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PubMed1994

Variation in acceptance of common oral antibiotic suspensions.

Palatability of oral antibiotic suspensions is important and may be a substantial factor in determining compliance in young pediatric patients. Because no comparative systematic data are available, we undertook the present study to assess the acceptance of and compliance with oral antibiotic suspensions commonly used in Israel. During a 4-month period lists of children receiving oral antibiotic suspensions were obtained from 3 major pediatric clinics, and parents were contacted by telephone 10 to 14 days after initiation of therapy, at which time information on age, sex, main disease, prescribed drugs and duration of treatment was obtained. Information regarding acceptance, side effects and compliance was obtained from 11 questions with graded scores. In the study 546 children received one of the following drugs: amoxicillin (n = 222); cefaclor (n - 142); cefuroxime axetil (n = 107); trimethoprim/sulfamethoxazole (n = 75). No major differences in background data were noted; more than 50% of each group had acute otitis media. Seventy-three percent of the cefaclor group reported acceptance of the drug with "pleasure" or "without problems" vs. 60, 55 and 20% for amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively, whereas "resentment" or "refusal" was reported in 11, 16, 26 and 56%, respectively (P < 0.0001). Mothers reported to be generally "satisfied" or "extremely satisfied" with the drug in 89, 81, 74 and 67% with cefaclor, amoxicillin, trimethoprim/sulfamethoxazole and cefuroxime axetil, respectively, and 85, 77, 73 and 67% of the children, respectively, received the drug for the entire prescribed course (P < 0.001). Our data demonstrate that marked variations exist in acceptance and compliance of oral antibiotic suspensions with children.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed2005

LRRK2 gene in Parkinson disease: mutation analysis and case control association study.

BACKGROUND: In addition to the four well-confirmed genes linked to early-onset Parkinson disease (PD) (SNCA, PARKIN, DJ-1, and PINK1), mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have recently been identified in families with autosomal dominant late-onset PD. OBJECTIVE: To perform mutation analysis of LRRK2 in probands of families showing dominant inheritance of PD and to conduct a case control association study to test the hypothesis that common coding variations might be associated with increased susceptibility to PD. METHODS: All 51 LRRK2 coding exons were sequenced in 23 probands and the mutation frequencies were evaluated in 180 neurologically normal control subjects. For the association study the authors genotyped four coding LRRK2 polymorphisms in 250 normal control subjects and 121 patients with PD (predominantly white patients of Canadian origin), 84% of whom had age at onset before 50 years and 42% had a positive family history. RESULTS: The authors identified three probands with heterozygous LRRK2 mutations: two of them have the known G2019S substitution and one proband has a novel I1371V substitution. Mutation analysis of a large family demonstrated complete segregation of the G2019S with PD. However, there was no association between PD and any of the four polymorphisms at the allelic or genotypic levels (p > 0.17). Furthermore, the authors did not detect a modifying effect for any genotype or of APOE genotypes upon the age at onset in the PD group (p > 0.20). CONCLUSIONS: The results support the prior suggestion that LRRK2 mutations cause PD. The disease in the families reported here presents a phenotype indistinguishable from typical PD. All three families demonstrate a very variable age at onset that is not explained by APOE genotypes. The common coding variations in the LRRK2 gene neither constitute strong PD risk factors nor modify the age at onset; however, the possibility of a modest risk effect remains to be assessed in large datasets.

Adult↗
PubMed2001

Catalog of 46 single-nucleotide polymorphisms (SNPs) in the microsomal glutathione S-transferase 1 (MGST1) gene.

A major goal in our laboratory is to understand the role of common genetic variations among individual patients as regards susceptibility to common diseases and differences in therapeutic efficacy and/or side effects of drugs. As an addition to the high-density SNP (single-nucleotide polymorphism) maps of 12 glutathione S-transferase and related genes reported earlier, we provide here an SNP map of the microsomal glutathione S-transferase 1 (MGST1) gene. Among 48 healthy Japanese volunteers examined. we identified a total of 46 SNPs at this locus, 36 of which had not been reported before: 4 in the promoter region, 34 in introns, 3 in the 3' untranslated region, and 5 in the 3' flanking region. No SNP was found in 5'untranslated or coding regions. The ratio of transition to transversion was approximately 1.2:1. Among the 13 insertion-deletion polymorphisms was a 2-bp deletion in the coding region of MGST1 in DNA from one of the volunteers, which resulted in a frame-shift mutation. Since the gene product encoded by this mutant allele would lack the C-terminal half including the MAPEG (membrane-associated proteins in eicosanoid and glutathione metabolism) domain, MGST1 activity is likely to be reduced in the carrier's cells. The SNP map presented here adds to the archive of tools for studying complex genetic diseases, population migration patterns, and a variety of pharmacogenetic possibilities.

3' Untranslated Regions↗
PubMed2002

C-reactive protein levels are influenced by common IL-1 gene variations.

Elevated markers of systemic inflammation are associated with the development of acute coronary syndromes, but there is no current explanation for increased inflammation in overtly healthy individuals. The influence of genetic control of the inflammatory response on the observed variability is unknown. We studied the frequency of four polymorphisms in interleukin (IL) 1 genes, known to modulate inflammation, in 454 individuals undergoing coronary angiography and analysed their influence on plasma C-reactive protein (CRP) and fibrinogen levels. Females and smokers had higher levels of CRP than males (Pi = 0.001) and non-smokers (Pi = 0.001). Patients with genotype 2.2 for the IL-1B(+3954) polymorphism had twice the median CRP levels of patients who were genotype 1.1 (4.33 vs 2.01 mg/l; P = 0.001). Patients with genotype 1.2 or 2.2 at the IL-1A(+4845) polymorphism also had higher median CRP (2.92 vs 2.05 mg/l, Pi = 0.023). In multivariate analyses, CRP levels remained significantly associated with IL-1 polymorphisms after adjustment for smoking, gender and age. Fibrinogen levels had similar associations with the IL-1 genotypes. These data indicate that IL-1 gene polymorphisms known to affect the inflammatory response are highly related to plasma levels of CRP and fibrinogen in patients referred for coronary angiography.

Adult↗
PubMed1999

Distribution and structural variation of arabinoxylans in common wheat mill streams.

In 19 wheat-milling fractions total pentosan content, calculated as 0.88 x (% L-arabinose + % D-xylose), varied between 1.44 and 30.66% on dry matter (dm). It increased with ash content once the latter exceeded 0.6% (dm basis). Water-extractable arabinoxylans were recovered by saturating water extracts to 65% ethanol. Their contents in the milling fractions varied between 0.35 and 1.38%, and above 0.6% ash content also increased with this parameter. Their L-arabinose-to-D-xylose ratios ranged between 0.65 and 0.39, with the lowest values found for the fractions with highest ash content, indicating that the ash-rich tissues contain more arabinoxylans that are less branched. (1)H NMR spectroscopy revealed that the decrease in L-arabinose-to-D-xylose ratio was accompanied by an increase in unsubstituted xylose residues and a decrease in disubstituted xylose residues, while the contents of monosubstituted xyloses were virtually constant.

Industry↗
PubMed2001

Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation.

OBJECTIVE: To investigate the association between the Trp64Arg beta3-adrenergic receptor (ADRB3) mutation and obesity-related phenotypes in a Mediterranean Spanish population considering the effect of other genetic and environmental factors. DESIGN AND SUBJECT: Cross-sectional study in 1063 (476 men and 587 women) randomly selected from this population (aged: 18-68 years). MEASUREMENTS: Anthropometric (weight, height and waist-to-hip ratio), blood pressure, biochemical (lipids, fasting glucose, and uric acid), life-style variables, and the Trp64Arg, HindIII-Lipoprotein lipase (LPL) and apolipoprotein E polymorphism. RESULTS: Frequency of the Arg64 allele was low (0.051; 95% CI: 0.042-0.060). We found gender-specific associations between the Trp64Arg mutation and obesity related phenotypes. In men, carriers of the Arg64 variant had higher body mass index (BMI) (27.63 +/- 3.81 vs. 26.34 +/- 3.57 kg m-2, P=0.049) and total cholesterol (5.85 +/- 1.45 vs. 5.28 +/- 1.06 mmol L-1; P=0.011) compared with wild-type individuals. Logistic regression analysis, revealed that the risk of overweight was two times higher in male carriers of the Arg64 allele. In women, the Arg64 variant was only associated with higher fasting glucose (P=0.031). These genotype effects persisted after adjustment for age, genetic and life-style variables. For the LPL polymorphism, the H-/H- genotype was associated with lower BMI and with lower risk of overweight (OR: 0.49; 95% CI: 0.30-0.81) in both men and women. However, after adjustment for covariates, these associations only remained statistically significant (P < 0.02) in women. Moreover, in women, a statistically significant interaction (P=0.026) between the LPL and the ADRB3 gene loci in determining BMI was found. Thus, the Arg64 allele was associated with a higher BMI only in H+/H+ women. CONCLUSIONS: The Trp64Arg mutation was associated with BMI and lipids in men. In women, an additional gene-gene interaction with the LPL-HindIII polymorphism may explain the results.

Adolescent↗
PubMed2006

A comprehensive analysis of common copy-number variations in the human genome.

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.

Chromosome Mapping↗
PubMed2006

Variations in management of common inpatient pediatric illnesses: hospitalists and community pediatricians.

OBJECTIVE: The goal was to test the hypothesis that pediatric hospitalists use evidence-based therapies and tests more consistently in the care of inpatients and use therapies and tests of unproven benefit less often, compared with community pediatricians. METHODS: A national survey was administered to hospitalists and a random sample of community pediatricians. Hospitalists and community pediatricians reported their frequency of use of diagnostic tests and therapies, on 5-point Likert scales (ranging from never to almost always), for common inpatient pediatric illnesses. Responses were compared in univariate and multivariable logistic regression analyses controlling for gender, race, years out of residency, days spent attending per year, hospital practice type, and completion of fellowship/postgraduate training. RESULTS: Two hundred thirteen pediatric hospitalists and 352 community pediatricians responded. In multivariable regression analyses, hospitalists were significantly more likely to report often or almost always using the following evidence-based therapies for asthma: albuterol and ipratropium in the first 24 hours of hospitalization. After the first urinary tract infection, hospitalists were more likely to report obtaining the recommended renal ultrasound and voiding cystourethrogram. Hospitalists were significantly more likely than community pediatricians to report rarely or never using the following therapies of unproven benefit: levalbuterol, inhaled steroid therapy, and oral steroid therapy for bronchiolitis; stool culture and rotavirus testing for gastroenteritis; and ipratropium after 24 hours of hospitalization for asthma. CONCLUSION: Overall, in comparison with community pediatricians, hospitalists reported greater adherence to evidence-based therapies and tests in the care of hospitalized patients and less use of therapies and tests of unproven benefit.

Administration, Inhalation↗
PubMed2006

TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease.

Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, although the genotype at four functional PON1 polymorphisms is not. To address this inconsistency, we investigated the role of all common PON1 genetic variability, as measured by tagging single-nucleotide polymorphisms (tagSNPs), in predicting PON1 activity for phenylacetate hydrolysis, LDL susceptibility to oxidation ex vivo, plasma homocysteine (Hcy) levels, and carotid artery disease (CAAD) status. The biological goal was to establish whether additional common genetic variation beyond consideration of the four known functional SNPs improves prediction of these phenotypes. PON2 and PON3 tagSNPs were secondarily evaluated. Expanded analysis of an additional 26 tagSNPs found evidence of previously undescribed common PON1 polymorphisms that affect PON1 activity independently of the four known functional SNPs. PON1 activity was not significantly correlated with LDL oxidative susceptibility, but genotypes at the PON1(-108) promoter polymorphism and several other PON1 SNPs were. Neither PON1 activity nor PON1 genotype was significantly correlated with plasma Hcy levels. This study revealed previously undetected common functional PON1 polymorphisms that explain 4% of PON1 activity and a high rate of recombination in PON1, but the sum of the common PON1 locus variation does not explain the relationship between PON1 activity and CAAD.

Adult↗
PubMed2004

Two-stage normalization using background intensities in cDNA microarray data.

BACKGROUND: In the microarray experiment, many undesirable systematic variations are commonly observed. Normalization is the process of removing such variation that affects the measured gene expression levels. Normalization plays an important role in the earlier stage of microarray data analysis. The subsequent analysis results are highly dependent on normalization. One major source of variation is the background intensities. Recently, some methods have been employed for correcting the background intensities. However, all these methods focus on defining signal intensities appropriately from foreground and background intensities in the image analysis. Although a number of normalization methods have been proposed, no systematic methods have been proposed using the background intensities in the normalization process. RESULTS: In this paper, we propose a two-stage method adjusting for the effect of background intensities in the normalization process. The first stage fits a regression model to adjust for the effect of background intensities and the second stage applies the usual normalization method such as a nonlinear LOWESS method to the background-adjusted intensities. In order to carry out the two-stage normalization method, we consider nine different background measures and investigate their performances in normalization. The performance of two-stage normalization is compared to those of global median normalization as well as intensity dependent nonlinear LOWESS normalization. We use the variability among the replicated slides to compare performance of normalization methods. CONCLUSIONS: For the selected background measures, the proposed two-stage normalization method performs better than global or intensity dependent nonlinear LOWESS normalization method. Especially, when there is a strong relationship between the background intensity and the signal intensity, the proposed method performs much better. Regardless of background correction methods used in the image analysis, the proposed two-stage normalization method can be applicable as long as both signal intensity and background intensity are available.

Cell Line, Tumor↗
PubMed2002

SNP alleles in human disease and evolution.

In two randomly selected human genomes, 99.9% of the DNA sequence is identical. The remaining 0.1% of DNA contains sequence variations. The most common type of such variation is called a single-nucleotide polymorphism, or SNP. SNPs are highly abundant, stable, and distributed throughout the genome. These variations are associated with diversity in the population, individuality, susceptibility to diseases, and individual response to medicine. Recently, it has been suggested that SNPs can be used for homogeneity testing and pharmacogenetic studies and to identify and map complex, common diseases such as high blood pressure, diabetes, and heart disease. Consistent with this proposal is the identification of the patterns of SNPs in conditions such as diabetes, schizophrenia, and blood-pressure homeostasis. Although these studies have provided insight into the nature of human sequence variation, it is not known at present whether these variations are truly significant toxicologically and pharmacologically. Moreover, it is possible that most complex, common disorders are caused by the combined effects of multigenes and nongenetic environmental factors (multifactorial). Therefore, it is likely that sequence variation alone is not sufficient to predict the risk of disease susceptibility, particularly in homeostatic organisms like humans. Nevertheless, these variants may provide a starting point for further inquiry.

Chromosome Mapping↗
PubMed1992

The contralateral variation of peak systolic velocity in common carotid arteries.

In order to evaluate the contralateral variation of the peak systolic velocity (Vmax) in common carotid arteries (CCAs), 9 clinically healthy persons (Group A), 11 patients with simple goiter (Group B) and 16 patients with diffuse toxic goiter (Graves' disease, Group C) were referred for radionuclide scanning, duplex Doppler ultrasonography (duplex US) and determination of serum level of the thyroid hormones (T3, T4, T3U) by radioimmunoassay. In Group A, Vmax of right CCA was 98.8 +/- 34.5 cm/sec and that of left CCA was 113.4 +/- 28.9 cm/sec; the left CCA had a higher blood flow velocity than the right one in normal subjects (p less than 0.01). However, the left and right CCA Vmaxes did not significantly differ to each other in Group B (93.5 +/- 21.4 cm/sec vs 98.6 +/- 21.4 cm/sec, p greater than 0.05) and Group C (146.9 +/- 29.3 cm/sec vs 149.9 +/- 28.9 cm/sec, p greater than 0.05). We conclude that there is a contralateral difference of blood flow velocity of common carotid arteries with the left value higher than the right one in healthy persons and this should be kept in mind in evaluation of thyroid functional and carotid arterial diseases.

Adult↗
PubMed2005

[Anatomic variations of the paranasal sinuses detected by computed tomography and the relationship between variations and sex].

OBJECTIVES: In this study, we evaluated anatomic variations detected by computed tomography (CT) of the paranasal sinuses and their relationship with sex. PATIENTS AND METHODS: Computed tomography scans of the paranasal sinuses of 464 patients (206 males, 258 females; mean age 37.5 years; range 4-87 years) were retrospectively analyzed. In cases requiring further investigation, axial and sagittal views were obtained using multiplanar reformatted images. Bone window images were also obtained particularly to evaluate dehiscence variations. Paranasal sinus variations were classified into eight subgroups according to their origins (nasal septum, ethmoid cells, maxillary sinus, uncinate process, frontal and sphenoid sinuses, orbit, and nasal concha). The frequency of variations was compared between male and females. RESULTS: The most common anatomic variation was agger nasi cells (80.4%) followed by pneumatization of the middle concha (37%). The least encountered variations were pneumatization of the inferior turbinate, bony dehiscence of the ethmoidal roof, and duplication of the middle and superior turbinates. The frequency of variations did not differ significantly with respect to gender (p>0.05) except for frontal hypoplasia, which was more often in females (p<0.05). CONCLUSION: Axial and sagittal views using multiplanar reformatted images can be helpful in eliminating artefacts and in identifying variations of the paranasal sinuses. Utilization of soft tissue and bone windows, when necessary, may facilitate evaluation of dehiscence abnormalities.

Adolescent↗
PubMed2002

Anatomic variations of the paranasal sinus area in pediatric patients with chronic sinusitis.

Endoscopic endonasal surgery has been performed in children. Therefore, we need to know the precise anatomy and anatomic variations of the lateral nasal wall. This is important in order to achieve better surgical results and avoid complications. We also need to know the relationship between the anatomic variations and sinonasal disease. For the purpose of this study we assessed the anatomic variations of the lateral nasal wall and the association of these variations with chronic sinusitis in children. Forty-seven children with chronic sinus disease were included in the study. There were 25 female and 22 male patients with ages ranging from 2 to 16 years (mean 10.5+/-3.8 years). On coronal and axial computed tomographic (CT) scans, the anatomic variations of the lateral nasal wall and sinusitis were assessed. A pneumatized middle concha (MC) was the most common anatomic variation, followed by pneumatization of the superior concha (SC), Haller cell and agger nasi cell. Secondary MC, large ethmoidal bulla, maxillary sinus hypoplasia, Onodi cell, and uncinate process pneumatization were relatively rare. Maxillary sinusitis was the most common sinus infection, followed by ethmoidal, sphenoidal and frontal sinusitis in that order. There was no significant relationship between the sinusitis and anatomic variations except for some minor associations. In conclusion, anatomic variations in the lateral nasal wall are common in children. Local, systemic or environmental factors appear to be more important in pediatric sinusitis than the anatomic variations. Due to the absence of a definitive relationship between the anatomic variations and sinus disease, aggressive surgical interventions should be avoided while performing endonasal endoscopic surgery in the children.

Adolescent↗
PubMed2005

Variability in intravenous medication practices: implications for medication safety.

BACKGROUND: Infusion devices can be programmed with individual hospitals' "best practice" rules for intravenous (i.v.) drug administration, and alerts can be provided if dosages fall outside pre-established limits. High variation levelsare common in medical care but can increase safety risk if the variation is unnecessary. METHODS: The i.v. best practice data sets of drugs from 100 hospitals using one manufacturer's infusion devices were compared to assess the number of drug names used and thevariation in concentrations, dose units, dose limits, and administration practices. RESULTS: The 100 hospitals showed an average of 64 drugs per data set and an average of 113 different drug/concentration 4 combinations. On average, each hospital had designated 6 profiles or unique patient care areas; there were 4 different names per drug across the hospitals (for example, amiodarone had 45 different names). High levels of variation in concentrations were ubiquitous. Overall, 60% of medications had more than one continuous dosage unit (range, 1-9). Variation was also noted in bolus dosing; 59 (50%) of 119 drugs had more than one unit (range, 1-4). Dose limits also varied substantially but were difficult to assess since the limits typically varied withthe indication. CONCLUSIONS: Substantial unnecessary variation in i.v. medication practicesis likely associated with increased risk of harm. Standardization has the potential to substantially improve i.v. medication safety.

Humans↗
PubMed2003

Evaluation of normalization methods for microarray data.

BACKGROUND: Microarray technology allows the monitoring of expression levels for thousands of genes simultaneously. This novel technique helps us to understand gene regulation as well as gene by gene interactions more systematically. In the microarray experiment, however, many undesirable systematic variations are observed. Even in replicated experiment, some variations are commonly observed. Normalization is the process of removing some sources of variation which affect the measured gene expression levels. Although a number of normalization methods have been proposed, it has been difficult to decide which methods perform best. Normalization plays an important role in the earlier stage of microarray data analysis. The subsequent analysis results are highly dependent on normalization. RESULTS: In this paper, we use the variability among the replicated slides to compare performance of normalization methods. We also compare normalization methods with regard to bias and mean square error using simulated data. CONCLUSIONS: Our results show that intensity-dependent normalization often performs better than global normalization methods, and that linear and nonlinear normalization methods perform similarly. These conclusions are based on analysis of 36 cDNA microarrays of 3,840 genes obtained in an experiment to search for changes in gene expression profiles during neuronal differentiation of cortical stem cells. Simulation studies confirm our findings.

Analysis of Variance↗
PubMed2004

Genomic approaches to identifying breast cancer susceptibility factors.

The majority of the genetic variants underlying susceptibility to breast cancer are yet to be discovered. Genome-wide linkage analyses, utilizing anonymous genetic markers, have been successful at identifying two genes, BRCA1 and BRCA2, which account for a sizeable fraction of the clearly inherited forms of breast cancer occurring in autosomal dominant Mendellian patterns. Mutations in these genes, however, account for less than (1/4) of the total genetic component of breast cancer susceptibility and the remaining component is likely to be polygenic in nature - the interaction of mutations in multiple genes, each with a weak effect, in combination with environmental influences. The identification of these polygenes will likely require the study of large numbers of unrelated subjects with and without breast cancer in case-control association studies. Until the time when complete genome sequence information is feasible for all study subjects, interim strategies involving a subset of all common genetic variation (primarily single nucleotide polymorphisms, SNPs) are being planned. Assuming the common disease-common variant theory of complex disease susceptibility, studying a very dense set of genetic markers is likely to identify breast cancer susceptibility genes by virtue of including either the biologically relevant variant, or one closely correlated with it due to linkage disequilibrium.

Journal Article↗