Search

Background The MRP 1 gene encodes the 190 kDa multidrug resistance-associated protein 1 (MRP1/ABCC1) and effluxes diverse drugs and xenobiotics. Sequence variations within this gene might account for differences in drug response in different individuals. To facilitate association studies of this gene with diseases and/or drug response, exons and flanking introns of MRP 1 were screened for polymorphisms in 142 DNA samples from four different populations. Results Seventy-one polymorphisms, including 60 biallelic single nucleotide polymorphisms (SNPs), ten insertions/deletions (indel) and one short tandem repeat (STR) were identified. Thirty-four of these polymorphisms have not been previously reported. Interestingly, the STR polymorphism at the 5' untranslated region (5'UTR) occurs at high but different frequencies in the different populations. Frequencies of common polymorphisms in our populations were comparable to those of similar populations in HAPMAP or Perlegen. Nucleotide diversity indices indicated that the coding region of MRP 1 may have undergone negative selection or recent population expansion. SNPs E10/1299 G>T (R433S) and E16/2012 G>T (G671V) which occur at low frequency in only one or two of four populations examined were predicted to be functionally deleterious and hence are likely to be under negative selection. Conclusion Through in silico approaches, we identified two rare SNPs that are potentially negatively selected. These SNPs may be useful for studies associating this gene with rare events including adverse drug reactions.

Background Systemic exposure to rosuvastatin had been observed to be approximately 2-fold higher in Japanese subjects living in Japan compared with white subjects in Western Europe or the United States. The organic anion transporting polypeptide 1B1 contributes to the hepatic uptake of rosuvastatin. Polymorphisms in the SLCO1B1 gene can lead to reduced transport function in vitro (T521>C). This study was conducted to determine whether the pharmacokinetic differences between Japanese and white subjects extended to other Asian ethnic groups and to determine whether polymorphisms in the SLCO1B1 gene contribute to any pharmacokinetic differences observed. Methods Rosuvastatin pharmacokinetics was studied in an open-label, parallel-group, single–oral dose (40 mg) study in 36 white, 36 Chinese, 35 Malay, and 35 Asian-Indian subjects living in Singapore, Singapore. Plasma concentrations of rosuvastatin and metabolites were determined by HPLC–mass spectrophotometry. Two SLCO1B1 polymorphisms (A388>G and T521>C) were genotyped. Results Ratios for rosuvastatin area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration were 2.31, 1.91, and 1.63 and ratios for maximum plasma concentration were 2.36, 2.00, and 1.68 in Chinese, Malay, and Asian-Indian subjects, respectively, compared with white subjects. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin-lactone were observed. SLCO1B1 genotypes did not account for the observed pharmacokinetic differences between Asians and white subjects. Conclusions Plasma exposure to rosuvastatin and its metabolites was significantly higher in Chinese, Malay, and Asian-Indian subjects compared with white subjects living in the same environment. Clinical Pharmacology & Therapeutics (2005) 78, 330–341; doi: 10.1016/j.clpt.2005.06.013

We investigate whether the market prices the change in net trading assets as an operating or non-operating activity or some mixture of the two, and whether this market pricing is consistent with the (fundamental) association of the change in net trading assets with future cash flows from operations (CFO). Our investigation is motivated by the observation that - despite the classification of the cash flows on trading positions as operating under FAS 102 - trading is economically a hybrid operating/non-operating activity. Reflecting this hybrid nature, we hypothesize and find that the change in net trading assets has a less positive association with returns and future CFO than do the pure operating components of cash flows and accruals, and that it has a more positive association with returns and future CFO than do the pure non-operating components of cash flows. To the best of our knowledge, our paper is the first to propose and test hypotheses about the valuation implications of such hybrid cash flows and accruals.

Miller, A.D., Waggy, G., Ryan, S.G., and Austin, C.M. 2004. Mitochondrial 12S rRNA sequences support the existence of a third species of freshwater blackfish (Percicthyidae: Gadopsis) from south-eastern Australia. Memoirs of Museum Victoria 61(2): 121‐127. Fish of the genus Gadopsis are a distinctive component of the freshwater fish fauna of south-eastern Australia. Gadopsis marmoratus and G. bispinosus are the only two species recognised within the genus, with the former of uncertain taxonomic status, as it is thought to be composed of at least two distinct geographical forms based on morphological and allozyme data. The objective of this study was to investigate DNA sequence divergence in Gadopsis, especially in the western portion of its distribution, using an approximately 400 base pair fragment of the mitochondrial small subunit 12S rRNA gene region in order to reassess the taxonomy of the genus. Individuals from 11 locations were sequenced and confirm that G. marmoratus and G. bispinosus are genetically distinct, and further that the G. marmoratus complex consists of two divergent clades representing the previously identified northern and southern forms. The degree of divergence between the three Gadopsis clades was similar (5‐6% nucleotide substitutions), suggesting that they diverged from a common ancestor at approximately the same period in geological time. These results are consistent with previous allozyme studies and highlight the usefulness of mitochondrial DNA data coupled with allozyme information for clarifying taxonomic boundaries in morphologically conservative aquatic organisms.

Purpose : Our research program uses genetic linkage and association analysis to identify human seizure sensitivity and resistance alleles. Quantitative trait loci mapping in mice led to identification of genetic variation in the potassium ion channel gene Kcnj10 , implicating it as a putative seizure susceptibility gene. The purpose of this work was to translate these animal model data to a human genetic association study. Methods : We used single stranded conformation polymorphism (SSCP) electrophoresis, DNA sequencing and database searching (NCBI) to identify variation in the human KCNJ10 gene. Restriction fragment length polymorphism (RFLP) analysis, SSCP and Pyrosequencing™ were used to genotype a single nucleotide polymorphism (SNP, dbSNP rs#1130183) in KCNJ10 in epilepsy patients ( n =407) and unrelated controls ( n =284). The epilepsy group was comprised of patients with refractory mesial temporal lobe epilepsy ( n =153), childhood absence ( n =84), juvenile myoclonic ( n =111) and idiopathic generalized epilepsy not otherwise specified (IGE-NOS, n =59) and all were of European ancestry. Results : SNP rs#1130183 (C>T) alters amino acid 271 (of 379) from an arginine to a cysteine (R271C). The C allele (Arg) is common with conversion to the T allele (Cys) occurring twice as often in controls compared to epilepsy patients. Contingency analysis documented a statistically significant association between seizure resistance and allele frequency, Mantel–Haenszel chi square=5.65, d.f.=1, P =0.017, odds ratio 0.52, 95% CI 0.33–0.82. Conclusion : The T allele of SNP rs#1130183 is associated with seizure resistance when common forms of focal and generalized epilepsy are analyzed as a group. These data suggest that this missense variation in KCNJ10 (or a nearby variation) is related to general seizure susceptibility in humans.

The use of pharmacogenetics and pharmacogenomics in the drug development process, and in the assessment of such data submitted to regulatory agencies by industry, has generated significant enthusiasm as well as important reservations within the scientific and medical communities. This situation has arisen because of the increasing number of exploratory and confirmatory investigations into variations in RNA expression patterns and DNA sequences being conducted in the preclinical and clinical phases of drug development, and the uncertainty surrounding the acceptance of these data by regulatory agencies. This report summarizes the outcome of a workshop cosponsored by the Food and Drug Administration (FDA), the Pharmacogenetics Working Group (PWG), the Pharmaceutical Research and Manufacturers of America (PhRMA), and the PhRMA Preclinical Safety Committee (DruSafe). The specific aim of the workshop was to identify key issues associated with the application of pharmacogenetics and pharmacogenomics, including the feasibility of a regulatory "safe harbor" for exploratory genome-based data, and to provide a forum for industry-regulatory agency dialogue on these important issues.

Large, prospective trials demonstrating the value of genotyping in patient management will be required to support the introduction of pharmacogenetics into routine medical practice. However, such studies will be costly and can be justified only if there is a reproducible association between genotype and a clinically relevant phenotype. Unfortunately, non-replication is prevalent among genetic association studies. In some cases non-replication may reflect real population differences but multiple comparisons, biases and other design limitations suggest that many initial positive associations represent Type I errors. Successful detection of a true genetic effect requires not only an informed and careful selection of candidate genes but also the assiduous application of sound principles of study design. Most important, independent and, ideally, prospective confirmation of the hypothesized genetic effect in a population similar to the one originally studied is required. In selected situations, pharmacogenetic studies in healthy volunteers may support a decision to perform such prospective association studies. When the potential health or economic consequences of therapy are significant and the results of pharmacogenetic association studies are convincing, it is reasonable to consider a major clinical trials program to assess the usefulness of genetically targeted therapy.

We report medullary injury during adenoidectomy in two children who received injections of local anesthetic agents into the operative bed. Initial manifestations included hemiparesis, nystagmus, and ataxia. Magnetic resonance imaging showed hemorrhagic, paramedian medullary lesions in both patients. The mechanism of injury is likely to be injection of fluid into the medulla.

Following an uneventful gestation, a newborn girl presented with hypertonia, hyperreflexia, tremor, and excessive startle response. Nose tap elicited a dramatic head recoil. Her mother had similar symptoms beginning as a child that improved but persisted into adulthood. In addition, several members of mother's family died unexpectedly in infancy. Hypertonia in the newborn period indicates central nervous system dysfunction of several possible causes, most of which are associated with severe cognitive deficits and limited neurological development.

A large body of evidence suggests that genetic factors influence liability to many common neurodevelopmental disorders. Examples include Tourette syndrome, attention-deficit hyperactivity disorder, autism, and dyslexia. Characterization of the genetic component of susceptibility to these conditions at a molecular level should improve classification, elucidate fundamental neurobiologic mechanisms of disease, and suggest novel approaches to treatment. Susceptibility loci for complex traits could be identified by detecting linkage to a well-mapped genetic marker or by detecting association with a putative high-risk allele at a candidate locus. This article reviews the principles underlying these complementary approaches, and notes recent progress in specific conditions. As the molecular epidemiology of susceptibility to common neurodevelopmental disorders emerges, it might be increasingly possible to identify "high-risk" and "low-risk" genotypes. Clinicians should understand the nature of this kind of information in order to appreciate its power as well as its limitations. (J Child Neurol 1999; 14:187-195).

Recent application of genetic analysis to rare, hereditary epilepsies has resulted in the identification of mutations in genes encoding ion channels or functionally related proteins in several human and animal syndromes. Reviewed here are selected human and murine epilepsies that result from ion channel mutations. In humans, three autosomal-dominant disorders— benign familial neonatal convulsions, nocturnal frontal lobe epilepsy, and "generalized epilepsy with febrile seizures plus"—result from mutations affecting voltage-sensitive potassium channels, a central nicotinic acetylcholine receptor, and a voltage-sensitive sodium channel, respectively. In mice, four genetically distinct, autosomal-recessive models of absence epilepsy are caused by mutations in genes encoding three types of calcium channel subunits and a sodium-hydrogen ion exchanger. These findings suggest that variation in genes encoding ion channels could determine susceptibility to common human epilepsies. ( J Child Neurol 1999;14:58-66).

Summary We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease. The disorder is characterized by slow progression, distal limb amyotrophy, and pyramidal tract signs associated with severe loss of motor neurons in the brain stem and spinal cord. The gene for this disorder, classified as a form of juvenile amyotrophic lateral sclerosis (ALS), is designated "ALS4." We performed a genomewide search and detected strong evidence for linkage of the ALS4 locus to markers from chromosome 9q34. The highest LOD score ( Z ) was obtained with D9S1847 ( Z =18.8, recombination fraction of .00). An analysis of recombinant events identified D9S1831 and D9S164 as flanking markers, on chromosome 9q34, that define an ∼5-cM interval that harbors the ALS4 gene. These results extend the degree of heterogeneity within familial ALS syndromes, and they implicate a gene on chromosome 9q34 as critical for motor-neuron function.

Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg271 by a glutamine (R271Q) in one case and a leucine (R271L) in the other. Here, 5 additional hyperekplexia families are shown to have the most common G-to-A transition mutation at nucleotide 1192. Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times). In 2 additional families, a third mutation is also presented that changes a tyrosine at amino acid 279 to a cysteine (Y279C). Five patients with atypical clinical features and equivocal or absent family history of hyperekplexia and 1 patient with a classical presentation but not family history are presented in whom a mutation in the GLRA1 gene was not detected. Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.

We report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bell-shaped chest, diastasis recti, short fingers, and mild developmental delay.

We report a patient who developed paroxysmal kinesigenic dystonia shortly after initiation of therapy with methylphenidate for presumed attention deficit-hyperactivity disorder. Attacks persisted long after methylphenidate was discontinued and responded completely to treatment with carbamazepine. Though it is possible that methylphenidate caused this syndrome in our patient, it is more likely that the stimulant triggered the onset of a genetically determined disorder. (J Child Neurol 1994;9:45-46).

Hereditary hyperekplexia, or familial startle disease (STHE), is an autosomal dominant neurologic disorder characterized by marked muscle rigidity of central nervous system origin and an exaggerated startle response to unexpected acoustic or tactile stimuli. Linkage analyses in several large families provided evidence for locus homogeneity and showed the disease gene was linked to DNA markers on the long arm of chromosome 5. Here we describe the identification of point mutations in the gene encoding the alpha 1 subunit of the glycine receptor (GLRA1) in STHE patients from four different families. All mutations occur in the same base pair of exon 6 and result in the substitution of an uncharged amino acid (leucine or glutamine) for Arg271 in the mature protein.

Familial startle disease (also known as hyperekplexia and congenital "stiff-man" syndrome) is an autosomal dominant disorder characterized by an exaggerated startle reaction of sudden, unexpected auditory or tactile stimuli; affected neonates also have severe and occasionally fatal hypertonia. We recently encountered a large, five-generation family with startle disease, and treated 16 patients (including 1 neonate) with clonazepam; all experienced dramatic and sustained improvement. We performed systematic linkage analysis in this family, and found tight linkage between the disease locus and a polymorphic genetic marker locus (colony-stimulating factor receptor, or CSF1R) that has been physically mapped to chromosome 5q33-q35. The maximum odds ratio favoring linkage over nonlinkage is greater than 10,000,000:1 (lod score, 7.10) at 3% recombination. Several genes encoding neurotransmitter receptor components have been physically mapped to the subtelomeric region of chromosome 5q, and are thus candidates for the startle disease gene. The availability of additional large pedigrees with startle disease should facilitate identification and characterization of the gene for this disorder.

We present a consanguineous sibship with benign familial neonatal seizures. The mode of transmission of the disorder in this family seems to be autosomal recessive, which is contrary to the usual autosomal dominant type. Linkage analysis failed to show tight linkage between the disease locus and the autosomal dominant locus assigned to chromosome 20q. We thus conclude that benign familial neonatal seizures is a genetically heterogeneous type of epilepsy.

Rotordynamical equations that account for disk flexibility are developed. These equations employ free – free rotor modes to model the rotor system. Only transverse vibrations of the disks are considered, with the shaft/disk system considered to be torsionally rigid. Second order elastic foreshortening effects that couple with the rotor speed to produce first order terms in the equations of motion are included. The approach developed in this study is readily adaptable for usage in many of the codes that are current used in rotordynamical simulations. The equations are similar to those used in standard rigid disk analyses but with additional terms that include the effects of disk flexibility. An example case is presented to demonstrate the use of the equations and to show the influence of disk flexibility on the rotordynamical behavior of a sample system.

The gene for autosomal dominant "benign" familial neonatal convulsions, a transient, primary epilepsy of infancy, has recently been assigned to chromosome 20q. To determine whether this disorder is genetically heterogeneous, we performed linkage analysis in two previously unreported pedigrees with benign familial neonatal convulsions in which clinical heterogeneity was evident. There were 14 affected persons in the first family, and none had seizures (febrile or afebrile) after the age of 2 months. The second family had 13 affected individuals and 2 obligate carriers; seizures frequently did not remit until 6 to 24 months, febrile convulsions occurred in at least 2 patients, apparent audiogenic seizures occurred in 4 patients, and 1 individual had refractory epilepsy until late adolescence. Linkage studies with the chromosome 20 markers D20S19 and D20S20 were performed in both families. The resulting data favored linkage of the disease and marker loci in Family 2 by a maximum odds ratio of 45:1 at 6% recombination. In Family 1, however, the odds were greater than 20,000:1 against linkage at 10% recombination or less. We conclude that the syndrome of benign familial neonatal convulsions is clinically and genetically heterogeneous. Further study will be necessary to clarify the relationship between phenotype and genotype in this disorder.

We investigate how banks' loan portfolio composition affects the timeliness of loan loss provisions and, thus, the relation between security returns and such provisions. We maintain that the timeliness of loss provisions relative to other information about loan default decreases as discretion over such provisions increases, and that discretion over loss provisions varies by loan type. Bank managers have more discretion over loss provisions for large and frequently renegotiated loans, e.g., foreign and commercial loans, than for small or infrequently renegotiated loans, e.g., consumer loans. Large size and the possibility of renegotiation provide rationales for banks to provide for losses on a loan-by-loan basis rather than by statistical analysis of historical data. Using the proportion of small or infrequently renegotiated loans as a measure of the timeliness of loan loss provisions, we hypothesize and find that both the sign of the market reaction to and the strength of the market anticipation of loan loss provisions differs by this timeliness measure.'

This paper constructs a model of accrual measurement and tests its implications for the evolution of the book-to-market ratio. The model captures the intuition that book value is untimely or smoothed relative to market value, so that movements in market value have relatively high variance and low predictability, compared with movements in book value. Empirical tests of the model use lagged market value changes to forecast the mean reversion of the book-to-market ratio. This paper complements recent research investigating the role of book-to-market ratios in security analysis. Accounting theorists (e.g., Edwards and Bell [1961] and Feltham and Ohlson [1995]) have long recognized the critical role of book-to-market ratios as predictors of abnormal earnings in earnings-based valuation models. Tests of such valuation models (e.g., Ou and Penman [1993]) confront the practical problem of determining the horizon beyond which abnormal earnings are expected to be zero. The model in this paper implies that this horizon is determined by the remaining useful life of assets, and that the expected path of abnormal earnings over this horizon reflects the pattern of expiration of the useful lives of assets in place.

Stiff-baby syndrome or hyperekplexia (also known as startle disease) is an unusual familial neurologic disorder that may be associated with fatal apnea or an apparent life-threatening event in infancy. While the neonatal clinical features of increased muscle tone, pathologic startle response, and occasional myoclonic jerks have been reported, 1 the association of hyperekplexia with apnea and feeding difficulties has not been emphasized in the pediatric literature. The purpose of this report is to document further the association of sudden infant death syndrome (SIDS) and recurrent apnea of infancy with hyperekplexia, to describe possible common pathogenic mechanisms, and to summarize the response to myorelaxing therapy. In addition, we provide further evidence for assignment of the hyperekplexia gene to chromosome 5q. Patient Report . A white male infant (propositus) was born after an uncomplicated pregnancy and weighed 2683 g at birth. His Apgar score was 7/9 at 1 and 5 minutes. At birth

We describe a young girl with neurofibromatosis and enlargement of the optic chiasm and intracranial left optic nerve. Serial MRIs over 32 months demonstrated spontaneous, marked reduction in the size of these lesions. Spontaneous regression must be considered in evaluating therapies for optic glioma.

The period of risk for recurrence of primitive neuroectodermal tumor/medulloblastoma (PNET/MB) is not clearly defined. With current treatment since more than 50% of children with PNET/MB can be expected to survive for at least 5 years after diagnosis, determining the evidence of "late" recurrence is of increasing concern. Collins has stated that patients with embryonal tumors who survive, disease free, for a period of time equal to the age at diagnosis plus 9 months can be declared cured. This, so-called Collins' law has been applied to patients with PNET/MB. To determine the incidence of "late" recurrence, factors which impact on recurrence and applicability of Collins' law, the authors studied all patients diagnosed with PNET/MB at the Children's Hospital of Philadelphia, Hospital of the University of Pennsylvania, Philadelphia, and Geisinger Medical Center, Danville, Pennsylvania, between 1970 and 1984. For the 44 patients in this study, the disease-free survival at 5, 10, and 12 years was 54%, 41% and 30%, respectively. For children surviving 5 years, the actuarial survival at 10 years was 75% and at 12 years, 51%. Age, sex, dose of radiotherapy, chemotherapy, or extent of surgery were not predictive of late relapse. Recurrence in three of seven patients (43%) occurred outside the "period of risk" as predicted by Collins. It appears that the "period of risk" for recurrent central nervous system tumors after PNET/MB is as yet undefined and probably indefinite.

The study derives a relationship between prices changes and earnings changes by expanding the information upon which earnings expectations are conditioned to include data other than prior earnings history. In particular, price is used as a surrogate for additional information available to market participants. This relationship provides an interpretation of the contemporaneous association between price changes and earnings changes previously observed by Ball and Brown (1968) and Beaver, Clarke and Wright (1979), among others. It also provides a basis for inferring from prices the earnings process and the expected future earnings as perceived by market participants. In doing so, it inverts the familiar price-earnings relationship and uses price as a predictor of earnings. The study differs from previous research which has examined the time series behavior of earnings based solely on previous earnings realizations. This approach can potentially lead to earnings forecasting models that are more accurate than the random walk with a drift that has been robust against challengers. In particular, the evidence indicates that security prices behave as if earnings are perceived to be dramatically different from a simple random walk process. Preliminary evidence also indicates that price-based forecasting models are more accurate than the random walk with a drift model.

A prominent feature of financial reporting regulation over the past 15 years has been the explosion in the volume of required financial disclosures. A plausible explanation for this development is the shift in regulatory emphasis from viewing the role of the primary financial statements as being to provide complete measures of net income and market value of common equity to viewing financial disclosures (both primary financial statements as well as supplemental disclosures) as providing a rich set