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PubMed2001

Nonspecific tests for pulmonary embolism.

Many tests have been proposed as useful in the diagnostic evaluation of suspected PE, but nonspecific tests for PE can only add to the level of suspicion one has for the diagnosis. As Anderson indicates, "virtually all clinical and laboratory findings neither diagnose nor exclude the diagnosis of PE. They merely serve to heighten suspicion of the diagnosis and prompt the clinician to pursue additional diagnostic studies." D-dimer measurement is promising as a test to exclude PE in young healthy out-patients, and further study and improvements in technology, can clarify the usefulness of the different methods of performing this assay. For now, diagnostic algorithms for PE should continue to incorporate multiple tests and decision points, but the standard remains specialized imaging techniques.

Blood Gas Analysis↗

PubMed2004

HER-2 testing and trastuzumab therapy for metastatic breast cancer: a cost-effectiveness analysis.

PURPOSE: Trastuzumab therapy has been shown to benefit metastatic breast cancer patients whose tumors exhibit HER-2 protein overexpression or gene amplification. Several tests of varying accuracy and cost are available to identify candidates for trastuzumab. We estimated the cost-effectiveness of alternative HER-2 testing and trastuzumab treatment strategies. PATIENTS AND METHODS: We performed a decision analysis using a state-transition model to simulate clinical practice in a hypothetical cohort of 65-year-old metastatic breast cancer patients. Outcomes were quality-adjusted life-years (QALYs), lifetime cost, and incremental cost-effectiveness ratio (ICER). Interventions included testing with the HercepTest (DAKO, Carpinteria, CA) immunohistochemical assay alone, fluorescence in situ hybridization (FISH) alone, and both tests, followed by trastuzumab and chemotherapy for patients with positive test results and chemotherapy alone for patients with negative test results. RESULTS: In the base case, initial HercepTest with FISH confirmation of all positive results had an ICER of $125,000 per QALY gained. The incremental cost-effectiveness of initial FISH was $145,000 per QALY gained. Other strategies yielded the same or poorer effectiveness at a higher cost, or lower effectiveness at a lower cost, but with a less favorable ICER. These findings persisted under a range of assumptions, and only changes in test characteristics substantially altered results. CONCLUSION: It is more cost-effective to use FISH alone or as confirmation of all positive HercepTest results, rather than using FISH to confirm only weakly positive results or using HercepTest alone. When multiple tests are available to identify treatment candidates, test characteristics may have a substantial impact on the aggregate costs and effectiveness of treatment.

Aged↗

PubMed2004

Hypoxia-inducible factor and vascular endothelial growth factor are expressed more frequently in embolized than in nonembolized cerebral arteriovenous malformations.

OBJECTIVE: In previous studies, we documented a marked neoangiogenesis and endothelial proliferation in cerebral arteriovenous malformations (AVMs) that were embolized before surgery compared with those that were not embolized. We hypothesized that embolization caused a local hypoxia that promotes neoangiogenesis as a possible pathomechanism. To support this hypothesis, we now examined the angiogenesis-related proteins in a larger cohort of patients. In addition, we investigated hypoxia-inducible factor-1 alpha as a possible protein operative during neoangiogenesis of cerebral AVMs. METHODS: Paraffin-embedded specimens of 56 AVMs obtained from surgical resection and 14 brain tissue controls were immunohistochemically stained with antibodies to proliferating cell nuclear antigen, MIB-1, vascular endothelial growth factor, Flk1, and hypoxia-inducible factor-1 alpha by standard protocols. RESULTS: In AVMs treated with embolization before surgery (n = 35, 63%), the expression of hypoxia-inducible factor-1 alpha (P = 0.0101) and vascular endothelial growth factor (P = 0.0007) was significantly higher (Fisher's exact test) than in patients who did not have previous endovascular treatment. Differences in the expression of Flk-1 (P = 0.0798) and proliferating cell nuclear antigen (P = 0.0423) were in the same direction but were not significant when corrected for multiple testing. CONCLUSION: Our results provide circumstantial evidence that a partial occlusion of cerebral AVMs might induce local hypoxia-related neoangiogenesis. To support these data, future animal studies should be performed.

Adolescent↗

PubMed1983

Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral 6-OHDA lesions following implantation of nigral cell suspensions in different forebrain sites.

Single and multiple implants of nigral cell suspensions were grafted to the forebrains of rats with unilateral 6-hydroxydopamine-induced dopamine denervations. Control lesions alone induced a marked behavioural asymmetry, as assessed by amphetamine- and apomorphine-induced rotation, sensorimotor tests and side bias in an unbaited T-maze, and the animals were hyperactive to a low dose of apomorphine. Single suspension placements into different denervated striatal regions were capable of reversing the behavioural asymmetries dependent upon the specific placement for each test. Multiple suspension grafts were capable of reversing all behavioural asymmetries, and additionally abolished the supersensitive hyperactivity to apomorphine. By contrast, single suspension grafts placed into the substantia nigra or lateral hypothalamus had no detectable effect on any functional measure. The results indicate that nigral suspension grafts can be at least as effective as solid grafts in reversing the functional deficits induced by dopamine denervation, provided that placements are selected within appropriate dopamine terminal regions of the forebrain (e.g. caudate-putamen or nucleus accumbens).

Animals↗

PubMed2000

Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups.

The present study evaluated the association between habitual caffeine intake via coffee and tea and cognitive performance. This was done as part of a larger research programme into the determinants of cognitive ageing (the Maastricht Aging Study: MAAS). Possible withdrawal effects that may have explained in part the positive association between performance and intake in an earlier study were controlled for. In addition, all cognitive tests in this study were administered under strict laboratory conditions. A group of 1875 healthy adults, stratified for age (range 24 - 81 years), sex, and general ability, were screened for habitual intake of coffee and tea and took part in extensive cognitive testing. Multiple regression analysis with control for age, sex, socio-demographic variables, and substance use showed that habitual caffeine consumption was significantly related to better long-term memory performance and faster locomotor speed. No relationships were found between habitual caffeine consumption and short-term memory, information processing, planning, and attention as measured with the Stroop Test. Moreover, no difference in sensitivity to caffeine intake between different age groups was found, suggesting that caffeine intake did not counteract age-related cognitive decline. Several recommendations are made to improve the design of future studies in this field. Copyright 2000 John Wiley & Sons, Ltd.

Journal Article↗

PubMed2026

Genetically predicted childhood traits and parental health and risk of pediatric psychiatric disorders: A 2-sample Mendelian randomization study.

The etiology of pediatric psychiatric disorders is complex, involving intergenerational influences and a child's own developmental health. We aimed to investigate the potential effects of genetically predicted childhood traits (childhood obesity, absence epilepsy, intelligence) and parental health traits (longevity, Alzheimer disease, severe depression) on the risk of several childhood and adolescent psychiatric disorders. We employed a 2-sample Mendelian randomization (MR) design using summary statistics from large-scale genome-wide association studies. Data for parental health exposures were primarily from the UK Biobank. Data for childhood trait exposures were from various consortia. Data for outcomes - conduct disorder, mixed conduct and emotional disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and broader behavioral/emotional and social disorders - were sourced from FinnGen and the Psychiatric Genomics Consortium, among others. We used the inverse-variance weighted method for the primary analysis, with MR-Egger, weighted median, and weighted mode as additional analyses. To test the robustness of the results, we conducted sensitivity analyses using MR-Egger regression, Cochran Q test for heterogeneity, the MR-pleiotropy residual sum and outlier test, and a leave-one-out analysis. Genetic liability for childhood obesity was associated with an increased risk of ASD (odds ratio = 1.06, P = .016) and ADHD (odds ratio = 1.09, P = .026), even though these associations did not withstand multiple testing correction. No other robust, statistically significant causal associations were identified. Sensitivity analyses showed limited evidence of bias from horizontal pleiotropy for the main findings. Our findings provide MR evidence supporting potential links from genetic liability for childhood obesity to increased risks of ASD and ADHD. These results highlight the importance of considering a child's early-life health trajectory in the etiology of pediatric psychiatric disorders.

Humans↗

PubMed2006

Genetic analysis of ADIPOR1 and ADIPOR2 candidate polymorphisms for type 2 diabetes in the Caucasian population.

Adiponectin is a metabolic link between adipose tissue and insulin action, mediating part of obesity-associated insulin resistance and type 2 diabetes. Two adiponectin receptors have been identified, and we investigated whether sequence variations in adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) genes could contribute to the genetic risk for type 2 diabetes in a case-control study of 1,498 Caucasian subjects. We sequenced the putative functional regions of the two genes in 48 subjects and selected single nucleotide polymorphisms (SNPs) from the public database. Five SNPs in ADIPOR1 and 12 in ADIPOR2 were tested for association with type 2 diabetes. No SNP of ADIPOR1 showed association in any of the samples from the French population. In contrast, three SNPs of ADIPOR2 showed nominal evidence for association with type 2 diabetes before correction for multiple testing (odds ratio [OR] 1.29-1.37, P = 0.034-0.014); only rs767870, located in intron 6, was replicated in an additional diabetes dataset (n = 636, OR 1.29, P = 0.020) with significant allelic association from the overall meta-analysis of 2,876 subjects (adjusted OR 1.25 [95% CI 1.07-1.45], P = 0.0051). In conclusion, our data suggest a modest contribution of ADIPOR2 variants in diabetes risk in the French population.

Adult↗

PubMed1995

The effect of body fat distribution on pulmonary function tests.

Although the influence of obesity on pulmonary function tests has been examined, the role of body fat distribution has received limited attention. Pulmonary studies of patients severely affected by upper body obesity suggest they have more severely compromised lung volumes than obese patients with lower body obesity. We examined 42 healthy but normal or mildly obese men to determine if body fat distribution influences pulmonary function tests. Multiple measures of adiposity showed a significant inverse relationship with both spirometry and static lung volumes. However, the biceps skinfold thickness had the strongest inverse relationship with total lung capacity (TLC) compared to other anthropometric measures. The waist-to-hip ratio (WHR) demonstrated a significant inverse relationship with static lung volumes only when controlling for cigarette smoking. However, comparing pulmonary function tests between patients with a WHR less than 0.950 (lower body fat distribution) and subjects with a WHR of 0.950 or greater (upper body fat distribution) revealed that FVC, FEV1, and TLC were significantly lower in the patients with upper body fat distribution. Stepwise multiple regression analysis was done using all anthropometric variables and age which generated predictive equations that included the biceps skinfold thickness for residual volume (RV) and TLC. This suggests that upper body fat distribution may be associated with a modest impairment of lung volumes in normal and mildly obese men. Until the findings of this study can be applied to a larger, ethnically and anthropometrically diverse population, and to women, we believe caution is warranted when standard equations are used to predict pulmonary function tests in an anthropometrically diverse population.

Adipose Tissue↗

PubMed2006

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

BACKGROUND: The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. METHODS AND RESULTS: We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). CONCLUSIONS: Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Aged↗

PubMed1987

Improvement of deficits in mnemonic rhyme for multiplication in Japanese aphasics.

Since Japanese learn the multiplication tables by means of mnemonic rhymes called kuku, i.e., via the auditory-speaking route, it is hypothesized that aphasics who have a deficit in kuku might relearn it via the visual-writing route. After having ordinary language therapy for more than 3 months, eight patients were admitted to this special kuku training. The comparisons of scores on multiplication tests showed that the visual-writing route improved most after a 1- or 2-month training period while the auditory-speaking route improved least. These results, suggesting that the visual processor can take on the new role in conducting multiplication, can be considered a realization of functional reorganization in the brain.

Adult↗

PubMed2006

Cognitive performance of patients with mesial temporal lobe epilepsy is not associated with human prion protein gene variant allele at codons 129 and 171.

Cognitive impairment has long been recognized in people with medically refractory epilepsies. Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS), the most common surgically remediable epileptic syndrome, has been associated with a cellular prion protein (PrPc) gene (Prnp) variant allele at codon 171. The polymorphism consisting of a methionine-for-valine substitution at codon 129 has been associated with early cognitive deterioration in elderly people and patients with Down syndrome. The same variant allele in homozygosis (V129V) has been associated to a lower long-term memory in healthy humans. PrPc mediates several processes related to neuroplasticity, and its role in cognitive processes remains unknown. In this study, we evaluated the genetic contribution of Prnp alleles to cognitive performance in patients with MTLE-HS. Cognitive performance, measured with 19 neuropsychological tests, of patients with refractory MTLE-HS with the normal Prnp genotypes was compared with that of patients with the variant alleles at codons 129 and 171. With the effects of clinical, demographic, electrophysiological, and neuroimaging variable interactions controlled by multiple linear regression analysis and adjustment for multiple test comparisons, the presence of Prnp variant alleles was found not to be significantly associated to cognitive performance of patients with MTLE-HS. The presence of variant alleles at codons 129 and 171 is not associated to cognitive performance of patients with refractory MTLE-HS.

Adult↗

PubMed2005

TNF as a malaria candidate gene: polymorphism-screening and family-based association analysis of mild malaria attack and parasitemia in Burkina Faso.

We have previously obtained strong evidence for linkage of mild malaria attack to the MHC region, with a peak close to the tumor necrosis factor (TNF) gene. We screened, for polymorphisms, the entire TNF gene in the same sample of 34 families comprising 197 individuals living in a Plasmodium falciparum endemic area and we found 17 polymorphisms. In a longitudinal study, we investigated whether the 11 most frequent and informative polymorphisms were associated with mild malaria attack and maximum parasitemia, which was the highest parasitemia in each individual over 2 years. Mild malaria attack and maximum parasitemia were positively correlated. Transmission disequilibrium tests showed nominal evidence for association between TNF-1031, TNF-308, TNF851 and TNF1304 polymorphisms, and mild malaria attack on the one hand, and between TNF-238, TNF851 and TNF1304 polymorphisms, and maximum parasitemia on the other hand. After accounting for multiple tests, we confirmed the association of TNF-238 with maximum parasitemia and the association of TNF1304 and TNF851 with maximum parasitemia and mild malaria attack. The association tests with mild malaria attack suggest a moderate effect of TNF-308 polymorphism. In conclusion, our study suggests that several TNF variants may be part of the genetic determinants for maximum parasitemia and/or mild malaria attack.

Alleles↗

PubMed2004

Diagnosis of intraocular lymphoma.

PURPOSE: To review current techniques for the diagnosis of intraocular lymphoma. METHODS: Literature review. RESULTS: There are a limited number of small case series and case reports reporting the diagnosis of intraocular lymphoma. Limitations in the ability to diagnose lymphoma through cytologic examination of the vitreous has led to investigations into immunohistochemistry either manually or by automated cytofluorography, intraocular cytokine determinations, and polymerase chain reaction of the vitreous or tissue lymphoid cells to detect gene rearrangements in the IgH, bcl-2, or T-cell receptor gamma gene. Data regarding diagnostic efficiency of the various testing strategies is limited by small patient numbers. Careful handling of the vitreous specimen and adequate laboratory and pathological support is critical. CONCLUSIONS: Despite a proliferation of new techniques for the diagnosis of intraocular lymphoma, none is clearly superior. Use of multiple testing strategies may improve diagnostic yield.

Diagnostic Techniques, Ophthalmological↗

PubMed2005

Methylation discriminators in NSCLC identified by a microarray based approach.

Aberrant DNA methylation is a frequent phenomenon in non-small cell lung cancers. We have used a microarray approach to assess the methylation status of 245 CpG positions in 59 candidate genes in 26 squamous cell carcinomas, and 22 adenocarcinomas as well as 26 normal adjacent lung tissue samples from smokers to identify genes that show a distinct methylation status difference between the two different tumour type tissues and normal adjacent tissue. Tumour tissue samples were grouped together and compared to the normal tissue sample group. A multivariate test was performed, taking into account all CpG positions that were analyzed for a particular gene, to calculate p-values for each gene based on the observed methylation difference between the two groups, p-values obtained were corrected for multiple testing. The highest degree of differential DNA methylation in squamous cell carcinoma compared to normal was observed in ARHI, MGMT, GP1bbeta, RARbeta and TMEFF2 genes, while TMEFF2, MGMT and CDKNIC genes differentiated between adenocarcinomas and normal tissue. It is of note that some of the genes for which differential methylation status was observed, have not been previously described in lung cancer. Our results provide compelling evidence that different histological types of lung cancer may be distinguished from normal tissue based on methylation profiles of specific genes.

Adenocarcinoma↗

PubMed1995

Severe asthenozoospermia: a structural and functional study.

Ejaculates from 25 patients with severe asthenozoospermia (all spermatozoa immotile or only non-progressively motile) were studied to identify individually the cause of impaired motility. Multiple tests were performed, viz. light and electron microscopic studies and sperm function tests. An objective scoring was applied to both the routine and the functional analyses. Three categories of samples were identified: (1) necrozoospermia (n = 9), where sperm viability was very poor; (2) structural tail abnormality as seen by light microscopy (n = 4); and (3) ultrastructural abnormality (n = 12). In the last category, one case showed absence of dynein arms; this was associated with mitochondrial abnormalities. Mitochondrial abnormality with normal tail components was observed in the majority (n = 7) and accessory fibre abnormality in four cases. The scoring system revealed that, functionally, all samples were abnormal whereas routine analysis showed 15 samples to be subnormal and 10 to be abnormal, which indicates the need for functional analysis. Because of the multiple defects seen in these samples, there is a need for a battery of sperm function tests. This study indicates that mitochondrial defects are one of the causes that may account for the loss of sperm motility in the patient population.

Acrosome↗

PubMed2003

Transcriptional profiling identifies extensive downregulation of extracellular matrix gene expression in sarcopenic rat soleus muscle.

The direction of change in skeletal muscle mass differs between young and old individuals, growing in young animals and atrophying in old animals. The purpose of the experiment was to develop a statistically conservative list of genes whose expression differed significantly between young growing and old atrophying (sarcopenic) skeletal muscles, which may be contributing to physical frailty. Gene expression levels of >24,000 transcripts were determined in soleus muscle samples from young (3-4 mo) and old (30-31 mo) rats. Age-related differences were determined using a Student's t-test (alpha of 0.05) with a Bonferroni adjustment, which yielded 682 probe sets that differed significantly between young (n = 25) and old (n = 20) animals. Of 347 total decreases in aged/sarcopenic muscle relative to young muscles, 199 were functionally identified; the major theme being that 24% had a biological role in the extracellular matrix and cell adhesion. Three themes were observed from 213 of the 335 total increases in sarcopenic muscles whose functions were documented in databases: 1) 14% are involved in immune response; 2) 9% play a role in proteolysis, ubiquitin-dependent degradation, and proteasome components; and 3) 7% act in stress/antioxidant responses. A total of 270 differentially expressed genes and ESTs had unknown/unclear functions. By decreasing the sample sizes of young and old animals from 25 x 20 to 15 x 15, 10 x 10, and 5 x 5 observations, we observed 682, 331, 73, and 3 statistically different mRNAs, respectively. Use of large sample size and a Bonferroni multiple testing adjustment in combination yielded increased statistical power, while protecting against false positives. Finally, multiple mRNAs that differ between young growing and old, sarcopenic muscles were identified and may highlight new candidate mechanisms that regulate skeletal muscle mass during sarcopenia.

Aging↗

PubMed2001

Is betamethasone effective longer than 7 days after treatment?

OBJECTIVE: To determine whether perinatal outcomes are influenced by the interval between antenatal betamethasone administration and delivery. METHODS: We did a retrospective cohort analysis of live-born singleton neonates born between 28 and 34 weeks' gestation after a single course of betamethasone, defined as two 12-mg doses over 24 hours. Subjects were grouped according to length of interval between initial betamethasone dose and delivery (1-2 days, 3-7 days, and 8-14 days). We excluded women who had membranes ruptured for longer than 24 hours before delivery, delivery before the second dose of betamethasone, or more than two doses of betamethasone. Data were analyzed by Student t test, chi(2) test, or Fisher exact test. Multiple logistic regression analyses were done using suspected risk factors for respiratory distress syndrome (RDS) and intraventricular hemorrhage (IVH). We calculated that a sample of 200 women would provide more than 80% power to detect a 50% reduction in incidence of RDS for a two-sided test of significance at a critical level of.05. RESULTS: Among 216 women, 97 delivered in 1-2 days, 78 in 3-7 days, and 41 in 8-14 days after a single course of betamethasone. Groups were similar in selected demographics, tocolytic exposure, gestational age at delivery, modes of delivery, and mean birth weights. There were no significant differences in frequencies of RDS (39.2%, 41.1%, and 36.6%, respectively) or grades 3-4 IVH (1.1%, 1.3%, and 0%, respectively) between groups. Frequencies of selected perinatal infectious outcomes also were similar between groups. Multiple logistic regression analyses found no association between RDS or IVH and delivery more than 7 days from betamethasone therapy. CONCLUSION: There were no differences in perinatal outcomes in pregnancies delivered 8-14 days after antenatal exposure to betamethasone compared with those delivered within 7 days of exposure.

Adult↗

PubMed2004

Cognitive profile of topiramate as compared with lamotrigine in epilepsy patients on antiepileptic drug polytherapy: relationships to blood serum levels and comedication.

RATIONALE: This retrospective study was conducted to identify cognitive domains affected by topiramate (TPM), and to evaluate the role of blood serum levels of TPM and comedication in the etiology of TPM-induced cognitive impairment. METHODS: Forty-two patients on AED polytherapy containing topiramate and a random sample of 42 patients with lamotrigine as the corresponding agent underwent extensive neuropsychological testing. Current blood serum levels of TPM were correlated with test scores. RESULTS: Patients on TPM scored significantly worse in phonematic verbal fluency, memory spans, and working memory; language and memory function were not affected per se. In few cognitive domains, serum levels of TPM and performance were correlated before correction for multiple testing. Drug load of additional medication did not account for differences between or within groups. DISCUSSION: Consistent with previous reports, patients on AED polytherapy including TPM display a cognitive pattern with specific impairment in executive functions. The severity of the cognitive side effects of TPM may be related to dosing to a certain extent, but this relationship may be disclosed only with larger sample sizes. Accordingly, TPM dosage does not appear to be a good indicator of TPM-related cognitive side effects in the individual patient.

Adult↗