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Non-peptide glycoprotein IIb/IIIa antagonists. 11. Design and in vivo evaluation of 3,4-dihydro-1 (1H)-isoquinolinone-based antagonists and ethyl ester prodrugs.

The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency. In addition, substitution at the 3-position of the beta-amino acid enhanced potency with the 3-pyridyl and 3-ethynyl analogs being the most potent prepared. Attempts to improve the in vivo profile of these compounds focused on modification of the physical properties. Ester prodrugs were prepared to increase the lipophilicity and remove the zwitterionic nature of the antagonists. The prodrug approach, coupled with the arylpiperazine terminus (pKa = approximately 9.0), afforded moderately basic and relatively nonpolar compounds. The acid N-[[7-(piperazin-1-yl)-3,4-dihydro-1(1H)-oxoisoquinolin-2-yl ]acetyl]-3(S)- ethynyl-beta-alanine, 6d (L-767,679), is a potent fibrinogen receptor antagonist able to inhibit the ADP-induced aggregation of human gel-filtered platelets with an IC50 of 12 nM. Although 6d is orally active based on the results of an ex vivo dog assay at 0.3 mg/kg, the ethyl ester prodrug of this compound, 19 (L-767,685), is better absorbed at this dose than 6d. Upon oral dosing, the ester 19 is converted to 6d in vivo in dog with an estimated oral systemic availability of > 17% (0-8 h, AUC19po/AUC6div). In addition, studies in monkey at an oral dose of 1 mg/kg show that 19 affects the complete inhibition of the ex vivo platelet aggregation in response to ADP between 2 and 8 h postdose with the level of inhibition remaining at 40% at 12 h postdose. This level of activity was superior to that observed for 6d and 1 at the same dose. Using ex vivo ADP-induced aggregation data from rhesus monkey (n = 2, 0-8 h using the AUC19po/AUC6div), the estimated systemic oral availability of 6d when dosed as 19 is 32%.

Animals↗

Occupational exposure to vinyl chloride and cancer risk: a review of the epidemiologic literature.

Occupational exposure to vinyl chloride (VC) is causally related to liver angiosarcoma, whereas there is inconsistent epidemiologic evidence for other neoplasms. Two pooled analyses of worker cohorts from 56 plants in North America and Europe provide the most comprehensive and updated data on cancer risk among workers exposed to VC. These included over 22,000 workers, with a total of 640,000 person-years of observation, followed-up for up to 50 years. Overall, a total of 1,778 cancer deaths were observed versus 1,829.46 expected, corresponding to a standardized mortality ratio (SMR) of 0.97 (95% confidence interval (CI)=0.93-1.02). Excluding 71 confirmed angiosarcomas, there were 60 deaths from liver cancers versus 44.35 expected (SMR=1.35, 95% CI=1.03-1.74). Lung and laryngeal cancer mortality were significantly lower than expected (SMR=0.88 and 0.59, respectively). The SMRs for soft tissue sarcoma, brain, lymphoid and haematopoietic system cancers were not materially different from unity. Thus, the aggregate data from over 20,000 VC workers in North America and Europe exclude any excess mortality from lung, laryngeal, soft tissue sarcoma, brain, lymphoid and haematopoietic neoplasms. There appears to be a slight excess of liver cancer other than angiosarcoma, which is difficult to interpret and is likely due to residual misclassification of angiosarcomas.

Cohort Studies↗

In-depth analysis of anesthetic mishaps: tools and techniques.

In-depth analysis of an anesthetic mishap requires the acquisition and analysis of a complex body of data. These tasks are facilitated by specific tools and approaches. At the outset, the reviewer should create a registry for documents and seek a factual overview of events. Basic information about case management should be obtained with a structured survey instrument. Critical pieces of information must be explicitly indexed for later examination. Timelines are particularly effective for organizing and displaying key events. The process of data analysis can be expedited by starting with broad concerns and moving to finer distinctions in a stepwise manner. Preparation of a short summary is the first analytic task. Next, the relationships between the injury, the mechanism of injury, and the contributory actions of the caretakers are formally linked as a hypothesis of injury. Finally, each contributory action is examined individually to determine if it represents a deviation from the standard of care. Contradictory information is an expected feature of in-depth analysis. This problem can often be resolved by testing for clinical relevance, identifying obvious inaccuracies, and emphasizing findings from the most reliable sources. Recent work suggests that practicing anesthesiologists can analyze mishaps with a significant degree of interrater reliability. Thus, aggregate data obtained from in-depth analysis may play an increasingly important role in research, risk management, and peer review.

Anesthesiology↗

Using survival analysis to study spatial point patterns in geographical epidemiology.

The spatial K-function has become a well accepted method of investigating whether significant clustering can be detected in spatial point patterns. Unlike nearest neighbor-based methods, the K-function approach has the advantage of exploring spatial pattern across a range of spatial scales. However, K-functions still have a number of drawbacks. For instance, although K-functions are based on inter-event distances, they only use a count of the number of point events within successive distance bands. This represents data aggregation and information loss. Secondly, and perhaps more significantly, K-functions are based on a cumulative count of point events with distance. This feature raises the possibility that the investigation of pattern at different scales is compromised by the dependency of any one count to previous counts. This paper proposes a new approach to the analysis of spatial point patterns based upon survival analysis. Although typically used in the temporal domain, there is no reason why survival analysis cannot be applied to any positively-valued, continuous variable as well as time. In this paper, survival analysis is applied to the inter-event distance measures of bivariate spatial point patterns to investigate the 'random labeling' hypothesis. It is shown, through both a controlled data situation and empirical epidemiological applications, that such an approach may be a very useful complement to K-function analysis.

Accidents, Traffic↗

Prosthodontic and periodontal considerations for implant-supported dental restorations.

In the past two years, many reports concerning the outcome of treatment using dental implants have included more detailed data which allow insight into prosthodontic and periodontal considerations that affect success. It has become evident that unique biomechanical sequelae reflect the screw-joint character of the dental implant prosthesis. The relative stability of the screw joint and the biomechanical integrity of the components and prostheses themselves are new issues to contend with for restorative dentistry. The biologic sequelae of maintaining the implant-supported prostheses are revealed by bone maintenance and peri-implant mucosal health. The microbiologic similarity of tooth and implant-associated plaque at inflamed sites suggests that infected teeth are sources of potentially pathogenic bacteria at implants. However, the pathogenesis of inflammatory disease at implants is not fully defined. The evaluation and prognostic criteria of peri-implant inflammation remain controversial topics. The present aggregate data indicate that the long-term evaluation of implant-supported dental prosthesis must be performed with cautious optimism and attention to general biomechanical and biologic factors.

Dental Implants↗

Market power in the United States red meatpacking industry.

The basic question asked in the beginning of this article was whether the evidence from research is persuasive enough to conclude that competition in the meatpacking industry is deficient. The literature review led to the conclusion that the answer is no. Research varies widely in terms of data and methodologic approaches. The research, however, clearly finds evidence of market power. Many SCP studies indicated the existence and exercise of market power, but the failure of the paradigm makes definitive conclusions dangerous. The NEIO studies showed a persistent gap between the price of livestock and marginal costs but the studies did not incorporate sufficient detail to prove specific behavior. Azzam and Anderson [4] conducted an extensive review of competition in meatpacking. In their summary, they offered criticisms of the SCP approach and the conduct parameter approach. These investigators concluded that the body of empiric evidence was insufficient to persuasively argue that the meatpacking industry was not competitive. Sexton [69] discussed more recent critiques of the conduct parameter appraoch. Despite its weaknesses, he concluded that market power estimates in meatpacking are modest but that structural changes on balance are beneficial, from an efficiency viewpoint. Examining the evidence either by data aggregation, methodology, or time period results in little difference in the qualitative interpretation. The research community has done what Nicholls [2] said was needed. The need remains relevant. The research leaves us with a clear picture and nagging questions. Azzam and Anderson [4] recommended that further research focus on the process of competition or the rivalrous interaction between competitors, and on competitors' strategies for responding to technologic and market forces, as the business history of the industry suggests. Specifically, they recommended two approaches. First, to develop empiric pricing models for short-term monitoring. Such models infer conduct from spatial price linkages rather than from concentration as do SCP studies or estimation of conduct parameters as do NEIO studies. Second, to study the dynamics of the competitive process, making use of data describing changes at the firm and plant level, to better understand the effect of market and technologic forces on the evolution of firm behavior and industry structure. After discussing existing research quality and future research needs, two practical things remain to do. The first centers on the following question: How important are the relatively small measures of market power? Most believable price distortions are found to be 3% or less. These distortions are below the 5% regulatory standards related to mergers used by the US Department of Justice and US Federal Trade Commission [70]. These standards, however, are guidelines and not law. Antitrust laws state that the exercise of market power is illegal. Courts and regulatory agencies also have not defined how much market power is significant and for how long a firm or firms must maintain significant market power [71]. From the viewpoint of public welfare, small impacts on price make a substantial difference to livestock producers and rival meatpacking firms. In relatively low-profit commodity businesses, small degrees of market power have significant profit implications. Small price or percentage impacts represent large total dollar amounts, especially over long time periods. To some, the evidence of market power provides clear reasons for antitrust lawsuits, conclusive evidence of weak and disinterested antitrust enforcement, and undeniable grounds for corrective legislation. If we conclude that action is needed, then the second issue emerges: What should be done and will our actions result in a net improvement? The research reviewed in the article by MacDonald elsewhere in this issue clearly shows the economic benefits of large meat processing firms. Likewise, some of the research reviewed here shows that increased concentration benefits producers and consumers. Some of the benefits of lower costs are passed on to producers through improved prices. The clear problems seen in the 1910s and 1920s--the pools and trusts--are not present in the 1990s and 2000s. Legislative action requiring the restructuring of the meatpacking industry or limiting behavior (similar to the Packer Consent Decree of 1920) will come at a large cost to the industry and society. So what should be done? Some people want to do nothing and allow the market to function unencumbered by political action. This approach ignores the problems seen in research. Some people want to go back in time, forgetting the economic incentives for change. They would legislate change in the market structure where they perceive problems, break up large meatpacking firms, restrict supposed problematic conduct, and eliminate contracting and vertical integration. Some people want to treat agriculture as a unique sector of society and create laws and regulations applicable to agriculture alone, regardless of whether the issues driving these actions apply to other sectors of the economy. Little, if any, thought is given to public and private costs or public and private benefits. Structural changes are clear. Research findings on the impacts and consequences are robust. What should be done, however, is not clear or robust. We are in the realm of second-best choices. The fact that we are in a realm of second-best choices is not satisfying to me nor will it likely be to agricultural producers and policy makers. What to do from here is not an economic decision (i.e., economics cannot provide a clear best answer). Rather, it is a political and public choice question that has economic implications: What do we want our livestock and meat industry to look like?

Animals↗

The effects of a celebrity suicide on suicide rates in Hong Kong.

BACKGROUND: Deaths of celebrities, especially by suicide, can be followed by an increase in population suicide rates, particularly where there is extensive media reporting. We have examined the impact on suicides following the death of a famous Hong Kong pop singer whose death from suicide by jumping from a height, occurred on 1st April 2003, and resulted in extensive and often dramatic media coverage. METHODS: Data on suicides were obtained from the Hong Kong Census and Statistics Department and the Coroner's Court. The numbers of suicides in 2003 before and after the death of celebrity were compared to the same period in 1998-2002. The case files and suicide notes of people who died by suicide in 2003 were also studied qualitatively. RESULTS: There was a significant increase in suicides following the celebrity death, compared with the average over the preceding three months as well as the corresponding monthly average during 1998-2002. It was particularly marked in a subgroup comprising males, aged 25-39 years, many of whom died by jumping. The name of the celebrity was often mentioned in case files and suicide notes. LIMITATIONS: The statistical results in showing the excess of suicides were based on aggregated data only. CONCLUSIONS: This study provides further confirmation of the potential harmful consequences of sensational and excessive reporting of celebrity deaths.

Adult↗

Molecular phylogeny of the genus Hypochaeris using internal transcribed spacers of nuclear rDNA: inference for chromosomal evolution.

Sequences of the internal transcribed spacers (ITSs) of 18S-26S nuclear ribosomal DNA were used to resolve phylogenetic relationships and chromosomal evolution among 14 species of the genus Hypochaeris (Asteraceae). Parsimony analysis was performed for phylogenetic reconstruction, and sequence divergence between species was estimated. Pairwise sequence divergence within Hypochaeris genus ranged from 0% to 25.68% in ITS1 and from 0% to 17.08% in ITS2. A highly resolved strict-consensus tree was obtained that showed the phylogenetically useful information of ITS sequences within the genus Hypochaeris. Four clades could be well distinguished, one of them formed by the single species H. robertia, which appeared to be the most related to the ancestral species of the genus. The results agree with taxonomic classification based on morphological data, and the tree obtained, when indels are coded as missing data, aggregates the species having the same chromosome number, except in one clade. According to the ITS phylogenetic tree, the chromosomal evolution within the genus Hypochaeris conflicts with the previous hypothesis and suggests that karyotype evolution in Hypochaeris was accompanied with both decreasing and increasing dysploidy, probably with several chromosomal rearrangements, and from an ancestral basic chromosome number of 4 or 5.

Asteraceae↗

ASHP national survey of pharmacy practice in hospital settings: monitoring and patient education--2003.

PURPOSE: Results of the 2003 ASHP national survey of pharmacy practice in hospital settings that pertain to monitoring and patient education are presented. METHODS: A stratified random sample of pharmacy directors at 1173 general and children's medical-surgical hospitals in the United States was surveyed by mail. SMG Marketing Group, Inc., supplied data on hospital characteristics; the survey sample was drawn from SMG's hospital database. RESULTS: The response rate was 47.1%. Virtually all hospitals (95.3%) had pharmacists regularly monitoring medication therapy in some capacity. Patient monitoring has improved since 2000; fewer respondents reported monitoring less than 25% of patients in the hospital, and most hospitals reported an increase in the amount of time pharmacists devoted to monitoring activities. Pharmacists were provided computer access to laboratory information in 78% of hospitals to facilitate this function. Detection and reporting of adverse drug events (ADEs) have substantially increased since 1999, with an increase of 42% in events reported internally. Strategies to improve ADE reporting were in place in 84% of hospitals, indicating that pharmacists are adopting the widely recommended philosophy of learning from errors. Errors were less widely reported externally, limiting the value of aggregated data for improving the medication-use process. Most hospitals (85.5%) had an interprofessional infrastructure in place to discuss and learn from voluntary reports of ADEs. Medication counseling continued to be relatively infrequent, with nearly three fourths of hospitals reporting fewer than 26% of inpatients received medication education. Pharmacist staffing in hospitals has risen significantly, from an average of 8.6 full-time equivalents (FTEs) in 2002 to 9.4 FTEs per hospital. Vacancy rates for pharmacists decreased from 7.3% in 2002 to 43%. It is now estimated that there are 1846 vacancies in hospital pharmacies. CONCLUSION: Notable improvements in hospital pharmacy practice have been made. The percentage of patients whose medication therapy is monitored by pharmacists has increased, and most hospitals reported that the amount of time pharmacists spent monitoring patients' medication therapy had increased. Internal and external reporting of ADEs has increased, and pharmacist vacancies have decreased from 2002. Staffing has also improved, suggesting an abatement of the critical shortage of pharmacists in the hospital setting.

Adverse Drug Reaction Reporting Systems↗

Statistical inference by confidence intervals: issues of interpretation and utilization.

This article examines the role of the confidence interval (CI) in statistical inference and its advantages over conventional hypothesis testing, particularly when data are applied in the context of clinical practice. A CI provides a range of population values with which a sample statistic is consistent at a given level of confidence (usually 95%). Conventional hypothesis testing serves to either reject or retain a null hypothesis. A CI, while also functioning as a hypothesis test, provides additional information on the variability of an observed sample statistic (ie, its precision) and on its probable relationship to the value of this statistic in the population from which the sample was drawn (ie, its accuracy). Thus, the CI focuses attention on the magnitude and the probability of a treatment or other effect. It thereby assists in determining the clinical usefulness and importance of, as well as the statistical significance of, findings. The CI is appropriate for both parametric and nonparametric analyses and for both individual studies and aggregated data in meta-analyses. It is recommended that, when inferential statistical analysis is performed, CIs should accompany point estimates and conventional hypothesis tests wherever possible.

Bias↗

Does continuous heparinization influence platelet function in the intensive care patient?

OBJECTIVE: To study the influence of continuous administration of heparin on platelet function in intensive care patients. DESIGN: Prospective, serial investigation. SETTING: Clinical investigation on a surgical and neurosurgical intensive care unit in a university hospital. PATIENTS: The study included 45 patients: 15 postoperative with patients sepsis (Acute Physiology and Chronic Health Evaluation II score between 15 and 25), 15 trauma patients (Injury Severity Score 15 to 25), and 15 neurosurgical patients. INTERVENTIONS: Management of the patients was carried out according to the guidelines for modern intensive care therapy. Sepsis and trauma patients received standard (unfractionated) heparin continuously [aim: an activated partial thromboplastin time (aPTT) approximately 2.0 times normal value; sepsis-heparin and trauma-heparin patients], whereas neurosurgical patients received no heparin (neurosurgical patients). MEASUREMENTS AND RESULTS: From arterial blood samples, platelet aggregation was measured by the turbidimetric method. Platelet aggregation was induced by adenosine diphosphate (ADP; 2.0 mumol/l), collagen (10 micrograms/ml), and epinephrine (25 mumol/l). Measurements were carried out on the day of diagnosis of sepsis or 12 h after hemodynamic stabilization (trauma and neurosurgery patients) (baseline) and during the next 5 days at 12.00 noon. Standard coagulation parameters [platelet count and fibrinogen and antithrombin III (AT III) plasma concentrations] were also monitored. Heparin 4-10 U/kg per h (mean dose: approximately 500 U/h) was necessary to reach an aPTT of about 2.0 times normal. Platelet count was highest in the neurosurgical patients, but it did not decrease after heparin administration to the trauma and sepsis patients. AT III and fibrinogen plasma levels were similar in the three groups of patients. In the sepsis group, platelet aggregation variables decreased significantly (e.g., epinephrine-induced maximum platelet aggregation:-45 relative % from baseline value). Platelet function recovered during the study and even exceeded baseline values (e.g., ADP-induced maximum platelet aggregation: +42.5 relative % from baseline value). Continuous heparinization did not blunt this increase of platelet aggregation variables. In the heparinized trauma patients, platelet aggregation variables remained almost stable and were no different to platelet aggregation data in the untreated neurosurgical patients. CONCLUSIONS: Continuous administration of heparin with an average dose of approximately 500 U/h did not negatively influence platelet function in the trauma patients. Recovery from reduced platelet function in the sepsis group was not affected by continuous heparinization. Thus, continuous heparinization with this dose appears to be safe with regard to platelet function in the intensive care patient.

APACHE↗

Significance of platelet aggregability immediately after blood sampling and effect of cigarette smoking.

A novel type platelet aggregometer, a WBA Analyzer, has enabled us to obtain the platelet aggregability data immediately after blood sampling, which is considered to closely reflect in vivo platelet function. Using this analyzer, we measured the platelet aggregatory threshold index (PATI) 5 min after blood sampling and compared it with that 60 min after blood sampling in 20 healthy male volunteers (10 smokers and 10 non-smokers). In the non-smokers, PATI was 10.3+/-2.3 microM 5 min after blood sampling, and it decreased to 4.7+/-1.5 (P<0.001) 60 min after blood sampling. In the smokers, the PATI was 7.7+/-2.9 microM 5 min after blood sampling, and it decreased to 3.8+/-1.5 (P<0.001) at 60 min after blood sampling. In the smokers, the PATI 5 min after blood sampling increased after a 4-week cessation of smoking (10.4+/-2.9, P<0.01), although the PATI 60 min after blood sampling did not change (4.2+/-1.6 microM). The measurement of platelet aggregability immediately after blood sampling using a WBA Analyser may be useful to evaluate not only platelet function in various thrombotic disorders, but also the effects of various anti-platelet drugs. Cessation of smoking should also be encouraged in the light of the adverse effects on platelet function.

Adult↗

Fatal accident involvement rates by driver age for large trucks.

Survey data on large trucks involved in fatal accidents and on the travel of large trucks provide estimates of fatal accident involvement rates by driver age. The analysis is focused on the implications of lowering the minimum age for drivers of commercial trucks operating interstate from 21 to 19 years. Fatal accident involvement rates for drivers of large trucks are found to increase with decreasing driver age. The younger drivers are over-involved until about age 27. Drivers under the age of 21 are over-involved by a factor of 6 in comparison to the overall rate for all drivers. Other factors known to have significant influences on the probability of involvement in a fatal accident were examined to determine their association with the over-involvement of younger drivers. The general pattern of over-involvement for younger drivers pervades virtually every combination of factors examined. Thus, it is concluded that the basic trend with driver age shown in the aggregate data is primarily associated with age and is not associated with the other factors examined. The results of this analysis substantiate an elevated risk of fatal accident involvement for younger drivers of large trucks.

Accidents, Traffic↗

Critical comparison of consensus methods for molecular sequences.

Consensus methods are recognized as valuable tools for data analysis, especially when some sort of data aggregation is desired. Although consensus methods for sequences play a vital role in molecular biology, researchers pay little heed to the features and limitations of such methods, and so there are risks that criteria for constructing consensus sequences will be misused or misunderstood. To understand better the issues involved, we conducted a critical comparison of nine consensus methods for sequences, of which eight were used in papers appearing in this journal. We report the results of that comparison, and we make recommendations which we hope will assist researchers when they must select particular consensus methods for particular applications.

Algorithms↗

Multiscale detection of localized anomalous structure in aggregate disease incidence data.

We present a modelling framework for detection of potentially anomalous structure in aggregate spatial disease incidence data in a manner sensitive to localization at multiple scales and/or positions. The key technical contribution is the re-casting of the components of a multiscale disease mapping methodology, recently introduced by the authors in an earlier paper, into a form appropriate for hypothesis testing. In particular, we describe how hypotheses of spatially clustered variations in disease incidence may be linked in one-to-one correspondence with collections of hypotheses on the values of certain multiscale parameters associated with a user-defined hierarchy of nested partitions of an overall spatial region. A Bayesian hypothesis testing methodology is developed in the context of a standard Poisson measurement model, over the collection of possible multiscale hypotheses. We discuss the specification of hyper parameters and prior distributions on the space of models. The methodology is illustrated on both simulated and real data.

Cluster Analysis↗

A comparison of different methods for estimating the prevalence of problematic drug misuse in Great Britain.

AIMS: The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) has produced methodological guidelines for national drug prevalence estimation. This paper pilots the methods to estimate prevalence for Great Britain and provides a commentary on the methods and resulting estimates. DESIGN: Three types of methodology were used to estimate prevalence: (a) the multiple indicator (MI) method, (b) multipliers applied to (i) drug-treatment records (ii) HIV estimates and (iii) mortality statistics and (c) the British/Scottish Crime Surveys. SETTING: England, Scotland and Wales. PARTICIPANTS: Aggregated data on people recorded on databases and respondents in household surveys. MEASUREMENTS: Prevalence estimates of different forms of problematic drug use. FINDINGS: The estimates are 161,133 (range: 120,850-241,700) for people at risk of mortality due to drug overdose; 161,000-169,000 for people who have ever injected drugs; 202,000 (range: 162,000-244,000) problem opiate users and 268,000 problem drug users (all types). CONCLUSIONS: The multiple indicator method offers a comprehensive approach to estimating the prevalence of problematic drug use in the United Kingdom. Simple multiplier methods and household surveys also provide a range of estimates corresponding to different types of drug use in the United Kingdom. The current study suggests that previous national estimates of 100,000-200,000 were conservative. The new estimate of 161,000-266,000 should enable a more focused response. For further development of this method, reliable and timely estimates of anchor points are required for specific geographical areas such as cities or Drug Action Teams (DAT), as well as routine aggregation of drug indicators for these areas.

Epidemiologic Methods↗

Prevalence of physical activity levels by ethnicity among adults in Hawaii, BRFSS 2001.

BACKGROUND: Few studies have examined the differences in physical activity levels between subgroups of Asian or Pacific Islanders living in the United States. This study compared levels of physical activity for three subgroups of Asian or Pacific Islanders residing in Hawaii. METHODS: Data on Native Hawaiian/Part Native Hawaiian (N=585), Filipino (N=548), Japanese (N=871), and White (N=1728) adults were obtained from the Hawaii 2001 Behavioral Risk Factor Surveillance System (BRFSS), which contained more detailed questions on ethnicity than are collected by most states. Six physical activity categories were compared: inactive, insufficient (some activity but less than recommended activity), moderate activity (> or = 30 minutes of moderate activity > or = 5 days a week), vigorous activity (> or = 20 minutes of vigorous activity > or = 3 days a week), recommended activity (meeting either moderate or vigorous activity requirements), and a recently suggested target of > or = 60 minutes of moderate activity 7 days a week or > or = 20 minutes of vigorous activity > or = 4 days a week. RESULTS: Among Asians or Pacific Islanders, Native Hawaiians/Part Native Hawaiians were most active (38.9% moderate and 23.9% vigorous), followed by Japanese (32.1%, 20.4%) and Filipinos (31.8%, 18.6%). Whites were more active than any of these three subgroups (47.2%, 35.4%). CONCLUSIONS: Differences in physical activity levels between subgroups of Asians or Pacific Islanders in Hawaii suggests that aggregated data for all subgroups obscures important information about disparities in activity levels. State efforts to reduce disparities in activity levels should take into account differences between Asian or Pacific Islander subgroups.

Adolescent↗

The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.

The ubiquitin-proteasome pathway is critically involved in the pathology of neurodegenerative diseases characterized by protein misfolding and aggregation. Data in the present study suggest that the polyglutamine neurodegenerative disease protein, ataxin-3 (AT3), functions in the ubiquitin-proteasome pathway. AT3 contains an ubiquitin interaction motif (UIM) domain that binds polyubiquitylated proteins with a strong preference for chains containing four or more ubiquitins. Mutating the conserved leucine in the first UIM (L229A) almost totally eliminates binding to polyubiquitin chains while a similar mutation in the second UIM (L249A) also inhibits binding to polyubiquitin chains but to a lesser extent. Both wild-type and pathological AT3 increase cellular levels of a short-lived GFP that is degraded by the ubiquitin-proteasome pathway. AT3 has several properties characteristic of ubiquitin proteases including decreasing polyubiquitylation of 125I-lysozyme by removing ubiquitin from polyubiquitin chains, cleaving a ubiquitin protease substrate, and binding the specific ubiquitin protease inhibitor, ubiquitin-aldehyde. Mutating the predicted catalytic cysteine in AT3 inhibits each of these ubiquitin protease activities. The ability to bind and cleave ubiquitylated proteins is consistent with AT3 playing a role in the ubiquitin-proteasome system. This raises the possibility that pathological AT3, which tends to misfold and aggregate, may be exposed to aggregate-prone misfolded/denatured proteins as part of its normal function.

Animals↗