bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cost of Prostate Cancer Chemoprevention: A Decision Analysis Model
Authors: Svatek Robert S. , Lee J. Jack , Roehrborn Claus G. , Lippman Scott M. , Lotan Yair
Published: August 2006

Background: The Prostate Cancer Prevention Trial found reduced prostate cancer prevalence for men treated with finasteride. The public health cost of wide-scale chemoprevention is unclear. We developed a model to help clarify the cost effectiveness of public use of prostate cancer–preventive agents.

Methods: A Markov decision analysis model was designed to determine the lifetime prostate health-related costs, beginning at the age of 50 years, for men treated with finasteride compared with placebo. Model assumptions were based on data from the Prostate Cancer Prevention Trial, a literature review of survival and progression rates for patients treated with radical prostatectomy, and costs associated with prostate cancer disease states.

Results: Chemoprevention with finasteride resulted in a gain of 13.7 life years per 1,000 men at a cost of $704,000 per life year saved (LYS). However, if finasteride is assumed to not increase the incidence of high-grade tumors, it renders a gain of 21.4 life years per 1,000 men at a cost of $434,000 per LYS; finasteride must cost $15 monthly to reach $100,000 per LYS. When applied to a population at higher risk (lifetime prevalence of ≥30%) for developing prostate cancer, the cost of finasteride must be reduced from its current cost ($62/mo) to <$15 per month for the cost effectiveness to fall below $50,000 per LYS.

Conclusions: Given the natural history of treated prostate cancer, implementation of chemoprevention would require an inexpensive medication with substantial cancer risk reduction to be cost effective. Targeting populations at higher risk for developing prostate cancer, however, allows for considerable flexibility in the medication cost to make prostate cancer chemoprevention a more attainable goal. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1485–9)
Lung Cancer Chemoprevention: A Randomized, Double-Blind Trial in Linxian, China
Authors: Kamangar Farin , Qiao You-Lin , Yu Binbing , Sun Xiu-Di , Abnet Christian C. , Fan Jin-Hu , Mark Steven D. , Zhao Ping , Dawsey Sanford M. , Taylor Philip R.
Published: August 2006

We examined the effect of supplementation with four different combinations of vitamins and minerals in the prevention of lung cancer mortality among 29,584 healthy adults from Linxian, China. In accord with a partial factorial design, the participants were randomly assigned to take either a vitamin/mineral combination or a placebo for 5.25 years. The combinations tested in this trial were as follows: factor A, retinol and zinc; factor B, riboflavin and niacin; factor C, ascorbic acid and molybdenum; factor D, β-carotene, α-tocopherol, and selenium. Lung cancer deaths (n = 147) identified during the trial period (1986-1991) and 10 years after the trial ended (1991-2001) were the study outcome. No significant differences in lung cancer death rates were found for any of the four combinations of supplements tested in this study, using log-rank tests (all P values are >0.20) or Cox proportional hazards models adjusted for age, sex, commune, and other treatments. No significant interactions were seen for age, sex, or smoking status. Supplementation with combinations of vitamins and minerals at nutrient-repletion levels for 5.25 years did not reduce lung cancer mortality in this nutrient-inadequate population in Linxian, China. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1562–4)
Nox2, Ca
2+
, and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius
Authors: Wang Gang , Anrather Josef , Glass Michael J. , Tarsitano M. Jacqueline , Zhou Ping , Frys Kelly A. , Pickel Virginia M. , Iadecola Costantino
Published: August 2006

The dorsomedial portion of the nucleus tractus solitarius (dmNTS) is the site of termination of baroreceptor and cardiorespiratory vagal afferents and plays a critical role in cardiovascular regulation. Angiotensin II (Ang II) is a powerful signaling molecule in dmNTS neurons and exerts some of its biological effects by modulating Ca
2+
currents via reactive oxygen species (ROS) derived from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. We investigated whether a Nox2-containing NADPH oxidase is the source of the Ang II—induced ROS production and whether the signaling mechanisms of its activation require intracellular Ca
2+
or protein kinase C (PKC). Second-order dmNTS neurons were anterogradely labeled with 4-(4-[didecylamino]styryl)-
N
-methylpyridinium iodide transported from the vagus and isolated from the brain stem. ROS production was assessed in 4-(4-[didecylamino]styryl)-
N
-methylpyridinium iodide-positive dmNTS neurons using the fluorescent dye 6-carboxy-2′,7′-dichlorodihydro-fluorescein di(acetoxymethyl ester). Ang II (3 to 2000 nmol/L) increased ROS production in dmNTS neurons (EC
50
=38.3 nmol/L). The effect was abolished by the ROS scavenger Mn (III) porphyrin 5,10,20-tetrakis (benzoic acid) porphyrin manganese (III), the Ang II type 1 receptor antagonist losartan, or the NADPH oxidase inhibitors apocynin or gp91ds-tat. Ang II failed to increase ROS production or to potentiate L-type Ca
2+
currents in dmNTS neurons of mice lacking Nox2. The PKC inhibitor GF109203X or depletion of intracellular Ca
2+
attenuated Ang II-elicited ROS production. We conclude that the powerful effects of Ang II on Ca
2+
currents in dmNTS neurons are mediated by PKC activation leading to ROS production via Nox2. Thus, a Nox2-containing NADPH oxidase is the critical link between Ang II and the enhancement of Ca
2+
currents that underlie the actions of Ang II on central autonomic regulation.
Plaque Volume and Occurrence and Location of Periprocedural Myocardial Necrosis After Percutaneous Coronary Intervention
Authors: Porto Italo , Selvanayagam Joseph B. , Van Gaal William J. , Prati Francesco , Cheng Adrian , Channon Keith , Neubauer Stefan , Banning Adrian P.
Published: August 2006

Background—

Myocardial necrosis can occur during percutaneous coronary intervention (PCI) despite optimal adjunctive pharmacology and careful technique. We investigated the mechanisms of procedural infarction using angiographic analysis, intravascular ultrasound, and delayed-enhancement magnetic resonance imaging.

Methods and Results—

Fifty-two patients (64 vessels) who underwent complex PCI were studied. All patients were preloaded with clopidogrel and received glycoprotein IIb/IIIa inhibitors. “Adjacent” myonecrosis was defined as the presence of an area of new gadolinium hyperenhancement close to the stent. “Distal” myonecrosis was defined as situated at least 10 mm downstream from the stent. Fifteen vessels (23%) had evidence of new hyperenhancement after PCI. Of these, 8 (12%) had the distal type, and 7 (11%) had the adjacent type. Intravascular ultrasound showed a significantly greater reduction in plaque volume (91.6±51.5 versus 8±14 versus 20±35 mm
3
;
P
<0.001) in the group with distal hyperenhancement compared with patients without new hyperenhancement or adjacent hyperenhancement. In the entire sample, a significant correlation was seen between changes in plaque volume (ρ=0.58,
P
<0.001) after PCI and the mass of new necrosis measured by magnetic resonance imaging. Thrombolysis in Myocardial Infarction perfusion grade assessment of a closed microvasculature after PCI carried an odds ratio of 8.0 (95% confidence interval, 1.4 to 46.1;
P
=0.02) for the occurrence of hyperenhancement, whereas side-branch occlusion was associated with an odds ratio of 16.2 (95% confidence interval, 2.6 to 102.5;
P
=0.03). However, a closed microvasculature was associated with distal hyperenhancement (
P
=0.02), and side-branch occlusion was associated with adjacent hyperenhancement (
P
<0.001).

Conclusions—

These data suggest that distal embolization of plaque material occurs in contemporary PCI of native coronary arteries. Efforts to minimize procedural necrosis may require careful review of side branch anatomy and/or use of distal protection during extensive coronary stenting.
Orthostatic Hypotension Predicts Mortality in Middle-Aged Adults
Authors: Rose Kathryn M. , Eigenbrodt Marsha L. , Biga Rebecca L. , Couper David J. , Light Kathleen C. , Sharrett A. Richey , Heiss Gerardo
Published: August 2006

Background—

An association between orthostatic hypotension (OH) and mortality has been reported, but studies are limited to older adults or high-risk populations.

Methods and Results—

We investigated the association between OH (a decrease of 20 mm Hg in systolic blood pressure or a decrease of 10 mm Hg in diastolic blood pressure on standing) and 13-year mortality among middle-aged black and white men and women from the Atherosclerosis Risk in Communities Study (1987–1989). At baseline, 674 participants (5%) had OH. All-cause mortality was higher among those with (13.7%) than without (4.2%) OH. After we controlled for ethnicity, gender, and age, the hazard ratio (HR) for OH for all-cause mortality was 2.4 (95% confidence interval [CI], 2.1 to 2.8). Adjustment for risk factors for cardiovascular disease and mortality and selected health conditions at baseline attenuated but did not completely explain this association (HR=1.7; 95% CI, 1.4 to 2.0). This association persisted among subsets that (1) excluded those who died within the first 2 years of follow-up and (2) were limited to those without coronary heart disease, cancer, stroke, diabetes, hypertension, or fair/poor perceived health status at baseline. In analyses by causes of death, a significant increased hazard of death among those with versus without OH persisted after adjustment for risk factors for cardiovascular disease (HR=2.0; 95% CI, 1.6 to 2.7) and other deaths (HR=2.1; 95% CI, 1.6 to 2.8) but not for cancer (odds ratio=1.1; 95% CI, 0.8 to 1.6).

Conclusions—

OH predicts mortality in middle-aged adults. This association is only partly explained by traditional risk factors for cardiovascular disease and overall mortality.
Detection of Chronic Kidney Disease in Patients With or at Increased Risk of Cardiovascular Disease
Authors: Brosius Frank C. , Hostetter Thomas H. , Kelepouris Ellie , Mitsnefes Mark M. , Moe Sharon M. , Moore Michael A. , Pennathur Subramaniam , Smith Grace L. , Wilson Peter W.F.
Published: August 2006

Chronic kidney disease (CKD) occurs commonly in patients with cardiovascular disease. In addition, CKD is a risk factor for the development and progression of cardiovascular disease. In this advisory, we present recommendations for the detection of CKD in patients with cardiovascular disease. CKD can be reliably detected with the combined use of the Modification of Diet in Renal Disease equation to estimate glomerular filtration rate and a sensitive test to detect microalbuminuria. All patients with cardiovascular disease should be screened for evidence of kidney disease with these two determinations.
Adiponectin and Coronary Heart Disease
Authors: Sattar Naveed , Wannamethee Goya , Sarwar Nadeem , Tchernova Julia , Cherry Lynne , Wallace A. Michael , Danesh John , Whincup Peter H.
Published: August 2006

Background—

There is uncertainty about the association between circulating concentrations of adiponectin and coronary heart disease (CHD) risk. We report new data from a prospective study in the context of a meta-analysis of previously published prospective studies.

Methods and Results—

We measured baseline adiponectin levels in stored serum samples of 589 men with fatal CHD or nonfatal myocardial infarction and in 1231 controls nested within a prospective study of 5661 men (aged 40 to 59 years) recruited during 1978–1980, as well as in paired samples obtained 4 years apart from 221 of these participants. Baseline adiponectin concentrations correlated (
P
<0.0001) positively with HDL cholesterol (
r
=0.33) and inversely with C-reactive protein (
r
=−0.11) and BMI (
r
=−0.21), and the year-to-year consistency of adiponectin values was comparable to those of blood pressure and total cholesterol levels. No significant difference between median adiponectin levels at baseline was observed between cases and controls (10.2 versus 10.8 μg/mL;
P
=0.5), despite the fact that body mass index, HDL, and C-reactive protein were all significant predictors of events in this cohort. The odds ratio for CHD was 0.89 (95% CI, 0.67 to 1.18) in a comparison of men in the top third of adiponectin concentrations compared with those in the bottom third, similar to a meta-analysis (including the present study) of 7 prospective studies involving a total of 1318 CHD cases (odds ratio, 0.84 [95% CI, 0.70 to 1.01]).

Conclusions—

In contrast to the strong associations previously reported between adiponectin levels and risk of type 2 diabetes, any association with CHD risk is comparatively moderate and requires further investigation.
Quantitative Assessment of Left Ventricular Size and Function
Authors: Sugeng Lissa , Mor-Avi Victor , Weinert Lynn , Niel Johannes , Ebner Christian , Steringer-Mascherbauer Regina , Schmidt Frank , Galuschky Christian , Schummers Georg , Lang Roberto M. , Nesser Hans-Joachim
Published: August 2006

Background—

Cardiac CT (CCT) and real-time 3D echocardiography (RT3DE) are being used increasingly in clinical cardiology. CCT offers superb spatial and contrast resolution, resulting in excellent endocardial definition. RT3DE has the advantages of low cost, portability, and live 3D imaging without offline reconstruction. We sought to compare both CCT and RT3DE measurements of left ventricular size and function with the standard reference technique, cardiac MR (CMR).

Methods and Results—

In 31 patients, RT3DE data sets (Philips 7500) and long-axis CMR (Siemens, 1.5 T) and CCT (Toshiba, 16-slice MDCT) images were obtained on the same day without β-blockers. All images were analyzed to obtain end-systolic and end-diastolic volumes and ejection fractions using the same rotational analysis to eliminate possible analysis-related differences. Intertechnique agreement was tested through linear regression and Bland-Altman analyses. Repeated measurements were performed to determine intraobserver and interobserver variability. Both CCT and RT3DE measurements resulted in high correlation (
r
2
>0.85) compared with CMR. However, CCT significantly overestimated end-diastolic and end-systolic volumes (26 and 19 mL;
P
<0.05), resulting in a small but significant bias in ejection fraction (−2.8%). RT3DE underestimated end-diastolic and end-systolic volumes only slightly (5 and 6 mL), with no significant bias in EF (0.3%;
P
=0.68). The limits of agreement with CMR were comparable for the 2 techniques. The variability in the CCT measurements was roughly half of that in either RT3DE or CMR values.

Conclusions—

CCT provides highly reproducible measurements of left ventricular volumes, which are significantly larger than CMR values. RT3DE measurements compared more favorably with the CMR reference, albeit with higher variability.
Molecular Determinants of Altered Ca
2+
Handling in Human Chronic Atrial Fibrillation
Authors: El-Armouche Ali , Boknik Peter , Eschenhagen Thomas , Carrier Lucie , Knaut Michael , Ravens Ursula , Dobrev Dobromir
Published: August 2006

Background—

Abnormal Ca
2+
handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca
2+
handling and contractility in cAF patients.

Methods and Results—

Total and phosphorylation levels of Ca
2+
-handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca
2+
-calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35–phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1.

Conclusions—

Altered Ca
2+
handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum–associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.
No Place to Hide: Refugees, Displaced Persons, and the Recruitment of Child Soldiers
Authors: Achvarina Vera , Reich Simon F.
Published: August 2006

The global number of child soldiers has grown significantly in the last two decades despite a series of protocols designed to curb this trend. They are generally employed in wars where belligerents spend more time attacking civilian populations than fighting professional armies. Used by both governments and rebel groups, child soldiers epitomize many of the problems associated with states at risk: intergenerational violence, poverty, and the failure of efforts to instill the rule of war. Both scholars in security studies and policymakers have largely regarded child soldier recruitment as a humanitarian issue. But recent events have linked child soldiering to insurgency and terrorism, suggesting that this issue is also developing a security dimension. This article examines contrasting arguments about the causes of child soldiering. Using data drawn from nineteen African conflicts, the authors argue that the major explanation for the significant variation in the percentage of child soldiers recruited is the degree of protection against abduction provided by governments and external actors to camps housing internally displaced persons and refugees.
How al-Qaida Ends: The Decline and Demise of Terrorist Groups
Authors: Cronin Audrey Kurth
Published: August 2006

Al-Qaida will end. The fear that a small terrorist organization with a loose network has transformed itself into a protracted global ideological struggle without an end in sight is misguided. There are centuries of experience with modern terrorist movements, many bearing important parallels with al-Qaida; yet the lessons arising from the demise of these groups are little studied. Unfortunately, terrorist organizations in their final stages are often at their most dangerous. The outcomes can range from implosion of a group and its cause to transition to astonishing acts of violence and interstate war. Comparing al-Qaida's differences and similarities with those of earlier terrorist organizations, and applying relevant lessons to this case, can provide insights into al-Qaida's likely demise. It can also inform thinking about how to manage and hasten al-Qaida's end.
Watered Down
Authors: Tartaro Christine
Published: August 2006

Podular direct-supervision jails, also known as new generation jails, are a radical departure from the design and management strategy of traditional institutions. These facilities provide a normalized physical environment plus a proactive supervision and management strategy in an attempt to provide a safer and more comfortable living environment than what has historically been found in jails. Are these jails truly different from traditional facilities? The current article presents the results of a national survey of new generation jails conducted in 2004. Results of the data analysis indicate that many of these jails are not including important components of the new generation jail model, such as a normalized living environment, in their facilities.
The Criminal Offending–Self-Esteem Nexus
Authors: Oser Carrie B.
Published: August 2006

Traditionalists regard crime to be associated with low self-esteem. A second body of literature suggests a rival hypothesis supporting a relationship between crime and high self-esteem. A multivariate model explored this nexus by examining the impact of demographic characteristics, criminal history, personality traits, and participation in prison programming on self-esteem levels of 134 inmates in two medium-security prisons. Results support the relationship between crime and low self-esteem, with state-raised convicts reporting lower self-esteem levels. In addition, inmates who are emotionally stable, who are less open to novel experiences, and who have participated in counseling or education during incarceration manifest higher self-esteem.
An Evaluation of the Federal Government’s Violent Offender Incarceration and Truth-in-Sentencing Incentive Grants
Authors: Turner Susan , Greenwood Peter W. , Fain Terry , Chiesa James R.
Published: August 2006

The 1994 Crime Act authorized $10 billion through fiscal year 2000 to help states expand prison space for violent offenders, provided states had truth-in-sentencing (TIS) laws. Few states enacted new TIS statutes to qualify for funding; only $2.7 million actually reached the states. By the end of fiscal year 1999, more than 50,000 new beds had been added using violent offender incarceration (VOI) and TIS funds, a capacity increase of around 4%. TIS did not increase incarcerations per violent crime committed. The percentage of sentence served by released violent offenders has increased since 1993 for both TIS and non-TIS states. By fiscal year 2002, VOI/TIS funding was discontinued.
Research on Well-Being
Authors: Collard David
Published: August 2006

Jeremy Bentham provided a comprehensive list of the sources of pleasure and pain, rather in the manner of modern researchers into human well-being. He explicitly used the term well-being and made both qualitative and quantitative proposals for its measurement. Bentham insisted that the measurement of well-being should be firmly based on the concerns and subjective valuations of those directly concerned, in the context of a liberal society. Those who wished to superimpose other judgements were dismissed as “ipsedixitists.” He also addressed, though of course could not solve, some of the measurement problems more recently tackled by “neo-Benthamites.” The paper concludes that many of Bentham’s observations about the measurement of well-being are still relevant to issues in current research.
Exposure of neonates to Respiratory Syncytial Virus is critical in determining subsequent airway response in adults
Authors: You Dahui , Becnel David , Wang Kai , Ripple Michael , Daly Melissa , Cormier Stephania A
Published: August 2006

Background

Respiratory syncytial virus (RSV) is the most common cause of acute bronchiolitis in infants and the elderly. Furthermore, epidemiological data suggest that RSV infection during infancy is a potent trigger of subsequent wheeze and asthma development. However, the mechanism by which RSV contributes to asthma is complex and remains largely unknown. A recent study indicates that the age of initial RSV infection is a key factor in determining airway response to RSV rechallenge. We hypothesized that severe RSV infection during neonatal development significantly alters lung structure and the pulmonary immune micro-environment; and thus, neonatal RSV infection is crucial in the development of or predisposition to allergic inflammatory diseases such as asthma.

Methods

To investigate this hypothesis the present study was conducted in a neonatal mouse model of RSV-induced pulmonary inflammation and airway dysfunction. Seven-day-old mice were infected with RSV (2 × 105TCID50/g body weight) and allowed to mature to adulthood. To determine if neonatal RSV infection predisposed adult animals to enhanced pathophysiological responses to allergens, these mice were then sensitized and challenged with ovalbumin. Various endpoints including lung function, histopathology, cytokine production, and cellularity in bronchoalveolar lavage were examined.

Results

RSV infection in neonates alone led to inflammatory airway disease characterized by airway hyperreactivity, peribronchial and perivascular inflammation, and subepithelial fibrosis in adults. If early RSV infection was followed by allergen exposure, this pulmonary phenotype was exacerbated. The initial response to neonatal RSV infection resulted in increased TNF-α levels in bronchoalveolar lavage. Interestingly, increased levels of IL-13 and mucus hyperproduction were observed almost three months after the initial infection with RSV.

Conclusion

Neonatal RSV exposure results in long term pulmonary inflammation and exacerbates allergic airways disease. The early increase in TNF-α in the bronchoalveolar lavage implicates this inflammatory cytokine in orchestrating these events. Finally, the data presented emphasize IL-13 and TNF-α as potential therapeutic targets for treating RSV induced-asthma.
UniFrac – An online tool for comparing microbial community diversity in a phylogenetic context
Authors: Lozupone Catherine , Hamady Micah , Knight Rob
Published: August 2006

Background

Moving beyond pairwise significance tests to compare many microbial communities simultaneously is critical for understanding large-scale trends in microbial ecology and community assembly. Techniques that allow microbial communities to be compared in a phylogenetic context are rapidly gaining acceptance, but the widespread application of these techniques has been hindered by the difficulty of performing the analyses.

Results

We introduce UniFrac, a web application available athttp://bmf.colorado.edu/unifrac, that allows several phylogenetic tests for differences among communities to be easily applied and interpreted. We demonstrate the use of UniFrac to cluster multiple environments, and to test which environments are significantly different. We show that analysis of previously published sequences from the Columbia river, its estuary, and the adjacent coastal ocean using the UniFrac interface provided insights that were not apparent from the initial data analysis, which used other commonly employed techniques to compare the communities.

Conclusion

UniFrac provides easy access to powerful multivariate techniques for comparing microbial communities in a phylogenetic context. We thus expect that it will provide a completely new picture of many microbial interactions and processes in both environmental and medical contexts.
Distinct differentiation characteristics of individual human embryonic stem cell lines
Authors: Mikkola Milla , Olsson Cia , Palgi Jaan , Ustinov Jarkko , Palomaki Tiina , Horelli-Kuitunen Nina , Knuutila Sakari , Lundin Karolina , Otonkoski Timo , Tuuri Timo
Published: August 2006

Background

Individual differences between human embryonic stem cell (hESC) lines are poorly understood. Here, we describe the derivation of five hESC lines (called FES 21, 22, 29, 30 and 61) from frozen-thawed human embryos and compare their individual differentiation characteristic.

Results

The cell lines were cultured either on human or mouse feeder cells. The cells grew significantly faster and could be passaged enzymatically only on mouse feeders. However, this was found to lead to chromosomal instability after prolonged culture. All hESC lines expressed the established markers of pluripotent cells as well as several primordial germ cell (PGC) marker genes in a uniform manner. However, the cell lines showed distinct features in their spontaneous differentiation patterns. The embryoid body (EB) formation frequency of FES 30 cell line was significantly lower than that of other lines and cells within the EBs differentiated less readily. Likewise, teratomas derived from FES 30 cells were constantly cystic and showed only minor solid tissue formation with a monotonous differentiation pattern as compared with the other lines.

Conclusion

hESC lines may differ substantially in their differentiation properties although they appear similar in the undifferentiated state.
Differences in the evolutionary history of disease genes affected by dominant or recessive mutations
Authors: Furney Simon J , Albà M Mar , López-Bigas Núria
Published: August 2006

Background

Global analyses of human disease genes by computational methods have yielded important advances in the understanding of human diseases. Generally these studies have treated the group of disease genes uniformly, thus ignoring the type of disease-causing mutations (dominant or recessive). In this report we present a comprehensive study of the evolutionary history of autosomal disease genes separated by mode of inheritance.

Results

We examine differences in protein and coding sequence conservation between dominant and recessive human disease genes. Our analysis shows that disease genes affected by dominant mutations are more conserved than those affected by recessive mutations. This could be a consequence of the fact that recessive mutations remain hidden from selection while heterozygous. Furthermore, we employ functional annotation analysis and investigations into disease severity to support this hypothesis.

Conclusion

This study elucidates important differences between dominantly- and recessively-acting disease genes in terms of protein and DNA sequence conservation, paralogy and essentiality. We propose that the division of disease genes by mode of inheritance will enhance both understanding of the disease process and prediction of candidate disease genes in the future.
Regulatory role of pro-Th1 and pro-Th2 cytokines in modulating the activity of Th1 and Th2 cells when B cell and macrophages are used as antigen presenting cells
Authors: Singh Vinod , Agrewala Javed N
Published: August 2006

Background

Presence of antigen presenting cells, expression of costimulatory molecules, the strength of first signal and cytokine milieu are quite important in influencing the reactivation of differentiated Th1 and Th2 cells.

Results

In the present study, we have analyzed the concerted action of pro-Th1 and pro-Th2 cytokines in the presence of B cells, peritoneal and splenic macrophages as antigen presenting cells and varied concentration of first (anti-CD3 Ab) and second (B7-1 transfectant) signals on the proliferation and cytokine secretion by Th1 and Th2 cells. Interesting observations were made that IFN-γ significantly augmented the secretion of IL-4 by Th2 cells when either B cells or splenic or peritoneal macrophages were used as APC. Further, IFN-γ significantly inhibited the proliferation of Th1 cells only in the presence of peritoneal macrophages. We have also observed that B cells could significantly respond to cytokines to further enhance the proliferation and cytokine release by Th1 and Th2 cells. But not much effect on addition of exogenous cytokines IL-1, IL-4, IL-5, IL-12 was observed on the proliferation of Th1 and Th2 cells in the presence of macrophages. In contrast, both IFN-γ and IL-2 significantly enhanced the production of IL-4 and IL-5 respectively, by Th2 cells in presence of B cells, splenic and peritoneal macrophages. Another important observation was that the addition of B7-1 transfectants in the cultures, which were stimulated with low dose of anti-CD3 Ab significantly, enhanced the proliferation and cytokine secretion.

Conclusion

This study indicates involvement of different type of APCs, cytokine milieu, dose of first and second signals in a concerted manner in the outcome of the immune response. The significance of this study is that the immunization with antigen along with costimulatory molecules may significantly reduce the dose of antigen and can generate better immune response than antigen alone.
Characterization of the mrgRS locus of the opportunistic pathogen Burkholderia pseudomallei: temperature regulates the expression of a two-component signal transduction system
Authors: Mahfouz Magdy E , Grayson T Hilton , Dance David AB , Gilpin Martyn L
Published: August 2006

Background

Burkholderia pseudomallei is a saprophyte in tropical environments and an opportunistic human pathogen. This versatility requires a sensing mechanism that allows the bacterium to respond rapidly to altered environmental conditions. We characterized a two-component signal transduction locus from B. pseudomallei 204, mrgR and mrgS, encoding products with extensive homology with response regulators and histidine protein kinases of Escherichia coli, Bordetella pertussis, and Vibrio cholerae.

Results

The locus was present and expressed in a variety of B. pseudomallei human and environmental isolates but was absent from other Burkholderia species, B. cepacia, B. cocovenenans, B. plantarii, B. thailandensis, B. vandii, and B. vietnamiensis. A 2128 bp sequence, including the full response regulator mrgR, but not the sensor kinase mrgS, was present in the B. mallei genome. Restriction fragment length polymorphism downstream from mrgRS showed two distinct groups were present among B. pseudomallei isolates. Our analysis of the open reading frames in this region of the genome revealed that transposase and bacteriophage activity may help explain this variation. MrgR and MrgS proteins were expressed in B. pseudomallei 204 cultured at different pH, salinity and temperatures and the expression was substantially reduced at 25°C compared with 37°C or 42°C but was mostly unaffected by pH or salinity, although at 25°C and 0.15% NaCl a small increase in MrgR expression was observed at pH 5. MrgR was recognized by antibodies in convalescent sera pooled from melioidosis patients.

Conclusion

The results suggest that mrgRS regulates an adaptive response to temperature that may be essential for pathogenesis, particularly during the initial phases of infection. B. pseudomallei and B. mallei are very closely related species that differ in their capacity to adapt to changing environmental conditions. Modifications in this region of the genome may assist our understanding of the reasons for this difference.
Anticancer drug clustering in lung cancer based on gene expression profiles and sensitivity database
Authors: Gemma Akihiko , Li Cai , Sugiyama Yuka , Matsuda Kuniko , Seike Yoko , Kosaihira Seiji , Minegishi Yuji , Noro Rintaro , Nara Michiya , Seike Masahiro , Yoshimura Akinobu , Shionoya Aki , Kawakami Akiko , Ogawa Naoki , Uesaka Haruka , Kudoh Shoji
Published: August 2006

background

The effect of current therapies in improving the survival of lung cancer patients remains far from satisfactory. It is consequently desirable to find more appropriate therapeutic opportunities based on informed insights. A molecular pharmacological analysis was undertaken to design an improved chemotherapeutic strategy for advanced lung cancer.

Methods

We related the cytotoxic activity of each of commonly used anti-cancer agents (docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-FU, SN38, cisplatin (CDDP), and carboplatin (CBDCA)) to corresponding expression pattern in each of the cell lines using a modified NCI program.

Results

We performed gene expression analysis in lung cancer cell lines using cDNA filter and high-density oligonucleotide arrays. We also examined the sensitivity of these cell lines to these drugs via MTT assay. To obtain our reproducible gene-drug sensitivity correlation data, we separately analyzed two sets of lung cancer cell lines, namely 10 and 19. In our gene-drug correlation analyses, gemcitabine consistently belonged to an isolated cluster in a reproducible fashion. On the other hand, docetaxel, paclitaxel, 5-FU, SN-38, CBDCA and CDDP were gathered together into one large cluster.

Conclusion

These results suggest that chemotherapy regimens including gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Gene expression-drug sensitivity correlations, as provided by the NCI program, may yield improved therapeutic options for treatment of specific tumor types.
Effects of polymorphisms in ERCC1, ASE-1 and RAIon the risk of colorectal carcinomas and adenomas: a case control study
Authors: Skjelbred Camilla F , Sæbø Mona , Nexø Bjørn A , Wallin Håkan , Hansteen Inger-Lise , Vogel Ulla , Kure Elin H
Published: August 2006

Background

The risk of sporadic colorectal cancer is mainly associated with lifestyle factors and may be modulated by several genetic factors of low penetrance. Genetic variants represented by single nucleotide polymorphisms in genes encoding key players in the adenoma carcinoma sequence may contribute to variation in susceptibility to colorectal cancer. In this study, we aimed to evaluate whether the recently identified haplotype encompassing genes of DNA repair and apoptosis, is associated with increased risk of colorectal adenomas and carcinomas.

Methods

We used a case-control study design (156 carcinomas, 981 adenomas and 399 controls) to test the association between polymorphisms in the chromosomal region 19q13.2-3, encompassing the genes ERCC1, ASE-1 and RAI, and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR) and 95% confidence interval (CI) were estimated by binary logistic regression model adjusting for age and gender.

Results

The ASE-1 polymorphism was associated with an increased risk of adenomas, OR of 1.39 (95% CI 1.06–1.81), which upon stratification was apparent among women only, OR of 1.66 (95% CI 1.15–2.39). The RAI polymorphism showed a trend towards risk reduction for both adenomas (OR of 0.70, 95% CI 0.49–1.01) and carcinomas (OR of 0.49, 95% CI 0.21–1.13) among women, although not significant. Women who were homozygous carriers of the high risk haplotype had an increased risk of colorectal cancer, OR of 2.19 (95% CI 0.95–5.04) compared to all non-carriers although the estimate was not statistically significant.

Conclusion

We found no evidence that the studied polymorphisms were associated with risk of adenomas or colorectal cancer among men, but we found weak indications that the chromosomal region may influence risk of colorectal cancer and adenoma development in women.
Comorbidity in patients with diabetes mellitus: impact on medical health care utilization
Authors: Struijs Jeroen N , Baan Caroline A , Schellevis Francois G , Westert Gert P , van den Bos Geertrudis AM
Published: August 2006

Background

Comorbidity has been shown to intensify health care utilization and to increase medical care costs for patients with diabetes. However, most studies have been focused on one health care service, mainly hospital care, or limited their analyses to one additional comorbid disease, or the data were based on self-reported questionnaires instead of health care registration data. The purpose of this study is to estimate the effects a broad spectrum of of comorbidities on the type and volume of medical health care utilization of patients with diabetes.

Methods

By linking general practice and hospital based registrations in the Netherlands, data on comorbidity and health care utilization of patients with diabetes (n = 7,499) were obtained. Comorbidity was defined as diabetes-related comorbiiabetes-related comorbidity. Multilevel regression analyses were applied to estimate the effects of comorbidity on health care utilization.

Results

Our results show that both diabetes-related and non diabetes-related comorbidity increase the use of medical care substantially in patients with diabetes. Having both diabeterelated and non diabetes-related comorbidity incrases the demand for health care even more. Differences in health care utilization patterns were observed between the comorbidities.

Conclusion

Non diabetes-related comorbidity increases the health care demand as much as diabetes-related comorbidity. Current single-disease approach of integrated diabetes care should be extended with additional care modules, which must be generic and include multiple diseases in order to meet the complex health care demands of patients with diabetes in the future.
Mapping oral health related quality of life to generic health state values
Authors: Brennan David S , Spencer A John
Published: August 2006

Background

A summary utility index is useful for deriving quality-adjusted life years (QALY) for cost analyses or disability weights for burden of disease studies. However, many quality of life instruments provide descriptive profiles rather than a single utility index. Transforming quality of life instruments to a utility index could extend the use of quality of life instruments to costs analyses and burden of disease studies. The aims of the study were to map a specific oral health measure, the Oral Health Impact Profile to a generic health state measure, the EuroQol, in order to enable the estimation of health state values based on OHIP data.

Methods

Data were collected from patients treated by a random sample of South Australian dentists in 2001–02 using mailed self-complete questionnaires. Dentists recorded the diagnosis of dental conditions and provided patients with self-complete questionnaires to record the nature, severity and duration of symptoms using the EuroQol (EQ-5D) and 14-item version of the Oral Health Impact Profile (OHIP-14) instruments. Data were available from 375 patients (response rate = 72%). A random two-thirds sample of patients was used in tobit regressions of EQ-5D health state values estimated using OHIP-14 in a model with categories of OHIP responses as indicator variables and in a model with OHIP responses as continuous variables. Age and sex were included as covariates in both models. The remaining one-third sample of patients was used to test the models.

Results

The OHIP item 'painful aching in mouth' was significantly related to health state values in both models while 'life less satisfying' was also significant in the continuous model. Mean forecast errors relative to the mean observed health state value were higher when fitted to the categorical model (17.4%) compared to the continuous model (15.2%) (P < 0.05).

Conclusion

The findings enable health state values to be derived from OHIP-14 scores for populations where utility has not or cannot be measured directly.
The chaperone DnaK controls the fractioning of functional protein between soluble and insoluble cell fractions in inclusion body-forming cells
Authors: González-Montalbán Nuria , García-Fruitós Elena , Ventura Salvador , Arís Anna , Villaverde Antonio
Published: August 2006

Background

The molecular mechanics of inclusion body formation is still far from being completely understood, specially regarding the occurrence of properly folded, protein species that exhibit natural biological activities. We have here comparatively explored thermally promoted,in vivoprotein aggregation and the formation of bacterial inclusion bodies, from both structural and functional sides. Also, the status of the soluble and insoluble protein versions in both aggregation systems have been examined as well as the role of the main molecular chaperones GroEL and DnaK in the conformational quality of the target polypeptide.

Results

While thermal denaturation results in the formation of heterogeneous aggregates that are rather stable in composition, protein deposition as inclusion bodies renders homogenous but strongly evolving structures, which are progressively enriched in the main protein species while gaining native-like structure. Although both type of aggregates display common features, inclusion body formation but not thermal-induced aggregation involves deposition of functional polypeptides that confer biological activity to such particles, at expenses of the average conformational quality of the protein population remaining in the soluble cell fraction. In absence of DnaK, however, the activity and conformational nativeness of inclusion body proteins are dramatically impaired while the soluble protein version gains specific activity.

Conclusion

The chaperone DnaK controls the fractioning of active protein between soluble and insoluble cell fractions in inclusion body-forming cells but not during thermally-driven protein aggregation. This cell protein, probably through diverse activities, is responsible for the occurrence and enrichment in inclusion bodies of native-like, functional polypeptides, that are much less represented in other kind of protein aggregates.
Clear cell sarcoma of the scapula. A case report and review of the literature
Authors: Kazakos Constantinos J , Galanis Vasilios G , Giatromanolaki Alexandra , Verettas Dennis-Alexander J , Sivridis Efthimios
Published: August 2006

Background

Clear cell sarcoma of tendons and aponeuroses (CCSTA) appears usually in the extremities and rarely in the trunk.

Case presentation

We present an unusual case of CCSTA overlying the scapular region and with secondary osseous extension in the lower scapula. The patient underwent a wide local excision with removal of the tumor and the lower two thirds of the scapula. He had no local recurrences but he developed lung metastases after 5 months in spite of postoperative chemotherapy. He finally died ten months later.

Conclusion

The patients with CCSTA have a variable unpredictable course. Despite treatment the overall prognosis is poor.
Effects of dopexamine on the intestinal microvascular blood flow and leucocyte activation in a sepsis model in rats
Authors: Birnbaum Jürgen , Klotz Edda , Spies Claudia D , Lorenz Björn , Stuebs Patrick , Hein Ortrud Vargas , Gründling Matthias , Pavlovic Dragan , Usichenko Taras , Wendt Michael , Kox Wolfgang J , Lehmann Christian
Published: August 2006

Introduction

Dopexamine may be a therapeutic option to improve hepatosplanchnic perfusion in sepsis. To investigate this possibility, we administered dopexamine in an experimental sepsis model in rats.

Methods

This prospective, randomized, controlled laboratory study was conducted in 42 Wistar rats. The animals were divided into three groups. Group 1 served as the control group (CON group). The animals in both groups 2 (LPS group) and 3 (DPX group) received an endotoxin (lipopolysaccharide from Escherichia coli – LPS) infusion (20 mg/kg for 15 minutes). DPX group additionally received dopexamine (0.5 μg/kg per minute over four hours). One half of the animals in each group underwent studies of intestinal microvascular blood flow (IMBF) using laser Doppler fluxmetry. In the other half an intravital microscopic evaluation of leucocyte-endothelial cell interaction in intestinal microcirculation was conducted. Functional capillary density (FCD) in the intestinal mucosa and in the circular as well as longitudinal muscle layer was estimated.

Results

One hour after endotoxin challenge, IMBF decreased significantly in LPS group to 51% compared with baseline (P < 0.05). In DPX group (endotoxin plus dopexamine) we found IMBF values significantly higher than those in LPS group (approximately at the level of controls). The impaired FCD following endotoxin challenge was improved by dopexamine in the longitudinal muscle layer (+33% in DPX group versus LPS group; P < 0.05) and in the circular muscle layer (+48% in DPX group versus LPS group; P < 0.05). In DPX group, dopexamine administration reduced the number of firmly adherent leucocytes (-31% versus LPS group; P < 0.05). Plasma levels of tumour necrosis factor-α were reduced by dopexamine infusion (LPS group: 3637 ± 553 pg/ml; DPX group: 1933 ± 201 pg/ml) one hour after endotoxin challenge.

Conclusion

Dopexamine administration improved IMBF and FCD (markers of intestinal microcirculation) and reduced leucocyte activation (a marker of inflammation) in experimental sepsis.