Showing papers by "Oregon Health & Science University published in 1999"

Intra-arterial Prourokinase for Acute Ischemic Stroke: The PROACT II Study: A Randomized Controlled Trial

Abstract: ContextIntravenous tissue-type plasminogen activator can be beneficial to some patients when given within 3 hours of stroke onset, but many patients present later after stroke onset and alternative treatments are needed.ObjectiveTo determine the clinical efficacy and safety of intra-arterial (IA) recombinant prourokinase (r-proUK) in patients with acute stroke of less than 6 hours' duration caused by middle cerebral artery (MCA) occlusion.DesignPROACT II (Prolyse in Acute Cerebral Thromboembolism II), a randomized, controlled, multicenter, open-label clinical trial with blinded follow-up conducted between February 1996 and August 1998.SettingFifty-four centers in the United States and Canada.PatientsA total of 180 patients with acute ischemic stroke of less than 6 hours' duration caused by angiographically proven occlusion of the MCA and without hemorrhage or major early infarction signs on computed tomographic scan.InterventionPatients were randomized to receive 9 mg of IA r-proUK plus heparin (n = 121) or heparin only (n = 59).Main Outcome MeasuresThe primary outcome, analyzed by intention-to-treat, was based on the proportion of patients with slight or no neurological disability at 90 days as defined by a modified Rankin score of 2 or less. Secondary outcomes included MCA recanalization, the frequency of intracranial hemorrhage with neurological deterioration, and mortality.ResultsFor the primary analysis, 40% of r-proUK patients and 25% of control patients had a modified Rankin score of 2 or less (P = .04). Mortality was 25% for the r-proUK group and 27% for the control group. The recanalization rate was 66% for the r-proUK group and 18% for the control group (P<.001). Intracranial hemorrhage with neurological deterioration within 24 hours occurred in 10% of r-proUK patients and 2% of control patients (P = .06).ConclusionDespite an increased frequency of early symptomatic intracranial hemorrhage, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days.

Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations.

Abstract: The cause of many autoimmune and inflammatory diseases is unresolved, although dysregulated production of tumor necrosis factor (TNF) family members appears to be important in many cases. BAFF, a new member of the TNF family, binds to B cells and costimulates their growth in vitro. Mice transgenic for BAFF have vastly increased numbers of mature B and effector T cells, and develop autoimmune-like manifestations such as the presence of high levels of rheumatoid factors, circulating immune complexes, anti–DNA autoantibodies, and immunoglobulin deposition in the kidneys. This phenotype is reminiscent of certain human autoimmune disorders and suggests that dysregulation of BAFF expression may be a critical element in the chain of events leading to autoimmunity.

The insulin-like growth factor-binding protein (IGFBP) superfamily.

Abstract: Over the last decade, the concept of an IGFBP family has been well accepted, based on structural similarities and on functional abilities to bind IGFs with high affinities. The existence of other potential IGFBPs was left open. The discovery of proteins with N-terminal domains bearing striking structural similarities to the N terminus of the IGFBPs, and with reduced, but demonstrable, affinity for IGFs, raised the question of whether these proteins were "new" IGFBPs (22, 23, 217). The N-terminal domain had been uniquely associated with the IGFBPs and has long been considered to be critical for IGF binding. No other function has been confirmed for this domain to date. Thus, the presence of this important IGFBP domain in the N terminus of other proteins must be considered significant. Although these other proteins appear capable of binding IGF, their relatively low affinity and the fact that their major biological actions are likely to not directly involve the IGF peptides suggest that they probably should not be classified within the IGFBP family as provisionally proposed (22, 23). The conservation of this single domain, so critical to high-affinity binding of IGF by the six IGFBPs, in all of the IGFBP-rPs, as well, speaks to its biological importance. Historically, and perhaps, functionally, this has led to the designation of an "IGFBP superfamily". The classification and nomenclature for the IGFBP superfamily, are, of course, arbitrary; what is ultimately relevant is the underlying biology, much of which still remains to be deciphered. The nomenclature for the IGFBP related proteins was derived from a consensus of researchers working in the IGFBP field (52). Obviously, a more general consensus on nomenclature, involving all groups working on each IGFBP-rP, has yet to be reached. Further understanding of the biological functions of each protein should help resolve the nomenclature dilemma. For the present, redesignating these proteins IGFBP-rPs simplifies the multiple names already associated with each IGFBP related protein, and reinforces the concept of a relationship with the IGFBPs. Beyond the N-terminal domain, there is a lack of structural similarity between the IGFBP-rPs and IGFBPs. The C-terminal domains do share similarities to other internal domains found in numerous other proteins. For example, the similarity of the IGFBP C terminus to the thyroglobulin type-I domain shows that the IGFBPs are also structurally related to numerous other proteins carrying the same domain (87). Interestingly, the functions of the different C-terminal domains in members of the IGFBP superfamily include interactions with the cell surface or ECM, suggesting that, even if they share little sequence similarities, the C-terminal domains may be functionally related. The evolutionary conservation of the N-terminal domain and functional studies support the notion that IGFBPs and IGFBP-rPs together form an IGFBP superfamily. A superfamily delineates between closely related (classified as a family) and distantly related proteins. The IGFBP superfamily is therefore composed of distantly related families. The modular nature of the constituents of the IGFBP superfamily, particularly their preservation of an highly conserved N-terminal domain, seems best explained by the process of exon shuffling of an ancestral gene encoding this domain. Over the course of evolution, some members evolved into high-affinity IGF binders and others into low-affinity IGF binders, thereby conferring on the IGFBP superfamily the ability to influence cell growth by both IGF-dependent and IGF-independent means (Fig. 10). A final word, from Stephen Jay Gould (218): "But classifications are not passive ordering devices in a world objectively divided into obvious categories. Taxonomies are human decisions imposed upon nature--theories about the causes of nature's order. The chronicle of historical changes in classification provides our finest insight into conceptual revolutions

Analysis of missed cases of abusive head trauma.

Abstract: ContextAbusive head trauma (AHT) is a dangerous form of child abuse that can be difficult to diagnose in young children.ObjectivesTo determine how frequently AHT was previously missed by physicians in a group of abused children with head injuries and to determine factors associated with the unrecognized diagnosis.DesignRetrospective chart review of cases of head trauma presenting between January 1, 1990, and December 31, 1995.SettingAcademic children's hospital.PatientsOne hundred seventy-three children younger than 3 years with head injuries caused by abuse.Main Outcome MeasuresCharacteristics of head-injured children in whom diagnosis of AHT was unrecognized and the consequences of the missed diagnoses.ResultsFifty-four (31.2%) of 173 abused children with head injuries had been seen by physicians after AHT and the diagnosis was not recognized. The mean time to correct diagnosis among these children was 7 days (range, 0-189 days). Abusive head trauma was more likely to be unrecognized in very young white children from intact families and in children without respiratory compromise or seizures. In 7 of the children with unrecognized AHT, misinterpretation of radiological studies contributed to the delay in diagnosis. Fifteen children (27.8%) were reinjured after the missed diagnosis. Twenty-two (40.7%) experienced medical complications related to the missed diagnosis. Four of 5 deaths in the group with unrecognized AHT might have been prevented by earlier recognition of abuse.ConclusionAlthough diagnosing head trauma can be difficult in the absence of a history, it is important to consider inflicted head trauma in infants and young children presenting with nonspecific clinical signs.

An evidence-based appraisal of reflux disease management — the Genval Workshop Report

Abstract: This report summarises conclusions from an evidence-based workshop which evaluated major clinical strategies for the management of the full spectrum of gastro-oesophageal reflux disease, with an emphasis on medical management. The disease was defined by the presence of oesophageal mucosal breaks or by the occurrence of reflux induced symptoms severe enough to impair quality of life. Endoscopy negative patients were recognised as the most common subgroup; most of these patients can be diagnosed by a well structured symptom analysis. There is a consistent hierarchy of effectiveness of available initial and long term therapies that applies for all patient subgroups. Lifestyle measures were judged to be of such low efficacy that they were rejected as a primary therapy for all patient subgroups. Proton pump inhibitor therapy was considered the initial medical treatment of choice because of its clearly superior efficacy which results in the most prompt achievement of desirable outcomes at the lowest overall medical cost. It was acknowledged that most of patients require long term management and that any maintenance therapy should be chosen by step down to the regimen that is still effective, but least costly. Endoscopic monitoring of routine long term therapy was considered inappropriate, on the basis that control of symptoms is an acceptably reliable indicator of healing in patients with oesophagitis. Laparoscopic antireflux surgery was recognised as a significant therapeutic advance, the results of which, however, depend substantially on the experience of the surgeon. There are currently no published direct comparisons of cost and efficacy outcomes of optimal medical and surgical therapies for reflux disease. To a significant degree, the choice between medical and surgical therapy should depend on informed patient preference. Substantial advances have occurred recently in the understanding and treatment of reflux disease. By contrast, there has been relatively little research into the best …

Ca2+/calmodulin-kinase II enhances channel conductance of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

Abstract: The ability of central glutamatergic synapses to change their strength in response to the intensity of synaptic input, which occurs, for example, in long-term potentiation (LTP), is thought to provide a cellular basis for memory formation and learning. LTP in the CA1 field of the hippocampus requires activation of Ca2+/calmodulin-kinase II (CaM-KII), which phosphorylates Ser-831 in the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate glutamate receptor (AMPA-R), and this activation/phosphorylation is thought to be a postsynaptic mechanism in LTP. In this study, we have identified a molecular mechanism by which CaM-KII potentiates AMPA-Rs. Coexpression in HEK-293 cells of activated CaM-KII with GluR1 did not affect the glutamate affinity of the receptor, the kinetics of desensitization and recovery, channel rectification, open probability, or gating. Single-channel recordings identified multiple conductance states for GluR1, and coexpression with CaM-KII or a mutation of Ser-831 to Asp increased the contribution of the higher conductance states. These results indicate that CaM-KII can mediate plasticity at glutamatergic synapses by increasing single-channel conductance of existing functional AMPA-Rs or by recruiting new high-conductance-state AMPA-Rs.

The Incorporation of NMDA Receptors with a Distinct Subunit Composition at Nascent Hippocampal Synapses In Vitro

Abstract: Activity-dependent synaptic rearrangements during CNS development require NMDA receptor activation. The control of NMDA receptor function by developmentally regulated subunit expression has been proposed as one mechanism for this receptor dependence. We examined the phenotype of synaptic and extrasynaptic NMDA receptors during the development of synaptic load using the NMDA receptor 2B (NR2B)-selective antagonist ifenprodil. In cultured rat hippocampal neurons when relatively few synapses had formed, the ifenprodil block of EPSCs was less than whole-cell currents, the latter of which included both synaptic and extrasynaptic receptors. At the same developmental stage, we found that extrasynaptic receptors outnumbered synaptic receptors by 3:1; thus whole-cell currents were dominated by the extrasynaptic population. We used the macroscopic kinetics of ifenprodil block to distinguish between the receptor populations. The ifenprodil kinetics of whole-cell currents from neurons before and during the development of synaptic load was comparable with that of whole-cell currents in HEK293 cells transfected with NR1 and NR2B cDNA, indicating that extrasynaptic receptors are largely NR1/NR2B heteromers. In contrast, synaptic receptors included both a highly ifenprodil-sensitive (NR1/NR2B) component as well as a second population with lower ifenprodil sensitivity; the reduced ifenprodil block of EPSCs was attributable to synaptic receptors with lower ifenprodil sensitivity rather than to the appearance of ifenprodil-insensitive (NR1/NR2A) receptors. Our data indicate that the synaptic NMDA receptor complement changes quickly after synapse formation. We suggest that synapses containing predominately NR1/NR2B heteromers represent "immature" sites, whereas mature sites express NMDA receptors with a distinct, presumably triheteromeric, subunit composition.

Ten myths of multimodal interaction

Abstract: Multimodal systems process combined natural input modes—such as speech, pen, touch, hand gestures, eye gaze, and head and body movements—in a coordinated manner with multimedia system output. These systems represent a new direction for computing that draws from novel input and output technologies currently becoming available. Since the appearance of Bolt's [1] \" Put That There \" demonstration system, which processed speech in parallel with manual pointing, a variety of multimodal systems has emerged. Some rudimentary ones process speech combined with mouse pointing, such as the early CUBRICON system [8]. Others recognize speech while determining the location of pointing from users' manual gestures or gaze [5]. Moving from traditional interfaces toward interfaces offering users greater expressive power, naturalness, and portability. Recent multimodal systems now recognize a broader range of signal integrations, which are no longer limited to the simple point-and-speak combinations handled by earlier systems. For example, the Quickset system integrates speech with pen input that includes drawn graphics, symbols, gestures, and pointing. It uses a semantic unification process to combine the meaningful multimodal information carried by two input signals, both of which are rich and multidimensional. Quickset also uses a multi-agent architecture and runs on a handheld PC [3]. Figure 1 illustrates Quickset's response to the multi-modal command \" Airstrips... facing this way, facing this way, and facing this way, \" which was spoken while the user drew arrows placing three airstrips in correct orientation on a map. Multimodal systems represent a research-level paradigm shift away from conventional windows-icons-menus-pointers (WIMP) interfaces toward providing users with greater expressive power, naturalness, flexibility , and portability. Well-designed multimodal systems integrate complementary modalities to yield a highly synergistic blend in which the strengths of each mode are capitalized upon and used to overcome weaknesses in the other. Such systems potentially can function more robustly than unimodal systems that involve a single recognition-based technology such as speech, pen, or vision.

Methods for analyzing health care utilization and costs

Abstract: Important questions about health care are often addressed by studying health care utilization. Utilization data have several characteristics that make them a challenge to analyze. In this paper we discuss sources of information, the statistical properties of utilization data, common analytic methods including the two-part model, and some newly available statistical methods including the generalized linear model. We also address issues of study design and new methods for dealing with censored data. Examples are presented.

Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.

Abstract: It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.

Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways

Abstract: Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein’s anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways. J. Clin. Invest. 104:1567–1573 (1999).

Dependent types in practical programming

Abstract: We present an approach to enriching the type system of ML with a restricted form of dependent types, where type index objects are drawn from a constraint domain C, leading to the DML(C) language schema. This allows specification and inference of significantly more precise type information, facilitating program error detection and compiler optimization. A major complication resulting from introducing dependent types is that pure type inference for the enriched system is no longer possible, but we show that type-checking a sufficiently annotated program in DML(C) can be reduced to constraint satisfaction in the constraint domain C. We exhibit the unobtrusiveness of our approach through practical examples and prove that DML(C) is conservative over ML. The main contribution of the paper lies in our language design, including the formulation of type-checking rules which makes the approach practical. To our knowledge, no previous type system for a general purpose programming language such as ML has combined dependent types with features including datatype declarations, higher-order functions, general recursions, let-polymorphism, mutable references, and exceptions. In addition, we have finished a prototype implementation of DML(C) for an integer constraint domain C, where constraints are linear inequalities (Xi and Pfenning 1998).

Ubiquitin tag for sperm mitochondria

Abstract: Like other mammals, humans inherit mitochondria from the mother only, even though the sperm contributes nearly one hundred mitochondria to the fertilized egg. In support of the idea that this strictly maternal inheritance of mitochondrial DNA arises from the selective destruction of sperm mitochondria1,2, we show here that sperm mitochondria inside fertilized cow and monkey eggs are tagged by the recycling marker protein ubiquitin3. This imprint is a death sentence that is written during spermatogenesis and executed after the sperm mitochondria encounter the egg's cytoplasmic destruction machinery.

p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage

Abstract: The protein p73 is a structural and functional homologue of the p53 tumour-suppressor protein but, unlike p53, it is not induced in response to DNA damage1,2. The tyrosine kinase c-Abl is activated by certain DNA-damaging agents3 and contributes tothe induction of programmed cell death (apoptosis) by p53-dependent and p53-independent mechanisms4. Here we show that c-Abl binds to p73 in cells, interacting through its SH3 domain with the carboxy-terminal homo-oligomerization domain of p73. c-Abl phosphorylates p73 on a tyrosine residue at position 99 both in vitro and in cells that have been exposed to ionizing radiation. Our results show that c-Abl stimulates p73-mediated transactivation and apoptosis. This regulation of p73 by c-Abl in response to DNA damage is also demonstrated by a failure of ionizing-radiation-induced apoptosis after disruption of the c-Abl–p73 interaction. These findings show that p73 is regulated by a c-Abl-dependent mechanism and that p73 participates in the apoptotic response to DNA damage.

A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer.

Abstract: Recombinant human TSH has been developed to facilitate monitoring for thyroid carcinoma recurrence or persistence without the attendant morbidity of hypothyroidism seen after thyroid hormone withdrawal. The objectives of this study were to compare the effect of administered recombinant human TSH with thyroid hormone withdrawal on the results of radioiodine whole body scanning (WBS) and serum thyroglobulin (Tg) levels. Two hundred and twenty-nine adult patients with differentiated thyroid cancer requiring radioiodine WBS were studied. Radioiodine WBS and serum Tg measurements were performed after administration of recombinant human TSH and again after thyroid hormone withdrawal in each patient. Radioiodine whole body scans were concordant between the recombinant TSH-stimulated and thyroid hormone withdrawal phases in 195 of 220 (89%) patients. Of the discordant scans, 8 (4%) had superior scans after recombinant human TSH administration, and 17 (8%) had superior scans after thyroid hormone withdrawal (P = 0.108). Based on a serum Tg level of 2 ng/mL or more, thyroid tissue or cancer was detected during thyroid hormone therapy in 22%, after recombinant human TSH stimulation in 52%, and after thyroid hormone withdrawal in 56% of patients with disease or tissue limited to the thyroid bed and in 80%, 100%, and 100% of patients, respectively, with metastatic disease. A combination of radioiodine WBS and serum Tg after recombinant human TSH stimulation detected thyroid tissue or cancer in 93% of patients with disease or tissue limited to the thyroid bed and 100% of patients with metastatic disease. In conclusion, recombinant human TSH administration is a safe and effective means of stimulating radioiodine uptake and serum Tg levels in patients undergoing evaluation for thyroid cancer persistence and recurrence.

Regulation of NMDA Receptors by an Associated Phosphatase-Kinase Signaling Complex

Abstract: Regulation of N-methyl-d-aspartate (NMDA) receptor activity by kinases and phosphatases contributes to the modulation of synaptic transmission. Targeting of these enzymes near the substrate is proposed to enhance phosphorylation-dependent modulation. Yotiao, an NMDA receptor–associated protein, bound the type I protein phosphatase (PP1) and the adenosine 3′,5′-monophosphate (cAMP)–dependent protein kinase (PKA) holoenzyme. Anchored PP1 was active, limiting channel activity, whereas PKA activation overcame constitutive PP1 activity and conferred rapid enhancement of NMDA receptor currents. Hence, yotiao is a scaffold protein that physically attaches PP1 and PKA to NMDA receptors to regulate channel activity.

Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots.

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum.

Humans use internal models to estimate gravity and linear acceleration

Abstract: Because sensory systems often provide ambiguous information, neural processes must exist to resolve these ambiguities. It is likely that similar neural processes are used by different sensory systems. For example, many tasks require neural processing to distinguish linear acceleration from gravity, but Einstein's equivalence principle states that all linear accelerometers must measure both linear acceleration and gravity. Here we investigate whether the brain uses internal models, defined as neural systems that mimic physical principles, to help estimate linear acceleration and gravity. Internal models may be used in motor contro, sensorimotor integration and sensory processing, but direct experimental evidence for such models is limited. To determine how humans process ambiguous gravity and linear acceleration cues, subjects were tilted after being rotated at a constant velocity about an Earth-vertical axis. We show that the eye movements evoked by this post-rotational tilt include a response component that compensates for the estimated linear acceleration even when no actual linear acceleration occurs. These measured responses are consistent with our internal model predictions that the nervous system can develop a non-zero estimate of linear acceleration even when no true linear acceleration is present.

Mammalian DNA Mismatch Repair

Abstract: DNA mismatch repair (MMR) is one of multiple replication, repair, and recombination processes that are required to maintain genomic stability in prokaryotes and eukaryotes. In the wake of the discoveries that hereditary nonpolyposis colorectal cancer (HNPCC) and other human cancers are associated with mutations in MMR genes, intensive efforts are under way to elucidate the biochemical functions of mammalian MutS and MutL homologs, and the consequences of defects in these genes. Genetic studies in cultured mammalian cells and mice are proving to be instrumental in defining the relationship between the functions of MMR in mutation and tumor avoidance. Furthermore, these approaches have raised awareness that MMR homologs contribute to DNA damage surveillance, transcription-coupled repair, and recombinogenic and meiotic processes.

Dopamine D4 Receptor-Knock-Out Mice Exhibit Reduced Exploration of Novel Stimuli

Abstract: The involvement of dopamine neurotransmission in behavioral responses to novelty is suggested by reports that reward is related to increased dopamine activity, that dopamine modulates exploratory behavior in animals, and that Parkinson9s disease patients report diminished responses to novelty Some studies have reported that polymorphisms of the human dopamine D4 receptor (D4R) gene are associated with personality inventory measures of the trait called “novelty-seeking” To explore a potential role for the D4R in behavioral responses to novelty, we evaluated D4R-knock-out (D4R−/−) and wild-type (D4R+/+) mice in three approach–avoidance paradigms: the open field, emergence, and novel object tests These three paradigms differ in the degree to which they elicit approach, or exploratory behavior, and avoidance, or anxiety-related behavior Thus, we used these three tests to determine whether the D4R primarily influences the exploratory or the anxious component of responses to approach–avoidance conflicts D4R−/− mice were significantly less behaviorally responsive to novelty than D4R+/+ mice in all three tests The largest phenotypic differences were observed in the novel object test, which maximizes approach behavior, and the smallest phenotypic differences were found in the open field test, which maximizes avoidance behavior Hence, D4R−/− mice exhibit reductions in behavioral responses to novelty, reflecting a decrease in novelty-related exploration

Axial Coding and the Grounded Theory Controversy

Abstract: The purpose of this article is to describe the similarities and differences between two approaches to grounded theory research: grounded theory as espoused by Glaser and grounded theory as espoused by Strauss and Corbin. The focus of the article is the controversy surrounding the use of axial coding. The author proposes a resolution to the controversy by suggesting that one does not need to view either approach as right or wrong; rather, the qualitative and grounded theory researcher can choose an approach, and that choice is based on the goal of the researcher’s study. Examples of both approaches, from the author’s research study on the experiences of living in a family with a child with attention deficit hyperactivity disorder (ADHD), are provided.

A Common Molecular Basis for Rearrangement Disorders on Chromosome 22q11

Abstract: The chromosome 22q11 region is susceptible to rearrangements that are associated with congenital anomaly disorders and malignant tumors. Three congenital anomaly disorders, cat-eye syndrome, der(22) syndrome and velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) are associated with tetrasomy, trisomy or monosomy, respectively, for part of chromosome 22q11. VCFS/DGS is the most common syndrome associated with 22q11 rearrangements. In order to determine whether there are particular regions on 22q11 that are prone to rearrangements, the deletion end-points in a large number of VCFS/DGS patients were defined by haplotype analysis. Most VCFS/DGS patients have a similar 3 Mb deletion, some have a nested distal deletion breakpoint resulting in a 1.5 Mb deletion and a few rare patients have unique deletions or translocations. The high prevalence of the disorder in the population and the fact that most cases occur sporadically suggest that sequences at or near the breakpoints confer susceptibility to chromosome rearrangements. To investigate this hypothesis, we developed hamster-human somatic hybrid cell lines from VCFS/DGS patients with all three classes of deletions and we now show that the breakpoints occur within similar low copy repeats, termed LCR22s. To support this idea further, we identified a family that carries an interstitial duplication of the same 3 Mb region that is deleted in VCFS/DGS patients. We present models to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. We identified five additional copies of the LCR22 on 22q11 that may mediate other rearrangements leading to disease.