bluuebunny/crossref_metadata_2025 huggingface dataset:
The pattern of mucocutaneous disorders in HIV – infected children attending care and treatment centres in Dar es Salaam, Tanzania
Authors: Panya Millembe F , Mgonda Yassin M , Massawe Augustine W
Published: July 2009

Background

HIV/AIDS is associated with a wide range of mucocutaneous disorders some of which are useful in the clinical staging and prognosis of the syndrome. There is paucity of information regarding the prevalence and pattern of mucocutaneous disorders among HIV infected children attending paediatric Care and Treatment Centres (CTC) in Dar es Salaam. Objective To determine the prevalence and pattern of mucocutaneous disorders among HIV infected children attending public paediatric 'Care and Treatment Centres' in Dar es Salaam.

Methods

This was a cross sectional descriptive study involving public paediatric 'Care and Treatment Centres' in Dar es Salaam. Clinical information was obtained using a questionnaire. Dermatological examination was carried out in daylight. Investigations were taken as appropriate. Data was analysed using the Statistical Package for Social Sciences (SPSS) program version 10.0. Chi-squared and Fisher's exact tests were utilized. A p-value of less than 0.05 was considered statistically significant.

Results

Three hundred and forty seven HIV infected children (52% males) attending CTCs were recruited into the study. Mucocutaneous disorders were encountered in 85% of them. There was no gender difference in the prevalence of the infective mucocutaneous disorders but males had a higher prevalence of non-infective/inflammatory dermatoses (58%) than females (42%) (p = 0.02). Overall, mucocutaneous disorders (infective + non infective) were more prevalent in advanced stages of HIV disease. Children with advanced HIV disease had a significantly increased frequency of fungal and viral infections (43% and 25% respectively than those with less advanced disease; 24% and 13% respectively (p = 0.01). Seventy four percent of the HIV-infected children with mucocutaneous disorders were already on ART.

Conclusion

Mucocutaneous disorders among HIV infected children attending Care and Treatment Centres are common and highly variable. Comprehensive management should also emphasize on the management of mucocutaneous disorders.
Delay in the diagnosis of tuberculosis in Nepal
Authors: Basnet Rajendra , Hinderaker Sven Gudmund , Enarson Don , Malla Pushpa , Mørkve Odd
Published: July 2009

Background

Identifying reasons for delay in diagnosis and treatment of tuberculosis is important for the health system to find ways to treat patients as early as possible, and hence reduce the suffering of patients and transmission of the disease. The objectives of this study was to assess the duration of delay in the diagnosis of tuberculosis and to investigate its determinants.

Methods

A cross-sectional survey was conducted using a structured questionnaire in 307 new tuberculosis patients registered by the National Tuberculosis Programme (NTP) in all DOTS centres in Banke district of Nepal.

Results

The median patient delay was 50 days, the median health system delay was 18 days, and the median total delay was 60 days. Sputum smear negative participants had significantly lower risk of patient delay. Smokers using >5 cigarettes per day had higher risk of patient delay and health system delay.

Conclusion

Total delay in the diagnosis of tuberculosis in Banke district is shorter compared to other places in Nepal and neighbouring countries. The shorter delay for smear negative pulmonary tuberculosis raises suspicion that many of these patients are not examined according to the NTP manual before being diagnosed. Increasing public awareness of the disease and expansion of the facilities with assured quality could be helpful to reduce the delay in the diagnosis of tuberculosis.
Spatio-temporal cluster analysis of county-based human West Nile virus incidence in the continental United States
Authors: Sugumaran Ramanathan , Larson Scott R , DeGroote John P
Published: July 2009

Background

West Nile virus (WNV) is a vector-borne illness that can severely affect human health. After introduction on the East Coast in 1999, the virus quickly spread and became established across the continental United States. However, there have been significant variations in levels of human WNV incidence spatially and temporally. In order to quantify these variations, we used Kulldorff's spatial scan statistic and Anselin's Local Moran's I statistic to uncover spatial clustering of human WNV incidence at the county level in the continental United States from 2002–2008. These two methods were applied with varying analysis thresholds in order to evaluate sensitivity of clusters identified.

Results

The spatial scan and Local Moran's I statistics revealed several consistent, important clusters or hot-spots with significant year-to-year variation. In 2002, before the pathogen had spread throughout the country, there were significant regional clusters in the upper Midwest and in Louisiana and Mississippi. The largest and most consistent area of clustering throughout the study period was in the Northern Great Plains region including large portions of Nebraska, South Dakota, and North Dakota, and significant sections of Colorado, Wyoming, and Montana. In 2006, a very strong cluster centered in southwest Idaho was prominent. Both the spatial scan statistic and the Local Moran's I statistic were sensitive to the choice of input parameters.

Conclusion

Significant spatial clustering of human WNV incidence has been demonstrated in the continental United States from 2002–2008. The two techniques were not always consistent in the location and size of clusters identified. Although there was significant inter-annual variation, consistent areas of clustering, with the most persistent and evident being in the Northern Great Plains, were demonstrated. Given the wide variety of mosquito species responsible and the environmental conditions they require, further spatio-temporal clustering analyses on a regional level is warranted.
Immunohistochemical study of the phenotypic change of the mesenchymal cells during portal tract maturation in normal and fibrous (ductal plate malformation) fetal liver
Authors: Villeneuve Julien , Pelluard-Nehme Fanny , Combe Chantal , Carles Dominique , Chaponnier Christine , Ripoche Jean , Balabaud Charles , Bioulac-Sage Paulette , Lepreux Sébastien
Published: July 2009

Background

In adult liver, the mesenchymal cells, portal fibroblasts and vascular smooth muscle cells can transdifferentiate into myofibroblasts, and are involved in portal fibrosis. Differential expression of markers, such as alpha-smooth muscle actin (ASMA), h-caldesmon and cellular retinol-binding protein-1 allows their phenotypic discrimination. The aim of our study was to explore the phenotypic evolution of the mesenchymal cells during fetal development in normal liver and in liver with portal fibrosis secondary to ductal plate malformation in a series of Meckel-Gruber syndrome, autosomal recessive polycystic kidney disease and Ivemark's syndrome.

Results

At the early steps of the portal tract maturation, portal mesenchymal cells expressed only ASMA. During the maturation process, these cells were found condensed around the biliary and vascular structures. At the end of maturation process, only cells around vessels expressed ASMA and cells of the artery tunica media also expressed h-caldesmon. In contrast, ASMA positive cells persisted around the abnormal biliary ducts in fibrous livers.

Conclusion

As in adult liver, there is a phenotypic heterogeneity of the mesenchymal cells during fetal liver development. During portal tract maturation, myofibroblastic cells disappear in normal development but persist in fibrosis following ductal plate malformation.
Employment and sociodemographic characteristics: a study of increasing precarity in the health districts of Belo Horizonte, Brazil
Authors: Coelho Maria Cristina Ramos de Vasconcello , Assunção Ada Ávila , Belisário Soraya Almeida
Published: July 2009

Background

The fundamental importance of human resources for the development of health care systems is recognized the world over. Health districts, which constitute the middle level of the municipal health care system in the city of Belo Horizonte, Brazil, deal with demands from all parts of the system. This research seeks to provide the essential features required in order to understand the phenomenon of increase in precarity of employment in these health districts.

Methods

The legal and human resource management documents used by the Municipal Health Secretariat of the City of Belo Horizonte were adopted as the corpus for this research. In order to analyse the changes in employment (2002–2006), the data were collected from ArteRH, a computerized database dealing specifically with data related to human resources, which began operating in 2001. The workers were classified into permanent and non-permanent groups, and their contractual rights were described. Employment dynamics and changes were examined, concentrating on the incorporation of workers and on their social and employment rights during the period under study. The comparative data for the two groups obtained were presented in frequency distribution tables according to type of employment, sex, age group, level of education and wages from 2002 to 2006.

Results

There was a clear difference between the permanent worker and non-permanent worker groups as regards existing guaranteed employment rights and social security. The increase in the number of non-permanent workers in the workforce, the growing proportion of older workers among the permanently employed and the real wage reductions during the period from 2002 to 2006 are indicative of the process of growing precarity of employment in the group studied.

Conclusion

It is a plausible supposition that the demand for health reforms, along with the legal limits imposed on financial expenditure, gave rise to the new types of contract and the present employment situation in the health districts in Belo Horizonte.
Mass spectrometry-based serum proteome pattern analysis in molecular diagnostics of early stage breast cancer
Authors: Pietrowska Monika , Marczak Lukasz , Polanska Joanna , Behrendt Katarzyna , Nowicka Elzbieta , Walaszczyk Anna , Chmura Aleksandra , Deja Regina , Stobiecki Maciej , Polanski Andrzej , Tarnawski Rafal , Widlak Piotr
Published: July 2009

Background

Mass spectrometric analysis of the blood proteome is an emerging method of clinical proteomics. The approach exploiting multi-protein/peptide sets (fingerprints) detected by mass spectrometry that reflect overall features of a specimen's proteome, termed proteome pattern analysis, have been already shown in several studies to have applicability in cancer diagnostics. We aimed to identify serum proteome patterns specific for early stage breast cancer patients using MALDI-ToF mass spectrometry.

Methods

Blood samples were collected before the start of therapy in a group of 92 patients diagnosed at stages I and II of the disease, and in a group of age-matched healthy controls (104 women). Serum specimens were purified and the low-molecular-weight proteome fraction was examined using MALDI-ToF mass spectrometry after removal of albumin and other high-molecular-weight serum proteins. Protein ions registered in a mass range between 2,000 and 10,000 Da were analyzed using a new bioinformatic tool created in our group, which included modeling spectra as a sum of Gaussian bell-shaped curves.

Results

We have identified features of serum proteome patterns that were significantly different between blood samples of healthy individuals and early stage breast cancer patients. The classifier built of three spectral components that differentiated controls and cancer patients had 83% sensitivity and 85% specificity. Spectral components (i.e., protein ions) that were the most frequent in such classifiers had approximate m/z values of 2303, 2866 and 3579 Da (a biomarker built from these three components showed 88% sensitivity and 78% specificity). Of note, we did not find a significant correlation between features of serum proteome patterns and established prognostic or predictive factors like tumor size, nodal involvement, histopathological grade, estrogen and progesterone receptor expression. In addition, we observed a significantly (p = 0.0003) increased level of osteopontin in blood of the group of cancer patients studied (however, the plasma level of osteopontin classified cancer samples with 88% sensitivity but only 28% specificity).

Conclusion

MALDI-ToF spectrometry of serum has an obvious potential to differentiate samples between early breast cancer patients and healthy controls. Importantly, a classifier built on MS-based serum proteome patterns outperforms available protein biomarkers analyzed in blood by immunoassays.
Changes in spatiotemporal gait variables over time during a test of functional capacity after stroke
Authors: Sibley Kathryn M , Tang Ada , Patterson Kara K , Brooks Dina , McIlroy William E
Published: July 2009

Background

Gait dysfunction and fatigue are common post-stroke, though it is unclear how extended walking activity, as would be performed during activities of daily living, may change over time. The purpose of this study was to examine if spatial and temporal gait variables deteriorate during an extended bout of walking in a test of functional capacity after stroke.

Methods

24 community dwelling, independently ambulating individuals greater than 3 months after stroke performed the Six-Minute Walk Test (6MWT). Participants walked over a pressure-sensitive mat on each pass of the 30 m course which recorded spatial and temporal parameters of gait. Mean gait speed and temporal symmetry ratio during each two-minute interval of the 6MWT were examined. Additional post hoc analyses examined the incidence of rests during the 6MWT and changes in gait speed and symmetry.

Results

On average, participants demonstrated a 3.4 ± 6.5 cm/s decrease in speed over time (p= 0.02). Participants who rested were also characterized by increased asymmetry in the final two minutes (p= 0.05). 30% of participants rested at some point during the test, and if a rest was taken, duration increased in the final two minutes (p= 0.001). Examination of factors which may have been associated with resting indicated that resters had poorer balance (p= 0.006) than non-resting participants.

Conclusion

This study supports previous findings establishing that walking performance after stroke declines over relatively short bouts of functionally-relevant ambulation. Such changes may be associated with both cardiorespiratory and muscular fatigue mechanisms that influence performance. The findings also indicate that rest duration should be routinely quantified during the 6MWT after stroke, and consequently, further research is necessary to determine how to interpret 6MWT scores when resting occurs.
Mathematical modeling supports substantial mouse neural progenitor cell death
Authors: McConnell Michael J , MacMillan Hugh R , Chun Jerold
Published: July 2009

Background

Existing quantitative models of mouse cerebral cortical development are not fully constrained by experimental data.

Results

Here, we use simple difference equations to model neural progenitor cell fate decisions, incorporating intermediate progenitor cells and initially low rates of neural progenitor cell death. Also, we conduct a sensitivity analysis to investigate possible uncertainty in the fraction of cells that divide, differentiate, and die at each cell cycle.

Conclusion

We demonstrate that uniformly low-level neural progenitor cell death, as concluded in previous models, is incompatible with normal mouse cortical development. Levels of neural progenitor cell death up to and exceeding 50% are compatible with normal cortical development and may operate to prevent forebrain overgrowth as observed following cell death attenuation, as occurs in caspase 3-null mutant mice.
Pulmonary involvement in Kaposi sarcoma: correlation between imaging and pathology
Authors: Gasparetto Taisa Davaus , Marchiori Edson , Lourenço Sílvia , Zanetti Gláucia , Vianna Alberto Domingues , Santos Alair ASMD , Nobre Luiz Felipe
Published: July 2009

Kaposi sarcoma is a low-grade mesenchymal tumor involving blood and lymphatic vessels. There are four variants of this disease, each presenting a different clinical manifestation: classic or sporadic, African or endemic, organ transplant-related or iatrogenic, and AIDS-related or epidemic. Kaposi sarcoma is the most common tumor among patients with HIV infection, occurring predominantly in homosexual or bisexual men. The pulmonary involvement in Kaposi sarcoma occurs commonly in critically immunosupressed patients who commonly have had preceding mucocutaneous or digestive involvement.

The etiology of Kaposi sarcoma is not precisely established; genetic, hormonal, and immune factors, as well as infectious agents, have all been implicated. There is evidence from epidemiologic, serologic, and molecular studies that Kaposi sarcoma is associated with human herpes virus type 8 infection. The disease starts as a reactive polyclonal angioproliferative response towards this virus, in which polyclonal cells change to form oligoclonal cell populations that expand and undergo malignant transformation.

The diagnosis of pulmonary involvement in Kaposi sarcoma usually can be made by a combination of clinical, radiographic, and laboratory findings, together with the results of bronchoscopy and transbronchial biopsy. Chest high-resolution computed tomography scans commonly reveal peribronchovascular and interlobular septal thickening, bilateral and symmetric ill-defined nodules in a peribronchovascular distribution, fissural nodularity, mediastinal adenopathies, and pleural effusions. Correlation between the high-resolution computed tomography findings and the pathology revealed by histopathological analysis demonstrate that the areas of central peribronchovascular infiltration represent tumor growth involving the bronchovascular bundles, with nodules corresponding to proliferations of neoplastic cells into the pulmonary parenchyma. The interlobular septal thickening may represent edema or tumor infiltration, and areas of ground-glass attenuation correspond to edema and the filling of air spaces with blood. These findings are a result of the propensity of Kaposi sarcoma to grow in the peribronchial and perivascular axial interstitial spaces, often as continuous sheets of tumor tissue.

In conclusion, radiological findings can play a major role in the diagnosis of pulmonary Kaposi sarcoma since characteristic patterns may be observed. The presence of these patterns in patients with AIDS is highly suggestive of Kaposi sarcoma.
Computing phenomenologic Adair-Klotz constants from microscopic MWC parameters
Authors: Stefan Melanie I , Edelstein Stuart J , Le Novère Nicolas
Published: July 2009

Background

Modellers using the MWC allosteric framework have often found it difficult to validate their models. Indeed many experiments are not conducted with the notion of alternative conformations in mind and therefore do not (or cannot) measure relevant microscopic constant and parameters. Instead, experimentalists widely use the Adair-Klotz approach in order to describe their experimental data.

Results

We propose a way of computing apparent Adair-Klotz constants from microscopic association constants and allosteric parameters of a generalised concerted model with two different states (R and T), with an arbitrary number of non-equivalent ligand binding sites. We apply this framework to compute Adair-Klotz constants from existing models of calmodulin and hemoglobin, two extreme cases of the general framework.

Conclusion

The validation of computational models requires methods to relate model parameters to experimentally observable quantities. We provide such a method for comparing generalised MWC allosteric models to experimentally determined Adair-Klotz constants.
Novel transcriptional profile in wrist muscles from cerebral palsy patients
Authors: Smith Lucas R , Pontén Eva , Hedström Yvette , Ward Samuel R , Chambers Henry G , Subramaniam Shankar , Lieber Richard L
Published: July 2009

Background

Cerebral palsy (CP) is an upper motor neuron disease that results in a progressive movement disorder. Secondary to the neurological insult, muscles from CP patients often become spastic. Spastic muscle is characterized by an increased resistance to stretch, but often develops the further complication of contracture which represents a prominent disability in children with CP. This study's purpose is to characterize alterations of spastic muscle on the transcriptional level. Increased knowledge of spastic muscle may lead to novel therapies to improve the quality of life for children with CP.

Method

The transcriptional profile of spastic muscles were defined in children with cerebral palsy and compared to control patients using Affymetrix U133A chips. Expression data were verified using quantitative-PCR (QPCR) and validated with SDS-PAGE for select genes. Significant genes were determined using a 2 × 2 ANOVA and results required congruence between 3 preprocessing algorithms.

Results

CP patients clustered independently and 205 genes were significantly altered, covering a range of cellular processes. Placing gene expression in the context of physiological pathways, the results demonstrated that spastic muscle in CP adapts transcriptionally by altering extracellular matrix, fiber type, and myogenic potential. Extracellular matrix adaptations occur primarily in the basal lamina although there is increase in fibrillar collagen components. Fiber type is predominately fast compared to normal muscle as evidenced by contractile gene isoforms and decrease in oxidative metabolic gene transcription, despite a paradoxical increased transcription of slow fiber pathway genes. We also found competing pathways of fiber hypertrophy with an increase in the anabolic IGF1 gene in parallel with a paradoxical increase in myostatin, a gene responsible for stopping muscle growth. We found evidence that excitation-contraction coupling genes are altered in muscles from patients with CP and may be a significant component of disease.

Conclusion

This is the first transcriptional profile performed on spastic muscle of CP patients and these adaptations were not characteristic of those observed in other disease states such as Duchenne muscular dystrophy and immobilization-induced muscle atrophy. Further research is required to understand the mechanism of muscle adaptation to this upper motor neuron lesion that could lead to the development of innovative therapies.
Neuropathic and nociceptive pain in head and neck cancer patients receiving radiation therapy
Authors: Epstein Joel B , Wilkie Diana J , Fischer Dena J , Kim Young-Ok , Villines Dana
Published: July 2009

Background

Pain is common in head and neck cancer (HNC) patients and may be attributed to the malignancy and/or cancer treatment. Pain mechanisms and patient report of pain in HNC are expected to include both nociceptive and neuropathic components. The purpose of this study was to assess the trajectory of orofacial and other pain during and following treatment, using patient reports of neuropathic pain and nociceptive pain and pain impact.

Methods

124 consecutive HNC patients receiving radiation therapy (RT) (95 men, 29 women; mean age: 54.7 ± 12.3 years) participated in a patient-reported outcome (PRO) assessment. Patients completed the McGill Pain Questionnaire three times during therapy and 3 months following study entry.

Results

The majority of patients related their pain to the tumor and/or cancer treatment. Whereas 59% reported their pain to be less severe than they expected, 29% were not satisfied with their level of pain despite pain management during cancer therapy. Worst pain was 3.0 ± 1.3 on a 0- to 5-point verbal descriptor scale. Pain intensity was present at entry, highest at 2-week follow-up, declining towards the end of treatment and persisting at 3-month follow-up. The most common neuropathic pain descriptors chosen were aching (20%) and burning (27%); nociceptive words chosen were dull (22%), sore (32%), tender (35%), and throbbing (23%), and affective/evaluative descriptors were tiring (25%) and annoying (41%). 57% of patients reported continuous pain, and combined continuous and intermittent pain was reported by 79% of patients.

Discussion

This study provides evidence that patients with HNC experience nociceptive and neuropathic pain during RT despite ongoing pain management. The affective and evaluative descriptors chosen for head and neck pain indicate considerable impact on quality of life even with low to moderate levels of pain intensity. These findings suggest that clinicians should consider contemporary management for both nociceptive and neuropathic pain in head and neck cancer patients.
Bronchoalveoloar lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients
Authors: Schmidt Katrin , Martinez-Gamboa Lorena , Meier Susan , Witt Christian , Meisel Christian , Hanitsch Leif G , Becker Mike O , Huscher Doerte , Burmester Gerd R , Riemekasten Gabriela
Published: July 2009

Introduction

Interstitial lung disease (ILD) is a frequent manifestation of systemic sclerosis (SSc), and cytokines can contribute to the disease pathology. The aim of the current study was to identify specific changes in cytokine levels that may serve as disease markers and possible targets for therapy.

Methods

Cytokines were measured with bioplex analysis in 38 bronchoalveolar fluids (BALFs) from 32 SSc patients (27 with alveolitis and 11 without alveolitis) and 26 control patients. In the case of SSc patients, cytokines were correlated with the respective bronchoalveolar lavage (BAL) cell differentiation, lung function, and thoracic HR-CT score. For 35 BALF samples derived from 29 SSc patients, follow-up investigations of clinical data, lung-function parameter, or thoracic HR-CT scans were available to evaluate the predictive capacity of BALF cytokines and chemokines.

Results

High IL-7 levels were characteristic of SSc-associated interstitial lung disease (ILD) and, in addition, when compared with ILD-negative SSc patients, ILD-positive SSc patients revealed higher IL-4, IL-6, IL-8, and CCL2 (MCP-1) BALF levels. High CCL2 and IL-8 BALF concentrations were associated with neutrophilic and mixed alveolitis. Cytokine levels of IL-4, IL-8, and CCL2 correlated negatively with lung-function parameters; CCL2 concentrations also correlated with HR-CT scores. High concentrations of several cytokines were associated with the progress of ILD and end-stage ILD. Univariate analyses revealed high IL-2 and tumor necrosis factor-alpha (TNF-α) levels as the best predictors for progressive disease, together with lung-function parameters, young age, and neutrophilic alveolitis. Multivariate analyses partially confirmed these results but did not sufficiently converge because of the limited number of patients.

Conclusions

The association of BALF cytokines with lung fibrosis and its progress suggests that cytokines contribute to the pathogenesis of ILD and hence could be regarded as potential therapeutic targets.
Changes in regional distribution of lung sounds as a function of positive end-expiratory pressure
Authors: Lev Shaul , Glickman Yael A , Kagan Ilya , Dahan David , Cohen Jonathan , Grinev Milana , Shapiro Maury , Singer Pierre
Published: July 2009

Introduction

Automated mapping of lung sound distribution is a novel area of interest currently investigated in mechanically ventilated, critically ill patients. The objective of the present study was to assess changes in thoracic sound distribution resulting from changes in positive end-expiratory pressure (PEEP). Repeatability of automated lung sound measurements was also evaluated.

Methods

Regional lung sound distribution was assessed in 35 mechanically ventilated patients in the intensive care unit (ICU). A total of 201 vibration response imaging (VRI) measurements were collected at different levels of PEEP between 0 and 15 cmH2O. Findings were correlated with tidal volume, oxygen saturation, airway resistance, and dynamic compliance. Eighty-two duplicated readings were performed to evaluate the repeatability of the measurement.

Results

A significant shift in sound distribution from the apical to the diaphragmatic lung areas was recorded when increasing PEEP (paired t-tests, P < 0.05). In patients with unilateral lung pathology, this shift was significant in the diseased lung, but not as pronounced in the other lung. No significant difference in lung sound distribution was encountered based on level of ventilator support needed. Decreased lung sound distribution in the base was correlated with lower dynamic compliance. No significant difference was encountered between repeated measurements.

Conclusions

Lung sounds shift towards the diaphragmatic lung areas when PEEP increases. Lung sound measurements are highly repeatable in mechanically ventilated patients with various lung pathologies. Further studies are needed in order to fully appreciate the contribution of PEEP increase to diaphragmatic sound redistribution.
Dosage compensation on the active X chromosome minimizes transcriptional noise of X-linked genes in mammals
Authors: Yin Shanye , Wang Ping , Deng Wenjun , Zheng Hancheng , Hu Landian , Hurst Laurence D , Kong Xiangyin
Published: July 2009

Background

Theory predicts that haploid-expressed genes should have noisier expression than comparable diploid-expressed ones with the same expression level. However, in mammals there are several classes of gene that are monoallelically expressed, including X-linked genes, imprinted genes and some other autosomal genes. Does it follow that the evolution of X chromosomes in eukaryotes comes at the cost of increased transcriptional noise in the heterogametic sex? Moreover, is escaping X-inactivation in mammalian females associated with an increase in transcriptional variation? To address these questions, we analyze gene expression variation between replicate samples of diverse mammalian cell lines in steady-state using microarray data.

Results

We observe that transcriptional variation of X-linked genes is no different to that of autosomal genes both before and after control for transcript abundance. By contrast, autosomal genes subject to allelic exclusion do have unusually high noise levels even allowing for their low transcript abundance. The prior theory we suggest was insufficient, at least as regards X-chromosomes, as it failed to appreciate the regulatory complexity of gene expression, not least the effects of genomic neighborhood.

Conclusions

These results suggest that high noise is not a necessary consequence of haploid expression and emphasize the primacy of expression level as a determinant of noise. The latter has consequences for understanding the etiology of haplo-insufficiency and the evolution of gene expression levels. Given the coupling between expression level and noise on the X-chromosome, we suggest that part of the selective advantage of dosage compensation is noise abatement of X-linked genes.
Obstacles to the successful development of an efficacious T cell-inducing HIV-1 vaccine
Authors: Haut Larissa Herkenhoff , Ertl Hildegund C J
Published: July 2009

Preclinical and clinical HIV-1 cell vaccine development continues to be hampered by the lack of validated preclinical animal models: a discussion about way forward.

An efficacious vaccine to HIV-1 is direly needed to stem the global pandemic. Immunogens that elicit broadly cross-neutralizing antibodies to HIV-1 remain elusive, and thus, most HIV-1 vaccine efforts are focusing on induction of T cells. The notion that T cells can mediate protection against HIV-1 has been called into question by the failure of the STEP trial, which was designed to test this concept by the use of an E1-deleted Ad vaccine carrier. Lack of efficacy of the STEP trial vaccine underscores our limited knowledge about correlates of immune protection against HIV-1 and stresses the need for an enhanced commitment to basic research, including preclinical and clinical vaccine studies. In this review, we discuss known correlates of protection against HIV-1 and different vaccine strategies that have been or are being explored to induce such correlates, focusing on T cell-inducing vaccines and particularly on Ad vectors.
Higher Incidence of Relapse With Peripheral Blood Rather Than Marrow As a Source of Stem Cells in Adults With Acute Myelocytic Leukemia Autografted During the First Remission
Authors: Gorin Norbert-Claude , Labopin Myriam , Blaise Didier , Reiffers Josy , Meloni Giovanna , Michallet Mauricette , de Witte Theo , Attal Michel , Rio Bernard , Witz Francois , Fouillard Loic , Willemze Roel , Rocha Vanderson
Published: July 2009

Purpose

The cell source for autologous stem cell transplantation has shifted from bone marrow (BM) to peripheral blood (PB). In acute myelocytic leukemia (AML), for patients who receive transplants during first complete remission (CR1), no prospective randomized study has compared relapse incidence (RI) to cell source.

Patients and Methods

We analyzed 2,165 patients who received autografts (1,607 PB and 558 BM) from 1994 to 2006 and were reported to the European Cooperative Group for Blood and Marrow Transplantation with complete research data. Relative to the time of CR1, PB transplants were performed earlier than BM transplants. Because a poorer outcome was associated with a shorter interval from CR1 to transplantation, patients were divided into three groups: BM, early PB (≤ 80 days after CR1), and late PB (> 80 days after CR1) transplantation.

Results

In a multivariate analysis adjusted for differences between groups and center, RI was higher with both early PB (56% ± 3%; hazard ratio [HR], 1.45; 95% CI, 1.11 to 1.9; P = .006) and late PB transplantation (46% ± 2%; HR, 1.3; 95% CI, 1.06 to 1.59; P = .01) as compared with BM transplantation (39% ± 2%). This translated into a significantly worse leukemia-free survival (LFS) for early PB transplantation (36% ± 3%; HR, 0.75; 95% CI, 0.58 to 0.96; P = .02) and a trend for a poorer LFS for late PB (46% ± 2%; HR, 0.84; 95% CI, 0.7 to 1.01; P = .06) as compared with BM (52% ± 2%).

Conclusion

For patients with AML in CR1, risk of relapse is greater with PB transplantation rather than BM, independent of the interval from CR1 to transplantation.
Efficacy and Safety of Axitinib in Patients With Advanced Non–Small-Cell Lung Cancer: Results From a Phase II Study
Authors: Schiller Joan H. , Larson Timothy , Ou S.-H. Ignatius , Limentani Steven , Sandler Alan , Vokes Everett , Kim Sinil , Liau Katherine , Bycott Paul , Olszanski Anthony J. , von Pawel Joachim
Published: July 2009

Purpose

This phase II study evaluated efficacy and safety of single-agent axitinib, an oral, potent, selective inhibitor of vascular endothelial growth factor receptors (VEGFR) -1, -2, and -3, in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received a starting dose of axitinib 5 mg orally BID. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) –defined objective response rate. Secondary end points included safety and tolerability, overall survival (OS), and progression-free survival (PFS).

Results

Thirty-two patients were enrolled, with a median age of 66.5 years. The majority of patients (75%) had adenocarcinoma. Nine patients (28%) had received no prior chemotherapy for metastatic disease, and 23 (72%) had received ≥ one regimen. Three patients (9%) had a RECIST investigator-assessed, confirmed partial response (PR); disease control rate (PR + stable disease) was 41%. Median PFS was 4.9 months overall (95% CI, 3.6 to 7.0 months). Median OS was 14.8 months (95% CI, 10.7 months to not estimable) overall and 14.8 months (95% CI, 12.5 months to not estimable) in patients receiving first-line axitinib. One-year survival rates for patients with or without prior therapy for metastatic disease were 57% and 78%, respectively. Grade 3 treatment-related adverse events in ≥ 5% of patients comprised fatigue (22%), hypertension (9%), and hyponatremia (9%).

Conclusion

Axitinib demonstrated single-agent activity in patients with advanced NSCLC. Therapy was well tolerated with manageable toxicities. Further investigation of this VEGFR inhibitor in NSCLC is of interest.
Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group
Authors: Stilgenbauer Stephan , Zenz Thorsten , Winkler Dirk , Bühler Andreas , Schlenk Richard F. , Groner Silja , Busch Raymonde , Hensel Manfred , Dührsen Ulrich , Finke Jürgen , Dreger Peter , Jäger Ulrich , Lengfelder Eva , Hohloch Karin , Söling Ulrike , Schlag Rudolf , Kneba Michael , Hallek Michael , Döhner Hartmut
Published: July 2009

Purpose

The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome.

Patients and Methods

One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter.

Results

The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased β2-microglobulin (β2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, β2-MG, and TK were independent prognostic factors for OS.

Conclusion

Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.
Impact of Irinotecan and Oxaliplatin on Overall Survival in Patients With Metastatic Colorectal Cancer: A Population-Based Study
Authors: Lim Howard J. , Gill Sharlene , Speers Caroline , Melosky Barbara , Barnett Jeff , Fitzgerald Catherine , O'Reilly Susan , Kennecke Hagen
Published: July 2009

A look at the temporal impact of advancements in therapeutic options in the last 10 years—from fluorouracil to irinotecan and oxaliplatin—on overall survival in a population-based cohort.
Patient Navigation Through the Cancer Care Continuum: An Overview
Authors: Hopkins Janice , Mumber Matthew P.
Published: July 2009

Technologic advances, medical specialization, novel payment structures, and an increased scientific knowledge base have resulted in a health care system requiring trained experts to deliver guidance as patients complete care plans: Enter the concept of patient navigation.
Withdrawing Medically Futile Treatment
Authors: Howard Dianna S. , Pawlik Timothy M.
Published: July 2009

Physicians confront clinical and ethical dilemmas when their patients wish to continue treatments they have deemed futile; they must consider ethical obligations in deciding whether treatment should be withdrawn and in transferring patients from futile treatment to supportive care.
Nck adaptor proteins link Tks5 to invadopodia actin regulation and ECM degradation
Authors: Stylli Stanley S. , I Stacey T. T. , Verhagen Anne M. , Xu San San , Pass Ian , Courtneidge Sara A. , Lock Peter
Published: July 2009

Invadopodia are actin-based projections enriched with proteases, which invasive cancer cells use to degrade the extracellular matrix (ECM). The Phox homology (PX)-Src homology (SH)3 domain adaptor protein Tks5 (also known as SH3PXD2A) cooperates with Src tyrosine kinase to promote invadopodia formation but the underlying pathway is not clear. Here we show that Src phosphorylates Tks5 at Y557, inducing it to associate directly with the SH3-SH2 domain adaptor proteins Nck1 and Nck2 in invadopodia. Tks5 mutants unable to bind Nck show reduced matrix degradation-promoting activity and recruit actin to invadopodia inefficiently. Conversely, Src- and Tks5-driven matrix proteolysis and actin assembly in invadopodia are enhanced by Nck1 or Nck2 overexpression and inhibited by Nck1 depletion. We show that clustering at the plasma membrane of the Tks5 inter-SH3 region containing Y557 triggers phosphorylation at this site, facilitating Nck recruitment and F-actin assembly. These results identify a Src-Tks5-Nck pathway in ECM-degrading invadopodia that shows parallels with pathways linking several mammalian and pathogen-derived proteins to local actin regulation.
Tssk6 is required for Izumo relocalization and gamete fusion in the mouse
Authors: Sosnik Julian , Miranda Patricia V. , Spiridonov Nikolay A. , Yoon Sook-Young , Fissore Rafael A. , Johnson Gibbes R. , Visconti Pablo E.
Published: July 2009

One of the most important processes in fertilization is the fusion of egg and sperm; however, the molecular mechanisms involved in this process are not well understood. So far, using genetic approaches, only two proteins have been demonstrated to be necessary for this process: Izumo in sperm and CD9 in the egg. Here we demonstrate that sperm produced by Tssk6 (Sstk)-null mice present defects that prevent the successful fertilization of eggs in vitro and the fusion to zona-pellucida-free eggs. Tssk6 is a member of the testis-specific serine kinase family of proteins and is expressed postmeiotically in male germ cells. In order for fusion to occur, during the process known as acrosome reaction Izumo needs to relocate from the anterior head to other regions, including the postacrosomal compartment. Tssk6-null sperm fails to relocate Izumo during the acrosome reaction. Agents that interfere with actin dynamics blocked the acrosome-reaction-associated translocation of Izumo that is required for fusion in wild-type sperm. Additionally, actin polymerization was compromised in Tssk6-null sperm. Taken together, our results indicate that Tssk6 is involved in sperm-egg fusion through the regulation of actin polymerization and changes in Izumo localization.
Dynamics and kinematics of ant locomotion: do wood ants climb on level surfaces?
Authors: Reinhardt Lars , Weihmann Tom , Blickhan Reinhard
Published: July 2009

The biomechanics of running in small animals have remained poorly characterized because of the difficulty of recording three-dimensional ground reaction forces. Available techniques limit investigations to animals with a body mass above 1 g. Here we present, for the first time, single-leg ground reaction forces of ants (body mass 10 mg), measured with a custom-built miniature force plate. We investigated forces and high-speed kinematics for straight level runs (average speed: 8.4 cm s–1) of Formica polyctena workers. The major finding was that the time course of ground reaction forces strongly differed from previous observations of larger insects. Maximum vertical force was reached during the first third of the tripod contact phase. During this period the body was decelerated predominantly by the front legs. Subsequently, the front legs pulled and accelerated the body. This `climbing' type of stride may be useful on the bumpy and unstable substrates that the animals face in their natural habitats,and may therefore also occur on level ground. Propulsive forces were generated predominantly by the front and hind legs. Dragging of the gaster on the substrate resulted in a breaking momentum, which was compensated by the legs. Future investigations will reveal, whether the identified pattern is due to specialization.
Aversion- vs fear-inducing properties of 2,4,5-trimethyl-3-thiazoline, a component of fox odor, in comparison with those of butyric acid
Authors: Endres Thomas , Fendt Markus
Published: July 2009

2,4,5-trimethyl-3-thiazoline (TMT), a component of fox feces, is a widely used odorant to induce innate fear behavior in rats and mice. However, based on the slight acrid smell it was argued that the observed behavioral effects are a result of the aversive and not of the fear-inducing properties of TMT. In the present study, we tried to directly compare the aversive and fear-inducing properties of TMT with those of the aversive control odor butyric acid. We first identified concentrations of butyric acid and TMT that induce similar amounts of avoidance behavior in rats, indicating that these concentrations have similar aversive properties. In a second experiment, these two concentrations were then tested for their ability to induce freezing, a species-specific defensive response. Only TMT but not butyric acid induced freezing in the rats. This supports the hypothesis that TMT indeed has specific fear-inducing properties and that the observed behavioral effects could not simply be reduced to the aversive properties of TMT.
SNPs in human miRNA genes affect biogenesis and function
Authors: Sun Guihua , Yan Jin , Noltner Katie , Feng Jinong , Li Haitang , Sarkis Daniel A. , Sommer Steve S. , Rossi John J.
Published: July 2009

MicroRNAs (miRNAs) are 21–25-nucleotide-long, noncoding RNAs that are involved in translational regulation. Most miRNAs derive from a two-step sequential processing: the generation of pre-miRNA from pri-miRNA by the Drosha/DGCR8 complex in the nucleus, and the generation of mature miRNAs from pre-miRNAs by the Dicer/TRBP complex in the cytoplasm. Sequence variation around the processing sites, and sequence variations in the mature miRNA, especially the seed sequence, may have profound affects on miRNA biogenesis and function. In the context of analyzing the roles of miRNAs in Schizophrenia and Autism, we defined at least 24 human X-linked miRNA variants. Functional assays were developed and performed on these variants. In this study we investigate the affects of single nucleotide polymorphisms (SNPs) on the generation of mature miRNAs and their function, and report that naturally occurring SNPs can impair or enhance miRNA processing as well as alter the sites of processing. Since miRNAs are small functional units, single base changes in both the precursor elements as well as the mature miRNA sequence may drive the evolution of new microRNAs by altering their biological function. Finally, the miRNAs examined in this study are X-linked, suggesting that the mutant alleles could be determinants in the etiology of diseases.
On the Decision to Take a Pitch
Authors: Bickel J. Eric
Published: July 2009

Baseball is a highly strategic game, with decisions being made almost continuously. In this paper, we analyze the decision to have the batter take a pitch, which means that he does not swing at the pitch under any circumstances—even if it is easily hittable. Why would a batter do this? Using decision-theoretic reasoning, we determine under what circumstances such a decision is good. We find that in some cases, taking pitches deterministically dominates not taking.