bluuebunny/crossref_metadata_2025 huggingface dataset:
Both p16
Ink4a
and the p19
Arf
-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse
Authors: Bardeesy Nabeel , Aguirre Andrew J. , Chu Gerald C. , Cheng Kuang-hung , Lopez Lyle V. , Hezel Aram F. , Feng Bin , Brennan Cameron , Weissleder Ralph , Mahmood Umar , Hanahan Douglas , Redston Mark S. , Chin Lynda , DePinho Ronald A.
Published: April 2006

Activating
KRAS
mutations and

p16
Ink4a

inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras
G12D
initiates formation of premalignant pancreatic ductal lesions, and loss of either
Ink4a
/
Arf
(

p16
Ink4a

/

p19
Arf

) or
p53
enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for

p16
Ink4a

in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16
Ink4a
, p19
Arf
, and/or p53 in the Kras
G12D
model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either
p53
or

p16
Ink4a

, the latter with intact germ-line p53 and

p19
Arf

sequences. Additionally, Kras
G12D
in the context of heterozygosity either for
p53
plus

p16
Ink4a

or for

p16
Ink4a

/

p19
Arf

produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of
p53
or

p16
Ink4a

/

p19
Arf

. Tumors from the double-heterozygous cohorts showed frequent p16
Ink4a
inactivation and loss of either p53 or p19
Arf
. Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous

p16
Ink4a

/

p19
Arf

mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16
Ink4a
and the p19
ARF
-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.
High expression of a cytokeratin-associated protein in many cancers
Authors: Egland Kristi A. , Liu Xiu Fen , Squires Stephen , Nagata Satoshi , Man Yan-Gao , Bera Tapan K. , Onda Masanori , Vincent James J. , Strausberg Robert L. , Lee Byungkook , Pastan Ira
Published: April 2006

We have described previously a cDNA library made from membrane-bound polysomal mRNA prepared from breast and prostate cancer cell lines. The library is highly enriched for cDNAs encoding membrane proteins, secreted proteins, and cytokeratins. To characterize this library, 25,277 cDNA clones were sequenced and aligned with various databases; 1,439 clones did not align with known genes. From this set of clones we identified a previously uncharacterized gene encoding a 334-aa protein. Although protein structural motif prediction programs indicate that the gene encodes a membrane protein comprising a signal sequence, a series of leucine-rich repeats, and a single transmembrane domain with a cytoplasmic tail, confocal microscopy of MCF7 breast cancer cells demonstrates that the protein is not directly associated with the plasma membrane or intracellular membranes but instead colocalizes with intermediate filaments and cytokeratins within the cell. Immunofluorescence studies also show that protein expression is increased greatly in mitotic MCF7 cells, and immunohistochemistry demonstrates its expression in human breast cancer cells. Analysis of mRNA levels in 25 different normal tissues by RT-PCR shows that this gene is expressed highly in normal prostate and salivary gland, very weakly in colon, pancreas, and intestine, and not at all in other tissues. RT-PCR studies on human cancer samples show that the RNA is expressed highly in many cancer cell lines and cancer specimens, including 26 of 33 human breast cancers, 3 of 3 prostate cancers, 3 of 3 colon cancers, and 3 of 3 pancreatic cancers. We name the protein CAPC, cytokeratin-associated protein in cancer.
Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities
Authors: Coleman Thomas R. , Westenfelder Christof , Tögel Florian E. , Yang Ying , Hu Zhuma , Swenson LeAnne , Leuvenink Henri G. D. , Ploeg Rutger J. , d’Uscio Livius V. , Katusic Zvonimir S. , Ghezzi Pietro , Zanetti Adriana , Kaushansky Kenneth , Fox Norma E. , Cerami Anthony , Brines Michael
Published: April 2006

Recombinant human erythropoietin (rhEPO) is receiving increasing attention as a potential therapy for prevention of injury and restoration of function in nonhematopoietic tissues. However, the minimum effective dose required to mimic and augment these normal paracrine functions of erythropoietin (EPO) in some organs (e.g., the brain) is higher than for treatment of anemia. Notably, a dose-dependent risk of adverse effects has been associated with rhEPO administration, especially in high-risk groups, including polycythemia–hyperviscosity syndrome, hypertension, and vascular thrombosis. Of note, several clinical trials employing relatively high dosages of rhEPO in oncology patients were recently halted after an increase in mortality and morbidity, primarily because of thrombotic events. We recently identified a heteromeric EPO receptor complex that mediates tissue protection and is distinct from the homodimeric receptor responsible for the support of erythropoiesis. Moreover, we developed receptor-selective ligands that provide tools to assess which receptor isoform mediates which biological consequence of rhEPO therapy. Here, we demonstrate that rhEPO administration in the rat increases systemic blood pressure, reduces regional renal blood flow, and increases platelet counts and procoagulant activities. In contrast, carbamylated rhEPO, a heteromeric receptor-specific ligand that is fully tissue protective, increases renal blood flow, promotes sodium excretion, reduces injury-induced elevation in procoagulant activity, and does not effect platelet production. These preclinical findings suggest that nonerythropoietic tissue-protective ligands, which appear to elicit fewer adverse effects, may be especially useful in clinical settings for tissue protection.
B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses
Authors: Hsu Mei-Chi , Toellner Kai-Michael , Vinuesa Carola G. , MacLennan Ian C. M.
Published: April 2006

Some antigens induce Ab responses without T lymphocyte help. Among these, many polysaccharide-based antigens cause marginal zone B cells to proliferate and differentiate into plasma cells. B1 cells also respond to some of these antigens. In this article, we report that antigen-specific B1b cells, in response to the T-independent antigen (4-hydroxy-3-nitrophenyl)-acetyl (NP)-Ficoll, develop into clones that sustain Ab production for months with continued production of plasma cells and the accumulation of antigen-specific B cells in follicles. The persistence of this T-independent plasmablast response contrasts with the short-term plasmablast growth associated with T-dependent extrafollicular responses. The nature of the cells responding to NP-Ficoll was probed by using chimeras that have B1 cells but lack primary B lymphopoietic capacity and have very few B2 cells or T cells. The chimeras were constructed by transferring 105IgM+IgD−peritoneal exudate cells into mice unable to produce their own T and B cells because of deficiency in recombinase-activating gene 1 (RAG-1). The chimeras mounted sustained IgM and IgG3 anti-NP Ab responses to NP-Ficoll. This finding was associated with continued NP-specific extrafollicular plasmablast growth and the accumulation of NP-specific B cells in follicles. B cells were not found in the marginal zones of chimeras, and they also lacked recirculating IgD+cells and CD3+cells. The absence of B2 and T cells confirms that hemopoietic cell chimerism leading to primary lymphopoiesis had not been established.
Short circuit of water vapor and polluted air to the global stratosphere by convective transport over the Tibetan Plateau
Authors: Fu Rong , Hu Yuanlong , Wright Jonathon S. , Jiang Jonathan H. , Dickinson Robert E. , Chen Mingxuan , Filipiak Mark , Read William G. , Waters Joe W. , Wu Dong L.
Published: April 2006

During boreal summer, much of the water vapor and CO entering the global tropical stratosphere is transported over the Asian monsoon/Tibetan Plateau (TP) region. Studies have suggested that most of this transport is carried out either by tropical convection over the South Asian monsoon region or by extratropical convection over southern China. By using measurements from the newly available National Aeronautics and Space Administration Aura Microwave Limb Sounder, along with observations from the Aqua and Tropical Rainfall-Measuring Mission satellites, we establish that the TP provides the main pathway for cross-tropopause transport in this region. Tropospheric moist convection driven by elevated surface heating over the TP is deeper and detrains more water vapor, CO, and ice at the tropopause than over the monsoon area. Warmer tropopause temperatures and slower-falling, smaller cirrus cloud particles in less saturated ambient air at the tropopause also allow more water vapor to travel into the lower stratosphere over the TP, effectively short-circuiting the slower ascent of water vapor across the cold tropical tropopause over the monsoon area. Air that is high in water vapor and CO over the Asian monsoon/TP region enters the lower stratosphere primarily over the TP, and it is then transported toward the Asian monsoon area and disperses into the large-scale upward motion of the global stratospheric circulation. Thus, hydration of the global stratosphere could be especially sensitive to changes of convection over the TP.
Toward understanding actin activation of myosin ATPase: The role of myosin surface loops
Authors: Onishi Hirofumi , Mikhailenko Sergey V. , Morales Manuel F.
Published: April 2006

To understand the complicated interplay when a traveling myosin head reaches interaction distance with two actins in a filament we looked to three myosin loops that early on exert their influences from the “outside” of the myosin. On these we conduct, functionally test, and interpret strategically chosen mutations at sites thought from crystallography to be a patch for binding the “first” of the two actins. One loop bears a hydrophobic triplet of residues, one is the so-called “loop 2,” and the third is the “cardiomyopathy” loop. So far as we know, the myosin sites that first respond are the two lysine-rich loops that produce an ionic strength-dependent weak-binding complex with actin. Subsequently, the three loops of interest bind the first actin simultaneously, and all three assist in closing the cleft in the 50-kDa domain of the myosin, a closure that results in transition from weak to strong binding and precedes rapid P
i
release and motility. Mutational analysis shows that each such loop contact is distinctive in the route by which it communicates with its specific target elsewhere in myosin. The strongest contact with actin, for example, is that of the triplet-bearing loop. On the other hand, that of loop 2 (dependent on drawing close two myosin lysines and two actin aspartates) is probably responsible for opening switch I and uncovering the γ-phosphate moiety of bound ATP. Taking into account these findings, we begin to arrange in order many molecular events in muscle function.
Effect of pericardiotomy on exercise-induced pulmonary hypertension in the horse
Authors: Textor JA , Ducharme NG , Gleed RD , Hackett RP , Erb HN , Mitchell L , Soderholm LV
Published: April 2006

The role of cardiac function or dysfunction in the pathogenesis of exercise-induced pulmonary hypertension and haemorrhage in horses has been minimally investigated. We hypothesize that pericardiotomy would enhance diastolic function and attenuate pulmonary vascular pressures in maximally exercising horses. Our objective was to evaluate diastolic function and cardiopulmonary pressures before and after pericardiotomy, at rest and at maximal exercise. Study design was both self- and externally controlled. Five horses underwent pericardiotomy after a baseline exercise test. They subsequently performed the same exercise protocol at 1 week and 13 weeks post-operatively. An external, unoperated control group of five horses performed the same experimental protocol. Pulmonary arterial pressure (PAP), pulmonary artery wedge pressure (PWP), right ventricular pressure, heart rate (HR) and oesophageal pressure were measured continuously at rest and at maximal exercise; maximum rates of ventricular pressure decrease (−dP/dtmax), relaxation half-time (t1/2), time constant of isovolumic relaxation (τ) and pulmonary capillary pressures (PcapP) were derived. Statistical analysis was performed using two-tailed Wilcoxon's signed-rank and rank-sum tests, with significance set atP<0.05. No significant differences were found in any variable after pericardiotomy was performed or between the experimental and external control groups. We conclude that during a 13-week study period, pericardiotomy does not alter pulmonary or ventricular pressures or rate of ventricular relaxation in the resting or maximally exercising horse. Results indicate that, in past and future studies requiring an open pericardium in normal horses, the cardiopulmonary parameters measured here are not affected by reduced pericardial pressure.
The Addiction Severity Index at 25: Origins, Contributions and Transitions
Authors: McLellan A. Thomas , Cacciola John C. , Alterman Arthur I. , Rikoon Samuel H. , Carise Carise
Published: April 2006

The Addiction Severity Index (ASI) is a multidimensional interview used to measure the substance use, health, and social problems of those with alcohol and other drug problems, both at admission to treatment and subsequently at follow‐up contacts. This article first discusses the conceptual and practical importance of the ASI's multi‐dimensional approach to measuring addiction severity, as illustrated by two case presentations. The second section of the paper reviews how this measurement approach has led to some important findings regarding the prediction and measurement of addiction treatment effectiveness. The third section describes the historical and practical considerations that have changed the instrument over time, details the problems with the instrument, and describes our efforts to correct those problems with the ASI‐6. Finally, some recent ASI data collected from over 8,400 patients admitted to a nationally representative sample of U.S. addiction treatment programs are presented.
Borderline Personality and Substance Use in Women
Authors: Feske Feske , Tarter Ralph E. , Kirisci Kirisci , Pilkonis Paul A.
Published: April 2006

The association between borderline personality disorder (BPD) and substance use disorder (SUD) was examined in a predominantly psychiatric (77.6%) sample of 232 women. BPD proved to be a significant predictor ofa lifetime diagnosis of SUD across four different categories: any SUD (including alcohol); alcohol use; drug use; and heroin, cocaine, or poly‐substance use. BPD continued to be a predictor of SUD even when the effects of other cluster B and all cluster C PDs were controlled statistically. Antisocial personality disorder generally yielded larger odds ratios than BPD and emerged as a partial mediator of the relation between BPD and SUD. Histrionic PD was the only other PD that showed meaningful relations with SUD.
Prevalence and Health Correlates of Gambling Problems in Substance Abuse Counselors
Authors: Weinstock Weinstock , Armentano Armentano , Petry Nancy M.
Published: April 2006

This study examined the prevalence of disordered gambling in substance abuse counselors. Participants (n = 328) completed an anonymous self‐report survey assessing lifetime disordered gambling, past two‐month gambling behavior, and current mental and physical health. The lifetime prevalence rates of pathological and problem gambling in this sample (11.9% and 6.4%, respectively) were higher than rates reported in general population surveys. Poorer physical health was associated with pathological gambling, but mental health was not. These results suggest that substance abuse counselors may benefit from education, prevention, and intervention efforts for disordered gambling.
Predictors of Retention in Naltrexone Maintenance for Opioid Dependence: Analysis of a Stage I Trial
Authors: Sullivan Maria A. , Rothenberg Jami L. , Vosburg Suzanne K. , Church Sarah H. , Feldman Shara J. , Epstein Eva M. , Kleber Herbert D. , Nunes Edward V.
Published: April 2006

Behavioral naltrexone therapy (BNT) was developed to address the shortcomings of naltrexone maintenance for opiate dependence and improve compliance by integrating several empirically validated methods, including the use of a significant other to monitor compliance, voucher incentives, and motivational techniques. An uncontrolled Stage I pilot trial (n = 47) of BNT was conducted. Baseline demographic and clinical variables were evaluated as predictors of retention with univariate tests. Significant predictors were entered together into a multiple regression model. Poorer (shorter) retention in treatment was associated with methadone use and higher average bags per day of heroin. Other variables that became non‐significant in multiple regression analysis included older age and depressive symptoms. Individuals with greater physiologic dependence and/or dependence on longer‐acting opiates are at higher risk to drop out from naltrexone maintenance and may require a more gradual detoxification and more intensive behavioral therapy aimed at enhancing initial compliance.
Receipt of Disability Payments by Substance Users: Mental and Physical Health Correlates
Authors: Stein Michael D. , Anderson Bradley J. , Lassor Lassor , Friedmann Peter D.
Published: April 2006

Since 1997, substance users have received disability benefits only for impairments apart from their substance use disorders. It is hypothesized that substance users currently receiving disability benefits would be more severely compromised, medically and/or psychiatrically, than those not receiving disability. Enrolling a community sample of 330 heroin and cocaine users between January 2002 and January 2004, it was found that individuals who were not receiving disability payments had similar mental health scores, current depressive symptoms scores, and lifetime rates of major depression compared to those receiving payments, but significantly lower rates of bipolar or psychotic disorders and psychiatric hospitalization (p < .01). Physically disabled persons had lower physical function scores and were more likely to be HIV‐infected or taking medications regularly (p < .001). The authors conclude that schizophrenia, bipolar disorders, and chronic physical illness, but not major depression, are qualifying substance users for disability benefits. Longitudinal studies of disability status and its effects on the lives of substance users are warranted.
Tramadol versus Buprenorphine for the Management of Acute Heroin Withdrawal: A Retrospective Matched Cohort Controlled Study
Authors: Threlkeld Threlkeld , Parran Theodore V. , Adelman Christopher A. , Grey Scott F. , Yu Yu
Published: April 2006

Many medications have been used over the past thirty years for the treatment of opioid withdrawal, including propoxyphene, methadone, clonidine, parenteral buprenorphine, and, more recently, sublingual buprenorphine. Each has been found to have clinical strengths and limitations. Tramadol is a centrally acting synthetic analgesic with opiate activity primarily due to the binding ofa metabolite to the μ receptor. Despite this μ receptor activity, tramadol appears to have low abuse potential and is a non‐scheduled analgesic. The pharmacologic profile of tramadol makes it a candidate for opiate withdrawal treatment. A chart review was undertaken to retrospectively compare treatment outcomes of heroin‐dependent patients when detoxified with parenteral buprenorphine (1996–1997) versus tramadol (1999–2000). Inclusion criteria for this study were heroin as drug of choice, current opioid physical dependence (ie, withdrawal symptoms), no current abuse of oral opioid analgesics, and no alcohol or benzodiazepine withdrawal symptoms. Patient cases that met inclusion criteria were group‐matched between buprenorphine and tramadol on the basis of age, sex, and amount of heroin used (bags/ day). Charts were audited for patient demographics, daily heroin use at admission, withdrawal symptoms, and discharge status. In total, 129 patient charts were reviewed, and 115 met all inclusion criteria and were group‐matched (45 patients in the buprenorphine group, seventy in the tramadol group). There were no differences in demographics between the two groups of patients. Fifty‐six percent of the buprenorphine group and 71% of the tramadol group completed detoxification; tramadol‐treated patients had significantly higher average withdrawal symptoms when compared to the buprenorphine group and a greater reduction in withdrawal symptoms over time. Finally, the number of side effects was small and did not differ between the groups. The results of this study are consistent with previous pilot reports that indicated few clinical differences between parenteral buprenorphine and oral tramadol protocols when used in the management of acute heroin withdrawal. As a consequence, tramadol shows some promise as an opioid withdrawal management medication.
Predictors of Increased Body Mass Index Following Cessation of Smoking
Authors: John John , Meyer Meyer , Rumpf Hans‐Jürgen , Hapke Hapke , Schumann Anja
Published: April 2006

The objective of this study was to explore nicotine withdrawal symptoms as predictors of increased body mass index (BMI) after an attempt to quit or reduce tobacco smoking. The authors used a survey study, with a probability sample of 4,075 18–64‐year‐old residents. The participation rate was 70.2%, which included 1,545 current daily smokers. Follow‐ups were carried out for current smokers after thirty and 36 months. The authors found that smokers who experienced increased appetite or weight gain (IAW) as a nicotine withdrawal symptom had a higher BMI than smokers without IAW. They concluded that IAW after quitting might be a specific determinant of the BMI increase following smoking cessation in a subgroup of smokers
Relationship of Comorbid Substance and Alcohol Use Disorders to Disability among Patients in Routine Psychiatric Practice
Authors: Wilk Wilk , West Joyce C. , Rae Donald S. , Regier Darrel A.
Published: April 2006

The primary aim of this study was to present data on the relationship of mental and comorbid substance use disorders to work disability and functioning in routine psychiatric practice in the United States. Data were used from the 1997 and 1999 American Psychiatric Institute for Research and Education's Practice Research Network Study of Psychiatric Patients and Treatments, totaling 754 psychiatrists and 3,088 patients. Results found patients with comorbid substance use disorders had significantly higher rates of work disability. These findings highlight the critical need to address the disturbing lack of substance use treatment and rehabilitation services for this population.
Gene Expression Analysis of Troglitazone Reveals Its Impact on Multiple Pathways in Cell Culture: A Case for In Vitro Platforms Combined with Gene Expression Analysis for Early (Idiosyncratic) Toxicity Screening
Authors: Vansant Gordon , Pezzoli Patrick , Saiz Robert , Birch Aaron , Duffy Chris , Ferre Francois , Monforte Joseph
Published: April 2006

Peroxisome proliferator-activated receptor gamma (PPAR γ) agonists of the thiazolidinedione family are used for the treatment of type 2 diabetes mellitus due to their ability to reduce glucose and lipid levels in patients with this disease. Three thiazolidinediones that were approved for treatment are Rezulin (troglitazone), Avandia (rosiglitazone), and Actos (pioglitazone). Troglitazone was withdrawn from the market due to idiosyncratic drug toxicity. Rosiglitazone and pioglitazone are still on the market for the treatment of type 2 diabetes. The authors present data from a gene expression screen that compares the impact these three compounds have in rats, in rat hepatocytes, and in the clone 9 rat liver cell line. The authors monitored the changes in expression in multiple genes, including those related to xenobiotic metabolism, proliferation, DNA damage, oxidative stress, apoptosis, and inflammation. Compared to the other two compounds, troglitazone had a significant impact on many of the pathways monitored in vitro although no major perturbation was detected in vivo. The changes detected predict not only general toxicity but potential mechanisms of toxicity. Based on gene expression analysis, the authors propose there is not just one but multiple ways troglitazone could be toxic, depending on a patient’s environment and genetic makeup, including immune response-related toxicity.
A One-Year Neonatal Mouse Carcinogenesis Study of Quinacrine Dihydrochloride
Authors: Cancel Aida M. , Smith Thomas , Rehkemper Ursula , Dillberger John E. , Sokal David , McClain R. Michael
Published: April 2006

Quinacrine is an acridine derivative under investigation for its use in nonsurgical female sterilization. Safety issues regarding the carcinogenic potential of quinacrine have been raised because it is mutagenic and clastogenic in vitro. The objective of the study was to evaluate the carcinogenic potential of quinacrine dihydrochloride (quinacrine) in neonatal mice treated with single intraperitoneal doses on postpartum days 8 and 15 and observed for 52 weeks. Neonatal Crl: CD-1 mice of each sex were randomly allocated into four treatment groups (0, 10, 50, and 150 mg/kg), dosed twice with quinacrine suspended in carboxymethylcellulose, observed for 52 weeks post dose, and then euthanized, necropsied, and subjected to a full histopathological examination. In male mice, tumor incidence was not significantly increased at any site at any dose level. In female mice, the incidence of benign uterine endometrial stromal polyps was slightly greater at the mid and high dose (≥50 mg/kg), as was the incidence of endometrial hyperplasia. The incidence of polyps in these groups was not significantly greater than in controls by pair-wise comparison but was significantly greater ( p = .042) by the linear trend test. The authors conclude that quinacrine administered twice to neonatal mice may have enhanced or accelerated the development of endometrial hyperplasia and uterine stromal polyps at higher doses. Because uterine stromal polyps are a commonly observed benign tumor in older mice, the significance of this finding is unclear and will require a weight of evidence evaluation for a conclusion on the carcinogenic potential of quinacrine.
Evaluation of the Developmental Toxicity of α-Methyl-3,4-Methylene-Dioxyhydrocinnamic Aldehyde in Rats
Authors: Api Anne Marie , Lewis Elise M. , Hoberman Alan M. , Christian Mildred S. , Diener Robert M.
Published: April 2006

The developmental toxicity of α-methyl-3,4-methylene-dioxyhydrocinnamic aldehyde (MMDHCA), a widely used fragrance ingredient, was evaluated for developmental toxicity in Sprague-Dawley rats (25/group; cesarean-sectioning identified 21 to 25 pregnant rats/group). Oral dosages of 0 (corn oil), 62, 125, or 250 mg/kg/day were administered by gavage on days 7 through 17 of gestation (GDs 7 through 17). Rats were observed for viability, clinical signs, body weights, and feed consumption. Necropsy and cesarean sectioning occurred on GD 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. Analysis of dosage preparations verified calculated dosages ±10%. No deaths occurred. Excessive salivation occurred in all groups, but the incidence was increased at 250 mg/kg/day. The 250 mg/kg/day dosage also was associated with a significant increase in the incidences of a clear, red or yellow perioral and/or red perivaginal substance and significant reductions in mean feed consumption and body weight gains (11.6% and 7.4%, respectively) during the entire dosage period. No gross changes attributable to MMDHCA were observed at necropsy. Cesarean section or litter parameters, as well as fetal alterations, were not affected by MMDHCA at 250 mg/kg/day or either of the lower dosages tested. Based on these data, maternal and developmental no-observable-effect levels (NOAELs) of 125 and >250 mg/kg/day, respectively, were established for MMDHCA. It is concluded that MMDHCA is not a developmental toxicant in rats under the conditions of this study and dosing regimen.
Range-Free Localization with Aerial Anchors in Wireless Sensor Networks
Authors: Ou Chia-Ho , Ssu Kuo-Feng , Jiau Hewijin C.
Published: April 2006

Localization is one of the essential issues in wireless sensor networks. Randomly deployed sensor nodes that do not own any positioning device need to determine their locations for further purposes. Range-based schemes typically utilize extra hardware to provide higher accuracy based on either node-to-node distances or angles. On the other hand, range-free mechanisms support coarse localization without the specific equipment. The paper presents a range-free localization scheme with aerial anchor nodes. Each aerial anchor flies across the sensing field and also periodically broadcasts its location information obtained from its GPS receiver. The sensor nodes use the information and geometry principles to calculate their positions. With the mechanism, the sensor nodes do not need distance-probing hardware or additional communication among them. The localization mechanism has been evaluated and the results show that the mechanism had better performance than other range-free mechanisms.
Infuse: A TDMA Based Data Dissemination Protocol for Sensor Networks
Authors: Kulkarni Sandeep S. , Arumugam Mahesh
Published: April 2006

Reliable dissemination of bulk data is one of the important problems in sensor networks. For example, programming or upgrading the software in sensors at run-time requires reliable dissemination of a new program across the network. In this paper, we present Infuse, a time division multiple access (TDMA) based reliable data dissemination protocol. Infuse takes two input parameters: the choice of the recovery algorithm (from one of two presented in this paper) to deal with unexpected channel errors (e.g., message corruption, varying signal strength), and whether a sensor should listen only to a subset of its neighbors to reduce the amount of active radio time.

Based on these parameters, we obtain four possible versions of Infuse. We compare the performance of these versions to assist a designer in selecting the appropriate version based on the network characteristics. Furthermore, we demonstrate Infuse in the context of network programming.
Variation in performance of elite cyclists from race to race
Authors: Paton Carl D. , Hopkins Will G.
Published: April 2006

The race‐to‐race variation in performance of a top athlete determines the smallest change in performance affecting the athlete's chances of winning. We report here the typical variation in competition times of elite cyclists in various race series. Repeated‐measures analysis of log‐transformed official race times provided the typical variation in a cyclist's performance as a coefficient of variation. The typical variation of a top cyclist (and its 95% likely limits) was 0.4% (0.3–0.5%) in World Cup road races, 0.7% (0.7–0.8%) in Tour de France road races, 1.2% (0.8–2.2%) in the Kilo, 1.3% (0.9–2.4%) in road time trials, 1.7% (1.2–2.6%) in Tour de France time trials, and 2.4% (2.1–2.8%) in World Cup mountain biking. Cyclist interdependence arising from team tactics and pack riding probably accounts for the lower variability in performance of cyclists in road races and precludes estimation of the smallest worthwhile change in performance time for cyclists in these events. The substantial differences in variability between the remaining events, where riders act independently of each other, arise from various event‐specific aspects. For these events the smallest worthwhile changes in performance time (∼0.5×typical variation) are ∼0.5% in the Kilo, ∼0.6% in road time trials, and ∼1.2% in mountain‐bike races.
System approach to games and competitive playing
Authors: Lebed Felix
Published: April 2006

A deep understanding of sport competition is essential for games because the success of coaches and players in such events is dependent on many qualitative and latent factors, which are explainable by means of highly problematic and complicated procedures. The difficulty of setting out the “winning‐factors” in games in orderly fashion has forced researchers to study a game as complex entitites, and in particular as dynamical systems (Bar‐Yam, Y. (2000). Applications of complex systems: Sport and complexity. NECSI. Website publication: http:/necsi.org/guide/examples/basketballcomplexity; Bar‐Yam, Y. (2003). Dynamics of complex systems. New England Complex Systems Institute: Perseus Books Group; Mayer‐Kress, G.J. (2001). Complex system as fundamental theory of sports coaching? Keynote presentation. International sports coaching symposium. Taichung, Taiwan, 01/11/16‐18, arXiv:nlin.AO/0111009 v1 2 Nov 2001; McGarry, T., Anderson, D. I., Wallace, S. A., Hughes, M., & Francs, I. M. (2002). Sport competition as a dynamical self‐organizing system. Journal of Sport Sciences, 20, 771–781). This article is a further attempt to explicate games in this fashion. The article examines games by analyzing three main and interrelated categories: “game” itself, “system”, and “conflict”. I will try to prove that the match (the process of game playing itself) is a conflict of at least two complex dynamical systems. Such a vision stands in debatable contrast to the published, well‐known approach of Tim McGarry and colleagues (McGarry, T., Anderson, D.I., Wallace, S.A., Hughes, M., Francs, I.M. (2002) Sport competition as a dynamical self‐organizing system. Journal of Sport Sciences, 20, 771–781), which contends that competitive playing itself constitutes a dynamical self‐organizing system.
Understanding motivation in sport: An experimental test of achievement goal and self determination theories
Authors: Spray Christopher M. , John Wang C. K. , Biddle Stuart J. H. , Chatzisarantis Nikos L. D.
Published: April 2006

This paper presents an experimental test of two contemporary motivation theories in the physical domain. The study combined experimentally‐induced achievement goal involvement with autonomous and controlling communication styles based on self determination theory to examine young people's enjoyment, free‐choice behavior and performance in relation to a golf task. Results showed that those in the autonomous condition, regardless of their goal involvement, reported greater enjoyment, persisted longer at the task and performed better than those in the controlling communication condition. Participants in the task involved condition performed better than those in the ego involved condition. Findings point to the need for further studies that test multiple theories in sport. The motivational impact of goal involvement may be better understood when considered concurrently with the autonomous or controlling nature of the context. Promoting autonomy and task involvement is likely to enhance positive affect and adaptive behaviors in sport among young people.
Prevention, diagnosis and treatment of the Overtraining Syndrome
Authors: Meeusen Romain , Duclos Martine , Gleeson Michael , Rietjens Gerard , Steinacker Jürgen , Urhausen Axel
Published: April 2006

Successful training must involve overload but also must avoid the combination of excessive overload plus inadequate recovery. Athletes can experience short term performance decrement, without severe psychological, or lasting other negative symptoms. This Functional Overreaching (FOR) will eventually lead to an improvement in performance after recovery. When athletes do not sufficiently respect the balance between training and recovery, Non‐Functional Overreaching (NFOR) can occur. The distinction between NFOR and the Overtraining Syndrome (OTS) is very difficult and will depend on the clinical outcome and exclusion diagnosis. The athlete will often show the same clinical, hormonal and other signs and symptoms. A keyword in the recognition of OTS might be ‘prolonged maladaptation’ not only of the athlete, but also of several biological, neurochemical, and hormonal regulation mechanisms. It is generally thought that symptoms of OTS, such as fatigue, performance decline, and mood disturbances, are more severe than those of NFOR. However, there is no scientific evidence to either confirm or refute this suggestion. One approach to understanding the aetiology of OTS involves the exclusion of organic diseases or infections and factors such as dietary caloric restriction (negative energy balance) and insufficient carbohydrate and/or protein intake, iron deficiency, magnesium deficiency, allergies, etc. together with identification of initiating events or triggers. In this paper we provide the recent status of possible markers for the detection of OTS. Currently several markers (hormones, performance tests, psychological tests, biochemical and immune markers) are used, but none of them meets all criteria to make its use generally accepted. We propose a “check list” that might help the physicians and sport scientists to decide on the diagnosis of OTS and to exclude other possible causes of underperformance.
The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation
Authors: Kline Susan L. , Cheeseman Iain M. , Hori Tetsuya , Fukagawa Tatsuo , Desai Arshad
Published: April 2006

During cell division, kinetochores form the primary chromosomal attachment sites for spindle microtubules. We previously identified a network of 10 interacting kinetochore proteins conserved between Caenorhabditis elegans and humans. In this study, we investigate three proteins in the human network (hDsn1Q9H410, hNnf1PMF1, and hNsl1DC31). Using coexpression in bacteria and fractionation of mitotic extracts, we demonstrate that these proteins form a stable complex with the conserved kinetochore component hMis12. Human or chicken cells depleted of Mis12 complex subunits are delayed in mitosis with misaligned chromosomes and defects in chromosome biorientation. Aligned chromosomes exhibited reduced centromere stretch and diminished kinetochore microtubule bundles. Consistent with this, localization of the outer plate constituent Ndc80HEC1 was severely reduced. The checkpoint protein BubR1, the fibrous corona component centromere protein (CENP) E, and the inner kinetochore proteins CENP-A and CENP-H also failed to accumulate to wild-type levels in depleted cells. These results indicate that a four-subunit Mis12 complex plays an essential role in chromosome segregation in vertebrates and contributes to mitotic kinetochore assembly.
Mcp5, a meiotic cell cortex protein, is required for nuclear movement mediated by dynein and microtubules in fission yeast
Authors: Saito Takamune T. , Okuzaki Daisuke , Nojima Hiroshi
Published: April 2006

During meiotic prophase I of the fission yeast Schizosaccharomyces pombe, oscillatory nuclear movement occurs. This promotes homologous chromosome pairing and recombination and involves cortical dynein, which plays a pivotal role by generating a pulling force with the help of an unknown dynein anchor. We show that Mcp5, the homologue of the budding yeast dynein anchor Num1, may be this putative dynein anchor. mcp5+ is predominantly expressed during meiotic prophase, and GFP-Mcp5 localizes at the cell cortex. Moreover, the mcp5Δ strain lacks the oscillatory nuclear movement. Accordingly, homologous pairing and recombination rates of the mcp5Δ strain are significantly reduced. Furthermore, the cortical localization of dynein heavy chain 1 appears to be reduced in mcp5Δ cells. Finally, the full function of Mcp5 requires its coiled-coil and pleckstrin homology (PH) domains. Our results suggest that Mcp5 localizes at the cell cortex through its PH domain and functions as a dynein anchor, thereby facilitating nuclear oscillation.
Suppression of experimental autoimmune encephalomyelitis by extracellular adherence protein of Staphylococcus aureus
Authors: Xie Changping , Alcaide Pilar , Geisbrecht Brian V. , Schneider Darius , Herrmann Mathias , Preissner Klaus T. , Luscinskas Francis W. , Chavakis Triantafyllos
Published: April 2006

Multiple sclerosis (MS) is a devastating inflammatory disorder of the central nervous system (CNS). A major hallmark of MS is the infiltration of T cells reactive against myelin components. T cell infiltration is mediated by the interaction of integrins of the β1 and β2 family expressed by lymphocytes with their endothelial counter-receptors, vascular cell adhesion molecule 1 and intercellular adhesion molecule (ICAM)-1, respectively. We have reported previously that extracellular adherence protein (Eap) of Staphylococcus aureus exerts antiinflammatory activities by interacting with ICAM-1 and blocking β2-integrin–dependent neutrophil recruitment. Here, we report that Eap inhibits experimental autoimmune encephalomyelitis (EAE) in mice. In vitro, Eap reduced adhesion of peripheral blood T cells to immobilized ICAM-1 as well as their adhesion and transmigration of TNF-activated human endothelium under static and shear flow conditions. These inhibitory effects were corroborated in two mouse models of inflammation. In a delayed-type hypersensitivity model, both T cell infiltration and the corresponding tissue edema were significantly reduced by Eap. In addition, Eap administration prevented the development of EAE and markedly decreased infiltration of inflammatory cells into the CNS. Strikingly, intervention with Eap after the onset of EAE suppressed the disease. Collectively, our findings indicate that Eap represents an attractive treatment for autoimmune neuroinflammatory disorders such as MS.
Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind aBorrelia burgdorferipeptide
Authors: Steere Allen C. , Klitz William , Drouin Elise E. , Falk Ben A. , Kwok William W. , Nepom Gerald T. , Baxter-Lowe Lee Ann
Published: April 2006

An association has previously been shown between antibiotic-refractory Lyme arthritis, the human histocompatibility leukocyte antigen (HLA)–DR4 molecule, and T cell recognition of an epitope of Borrelia burgdorferi outer-surface protein A (OspA163–175). We studied the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes in 121 patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis and correlated these frequencies with in vitro binding of the OspA163–175 peptide to 14 DRB molecules. Among the 121 patients, the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes were similar to those in control subjects. However, when stratified by antibiotic response, the frequencies of DRB1 alleles in the 71 patients with antibiotic-refractory arthritis differed significantly from those in the 50 antibiotic-responsive patients (log likelihood test, P = 0.006; exact test, P = 0.008; effect size, Wn = 0.38). 7 of the 14 DRB molecules (DRB1*0401, 0101, 0404, 0405, DRB5*0101, DRB1*0402, and 0102) showed strong to weak binding of OspA163–175, whereas the other seven showed negligible or no binding of the peptide. Altogether, 79% of the antibiotic-refractory patients had at least one of the seven known OspA peptide–binding DR molecules compared with 46% of the antibiotic-responsive patients (odds ratio = 4.4; P < 0.001). We conclude that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease.
Impact of the 2004-2005 Influenza Vaccine Shortage on Immunization Practices in Long-Term Care Facilities
Authors: Mody Lona , Langa Kenneth M. , Malani Preeti N.
Published: April 2006

Objective.

To assess the response of long-term care facilities (LTCFs) to the 2004-2005 influenza vaccine shortage and the impact on resident and healthcare worker (HCW) immunization rates.

Methods.

A 12-item questionnaire was sent to 824 randomly selected LTCFs in December 2004. The following 2 open-ended questions were also asked: “How did you cope with the vaccine shortage?” and “Who helped you get your supply?” Immunization rates reported by LTCF administrators for 2003-2003 and 2003-2004 were compared with those for 2004-2005. Immunization rates were defined as the proportion of all eligible residents and HCWs who received influenza vaccine.

Results.

Responses were received from 380 LTCFs (46.3%), which had a total of 38,447 beds. Resident mean influenza immunization rates (±SD) decreased from 85% ± 15.3% in 2002-2003 and 85.1% ± 15.3% in 2003-2004 to 81.9% ± 19.4% in the 2004-2005 influenza season (P = .025). The immunization rates among HCWs also decreased from 51% in 2002-2003 and 2003-2004 to 38.4% in 2004-2005 (P<.001). In response to one of the open-ended questions, 96 facilities (25.3%) reported that they obtained vaccine from 2 or more sources. Eight percent commented on specific intensified infection control efforts, and only 2.3% commented on emergency preparedness.

Conclusions.

The influenza vaccine shortage in 2004-2005 impacted immunization practices of LTCFs across the United States, leading to decreases in both resident and HCW vaccination rates. The significant decrease in vaccination rates in LTCFs is of concern and has broad implications for policy makers working on emergency preparedness for a possible pandemic of influenza.
Improving Antimicrobial Use in the Hospital Setting by Providing Usage Feedback to Prescribing Physicians
Authors: Arnold Forest W. , McDonald L. Clifford , Smith R. Scott , Newman David , Ramirez Julio A.
Published: April 2006

Objective.

To determine whether feedback on antimicrobial use improves physician compliance with local hospital guidelines on antimicrobial prescribing.

Design.

In this time series analysis, in which a historical control period was compared with an intervention period, all orders for antimicrobials (except those for surgical prophylaxis) placed from November 1, 2002, through April 30, 2004, were prospectively evaluated by an antimicrobial management team (AMT) for compliance with local hospital guidelines. During the control period, orders were evaluated to determine compliance with hospital guidelines before and after recommendations by the AMT were provided to physicians. Feedback was given for the second 9-month period in the form of a weekly report to prescribing physicians, a monthly hospital newsletter, and a quarterly report to various hospital committees. During the intervention period, orders were evaluated to determine compliance with hospital guidelines before and after recommendations by the AMT were provided to physicians.

Setting.

The Veterans Affairs Medical Center, a 110-bed facility, in Louisville, Kentucky.

Participants.

Internal medicine physicians and general surgeons.

Results.

A total of 2,807 antimicrobial courses were evaluated. Compliance with hospital guidelines before AMT recommendations was 70% during the control period and 74% during the intervention period (P= .02). Compliance after AMT recommendations was 90% during the control period and 93% during the intervention period (P≤ .01).

Conclusion.

The use of feedback had a significantly favorable impact on physician compliance with the hospital's guidelines on antimicrobial prescribing. Use of feedback should be added to the list of interventions that promote appropriate antimicrobial use in the hospital setting.