposition of these elements may be an early and essential factor in the pathogenesis of Alzheimer-type changes, reflecting an increased exposure to aluminium.

Aged↗
PubMed1992

Aluminium accumulation, beta-amyloid deposition and neurofibrillary changes in the central nervous system.

Deposition of beta-amyloid and the formation of neurofibrillary tangles (NFTs) are central to the aetiopathogenesis of Alzheimer's disease (AD). The possible effects of aluminium on these processes have been investigated in patients with renal failure who are exposed chronically to high blood levels of aluminium. Focal accumulation of aluminium was observed in neurons with high densities of transferrin receptors, indicating transferrin-mediated uptake, in regions such as cortex and hippocampus which are selectively vulnerable in AD. Increased staining for the beta-amyloid precursor protein (APP) in cortical pyramidal neurons was evident in the majority of renal patients and immature senile plaques were present in 30% of cases, suggesting that aluminium may induce or accelerate beta-amyloid deposition. The absence of neurofibrillary changes in this group of renal patients indicates that aluminium does not directly cause the formation of NFTs. The brain aluminium content was not raised in neuropathologically assessed cases of AD and we have been unable to confirm claims of defective transferrin binding in this disorder. If aluminium contributes to the development of sporadic AD, it must do so indirectly, perhaps via effects on the synthesis or metabolism of APP, or by contributing generally to the age-related attrition of neurons and thus reducing the threshold for deficits produced by more specific disease-related processes.

Aluminum↗
PubMedDate not supplied

Attenuation of 4-I-phenol-enhanced chemiluminescence by non-enhancer phenols.

The intensity of 4-I-phenol-enhanced chemiluminescence from the luminol-H2O2-horseradish peroxidase system is markedly attenuated in the presence of low concentrations of non-enhancer phenols. Under the conditions studied, the effect is not associated with competition between 4-I-phenol and non-enhancer phenol for the enzyme intermediates, Compounds I and II, but involves a competition between non-enhancer phenol and luminol most probably for the 4-I-phenoxy radical.

Cresols↗
PubMedDate not supplied

Estimation of tyrosine by the attenuation of 4-iodophenol enhanced chemiluminescence.

Tyrosine markedly attenuates the chemiluminescence output intensity from the 4-iodophenol enhanced chemiluminescence assay system in a manner consistent with competition between the amino acid and luminol for the 4-iodophenoxy radical. This effect provides the basis for a sensitive assay of tyrosine. Interference by the other amino acids has been assessed; major interference by cysteine can be removed by incubation with iodoacetic acid.

Chloromercuribenzoates↗
PubMed2000

Preventing "information overdose": developing information-literate practitioners.

The practice of medicine has been transformed by the convergence of a number of trends and developments. These include changes in the regulatory environment, scientific advances, the emergence of pressures for evidence-based medicine, advances in pharmaceutical knowledge and manufacture, and a shift in the nature of the patient/provider relationship. Many of these circumstances have been brought about or amplified by a variety of technological innovations. Collectively, these changes necessitate continuing--perhaps even continuous--learning and adaptation on the part of both new and established practitioners. At the heart of this need is the explosion of information and of information technologies, which shows little sign of abating. However, it is not simply the volume of information nor even its form that poses a challenge. It is also that outdated, incorrect, or unproven information is as accessible as correct, defensible, and reliable information. Therefore, doctors must be equipped not only with the ability to locate information but to evaluate its relevance and credibility. In short, they must be "information literate." Since both information and the technologies that give access to it are constantly expanding, a practitioner can never claim to be "information literate" in any absolute or final sense. It is a constantly evolving attribute and, alongside biomedical, clinical, pharmaceutical, legislative, and other domains, needs to form part of the provision of continuing education. Five propositions are advanced concerning this particular aspect of continuing medical education, and the article concludes by arguing that, in the same way that educating patients is the best defense against accidental overdose in the pharmaceutical sense, the best way to prevent "information overdose" is the education of practitioners.

Certification↗
PubMed2002

Ten-year survival with chemotherapy and radiotherapy in patients with squamous cell carcinoma of the esophagus.

BACKGROUND: The effects of multimodality treatment on the survival of patients with esophageal carcinoma are unclear. The authors performed a prospective, Phase II study to assess the long-term results of chemotherapy plus radiotherapy (RT) on patients with esophageal squamous cell carcinoma. METHODS: Of 106 consecutive patients who were recruited between 1985 and 1992, 101 patients were evaluable. Cisplatin (100 mg/m2 per day) on Day 1 and fluorouracil (1000 mg/m2 per day) on Days 1-4 were given for two cycles, with concomitant RT (30 grays [Gy] in 15 fractions) over 19 days. Patients with potentially resectable tumors were then assessed for curative surgery; the other patients received two more courses of chemotherapy and further RT (20 Gy in 10 fractions). RESULTS: Of 40 patients who were candidates for surgery, 32 patients underwent surgery, and 24 patients had complete resection; 8 patients (25%) had no residual tumor in the specimen, and 12 patients (37%) had microscopic foci only. Surgical mortality was high (22%). Of 61 nonsurgical patients, 37 patients (61%) achieved complete clinical remission, and 14 patients (23%) achieved partial remission. The median survival for the entire series was 15 months (range, 1-136 months). The overall survival rate was 22% at 5 years and 12% at 10 years. At 10 years, freedom from disease progression was similar in the two groups (24%), whereas the median survival (22 months vs. 12 months) and the overall survival rates (17% vs. 9%) were better in nonsurgical patients compared with surgical patients, respectively, probably in relation to high surgical mortality. The larynx was preserved in 28% of 32 patients with cervical disease sites, with a 10-year disease free survival rate of 31%. Three deaths were attributed to nonsurgical treatments. CONCLUSIONS: Careful multidisciplinary pretreatment evaluation can identify patients who are ineligible for surgery without compromising long-term results. For patients with inoperable disease, chemoradiotherapy can produce relatively good long-term results. The combined approach without surgery can permit laryngeal preservation in a useful fraction of patients.

Adult↗
PubMed2005

It's not that bad: error introduced by oral stimulants in salivary cortisol research.

Evidence that oral stimulants can produce interference effects in salivary cortisol assays has led to advice to avoid their use. However, in studies with young children, the use of these saliva-producing substances increases compliance with collection procedures. Four experiments are described to examine the effects of two commonly used stimulants, SweetTarts and Koolaid. Across these experiments, interference effects produced by different quantities of these stimulants (0.025, 0.1, and 0.2 g) and those produced in two commonly used assays, DELFIA and EIA, were explored. The impact of using cotton rolls soaked with an oral stimulant prior to saliva collection was also examined. In general, oral stimulants did not affect the rank ordering of cortisol values, as the results for stimulant-treated samples were highly correlated with those of untreated samples (approximately .90 for serially collected samples and .95 for aliquots of the same saliva pool). Depending on which assay was used, however, oral stimulants increased or decreased the cortisol levels reported, with effects sizes in the small to medium range. Thus, oral stimulants should not be used with only a portion of the subjects in a study, nor should researchers assay stimulant-treated samples from the same study using different assays. When used sparingly, oral stimulants can be employed without compromising the quality of salivary cortisol data.

Adult↗
PubMed2006

Subjective complaints and self-evaluation of memory test performance in Questionable dementia.

BACKGROUND: The clinical significance of subjective memory complaints in elderly subjects has been an area of active research. In this study, we evaluated subjective complaints and self-evaluation of memory test performance in subjects with Questionable dementia (QD) and mild Alzheimer's disease (AD). METHODS: Ninety-two subjects (35 cognitively intact normal controls NC, 33 QD, and 24 mild AD) were assessed. Subjective memory complaints were evaluated using a memory inventory for the Chinese (MIC); objective assessment of awareness was assessed by the self-evaluation of own memory test performance. Cognitive function was assessed with the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Category Verbal Fluency Test (CVFT) and Executive Interview (EXIT-25). Depressive symptoms were evaluated with the Cornell Scale for Depression in Dementia (CSDD). RESULTS: The total number of subjective memory complaints (MI-tol) were significantly different between different subject groups (Kruskal Wallis test, chi2 = 13.19, p = 0.001). Significant correlations between scores of the MI-tol and CSDD (r = 0.33, p < 0.001), CMMSE (r = -0.33, p < 0.001), CDR (r = 0.36, p < 0.001) were found. In self-evaluation of memory test performance, the NC group tended to under-estimate while the AD subjects tended to over-estimate their performance. Group differences in the discrepancies of self-evaluation of memory performance were significant for both the immediate (Kruskal Wallis test, chi2 = 9.86, p = 0.007) and delayed recall (Kruskal Wallis test, chi2 = 10.55, p < 0.001) trials. CONCLUSIONS: Subjects with QD and mild AD showed higher frequency of subjective memory complaints, reflecting that the subjects still retain some ability to appreciate own memory function. However, the trend for over-estimation of performance in AD subjects suggests that the precision of estimation may be suboptimal. Moreover, depressive symptoms may affect the presentation of memory complaints and this factor should be carefully considered in future prospective studies.

Aged↗