bluuebunny/crossref_metadata_2025 huggingface dataset:
Correcting Pediatric Flatfoot With Subtalar Arthroereisis and Gastrocnemius Recession
Authors: Jay Richard M. , Din Nadia
Published: December 2012

Background. Flatfoot deformities are common in children and are treated using many conservative and surgical approaches. Subtalar extra-articular arthroereisis, in particular, limits talar motion, spares the subtalar joint, and prevents excessive subtalar joint pronation. Addressing the underlying equinus deformity with gastrocnemius recession is an important factor in optimizing outcomes in patients with flatfoot deformity. Methods. This study included 20 children, 4 to 17 years old. The patients presented 34 cases of functional flexible flatfoot, and each was treated with gastrocnemius recession and a subtalar implant insertion of either a resorbable arthroereisis plug constructed of poly-L lactic acid or a threaded titanium alloy plug. Clinical evaluation was based on the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale as well as subjective assessments of pain, function, shoe wear, and overall preoperative and postoperative satisfaction. Results. The average AOFAS Ankle-Hindfoot Scale reading improved by 21.3 points (standard deviation = 8.1; 95% confidence interval = 17.5-25.1), from an average preoperative reading of 67.7 points to an average postoperative reading of 89 points (P < .0001). Subjectively, patients experienced reduced pain and improved function, cosmesis, and shoe wear. Conclusions. Treating equinus deformity with gastrocnemius recession significantly improved patient outcomes when treating flatfoot deformity. Reconstructive flatfoot surgery that combined subtalar arthroereisis with a resorbable arthroereisis plug and gastrocnemius recession resulted in favorable clinical outcomes and patient satisfaction. Symptom improvement and preservation of the subtalar joint were seen with these procedures, which are reasonable and useful options in treating children with symptomatic flexible flatfoot.

Levels of Evidence: Therapeutic, Level IV, Retrospective case series
Intramuscular Hemangiomas
Authors: Wierzbicki Joseph M. , Henderson Jeffrey H. , Scarborough Mark T. , Bush Charles H. , Reith John D. , Clugston James R.
Published: December 2012

Context:

Intramuscular hemangiomas are common in the general population and often present at medical and surgical clinics. Unfortunately, unfamiliarity with these lesions has led to a high percentage of misdiagnoses, inappropriate workup, and unnecessary referrals.

Evidence Acquisition:

A literature search was performed using Medline, Embase, PubMed, and Cochrane. The relevant articles and referenced sources were reviewed for additional articles that discussed the epidemiology, pathophysiology, investigation, and management of intramuscular hemangiomas. Clinical experience from experts in orthopaedics, musculoskeletal pathology, and musculoskeletal radiology was compared. The selected case studies are shared cases of the authors.

Results and Conclusion:

The pathophysiology of these lesions is not completely understood, but much can be implied from their underlying vascular nature. Isolated lesions are benign tumors that never metastasize but tend to enlarge and then involute over time. Magnetic resonance imaging is the imaging modality of choice. If a systemic disorder or malignancy is not suspected or has been ruled out, conservative management is the treatment of choice for most intramuscular hemangiomas.
Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies
Authors: Nasser Roudaina , Pelegrin Mireia , Plays Marc , Gros Laurent , Piechaczyk Marc
Published: December 2012

Key Points

Mab-based immunotherapy prevents Treg expansion and limits immunosuppressive activity.
Race and ethnicity in decisions about unrelated hematopoietic stem cell donation
Authors: Switzer Galen E. , Bruce Jessica G. , Myaskovsky Larissa , DiMartini Andrea , Shellmer Diana , Confer Dennis L. , Abress Linda K. , King Roberta J. , Harnaha Allyson G. , Ohngemach Sibylle , Dew Mary Amanda
Published: December 2012

Key Points

Across racial/ethnic groups, ambivalence is strongly associated with HSC donation decisions.
PBX3 is an important cofactor of HOXA9 in leukemogenesis
Authors: Li Zejuan , Zhang Zhiyu , Li Yuanyuan , Arnovitz Stephen , Chen Ping , Huang Hao , Jiang Xi , Hong Gia-Ming , Kunjamma Rejani B. , Ren Haomin , He Chunjiang , Wang Chong-Zhi , Elkahloun Abdel G. , Valk Peter J. M. , Döhner Konstanze , Neilly Mary Beth , Bullinger Lars , Delwel Ruud , Löwenberg Bob , Liu Paul P. , Morgan Richard , Rowley Janet D. , Yuan Chun-Su , Chen Jianjun
Published: December 2012

Key Points

PBX3 is a critical co-factor of HOXA9 in AMLs, particularly those carrying MLL rearrangements. Targeting HOXA9/PBX3 interaction holds a therapeutic potential to treat leukemia.
Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo
Authors: Zhi Huiying , Rauova Lubica , Hayes Vincent , Gao Cunji , Boylan Brian , Newman Debra K. , McKenzie Steven E. , Cooley Brian C. , Poncz Mortimer , Newman Peter J.
Published: December 2012

Key Points

These data establish FcγRIIa as a physiologically important functional conduit for αIIbβ3-mediated outside-in signaling.
Distinct gene-expression profiles associated with the susceptibility of pathogen-specific CD4 T cells to HIV-1 infection
Authors: Hu Haitao , Nau Martin , Ehrenberg Phil , Chenine Agnes-Laurence , Macedo Camila , Zhou Yu , Daye Z. John , Wei Zhi , Vahey Maryanne , Michael Nelson L. , Kim Jerome H. , Marovich Mary , Ratto-Kim Silvia
Published: December 2012

Key Points

Different pathogen-specific CD4 T cells manifest remarkable difference in susceptibility to HIV infection. Distinct gene-expression profiles of pathogen-specific CD4 T cells are associated with their susceptibilities to HIV infection.
Characteristics and outcome of early-onset, severe forms of Wiskott-Aldrich syndrome
Authors: Mahlaoui Nizar , Pellier Isabelle , Mignot Cécile , Jais Jean-Philippe , Bilhou-Nabéra Chrystèle , Moshous Despina , Neven Bénédicte , Picard Capucine , de Saint-Basile Geneviève , Cavazzana-Calvo Marina , Blanche Stéphane , Fischer Alain
Published: December 2012

Key Points

This study identified a distinct subgroup of WAS patients with an early onset (before the age of 2 years) of severe, life-threatening manifestations. HSCT is a curative strategy in this subgroup of patients and should be performed as early in life as possible, even when a fully matched donor is lacking.
Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling
Authors: Burger Jan A. , Montserrat Emili
Published: December 2012

Chronic lymphocytic leukemia (CLL) cells proliferate in pseudofollicles within the lymphatic tissues, where signals from the microenvironment and BCR signaling drive the expansion of the CLL clone. Mobilization of tissue-resident cells into the blood removes CLL cells from this nurturing milieu and sensitizes them to cytotoxic drugs. This concept recently gained momentum after the clinical activity of kinase inhibitors that target BCR signaling (spleen tyrosine kinase, Bruton tyrosine kinase, PI3Kδ inhibitors) was established. Besides antiproliferative activity, these drugs cause CLL cell redistribution with rapid lymph node shrinkage, along with a transient surge in lymphocytosis, before inducing objective remissions. Inactivation of critical CLL homing mechanism (chemokine receptors, adhesion molecules), thwarting tissue retention and recirculation into the tissues, appears to be the basis for this striking clinical activity. This effect of BCR-signaling inhibitors resembles redistribution of CLL cells after glucocorticoids, described as early as in the 1940s. As such, we are witnessing a renaissance of the concept of leukemia cell redistribution in modern CLL therapy. Here, we review the molecular basis of CLL cell trafficking, homing, and redistribution and similarities between old and new drugs affecting these processes. In addition, we outline how these discoveries are changing our understanding of CLL biology and therapy.
Local and systemic cytokine profiles in nonsevere and severe community-acquired pneumonia
Authors: Paats Marthe S. , Bergen Ingrid M. , Hanselaar Wessel E.J.J. , Groeninx van Zoelen E. Christine , Hoogsteden Henk C. , Hendriks Rudi W. , van der Eerden Menno M.
Published: December 2012

Local inflammatory responses in community-acquired pneumonia (CAP) remain insufficiently elucidated, especially in patients with nonsevere CAP. In this study we determined local and systemic cytokine responses in CAP patients and correlated these with disease severity and other clinical parameters.

Levels of interleukin (IL)-6, IL-8, IL-10, IL-1β, tumour necrosis factor-α, interferon (IFN)-γ, IL-22, IL-17A and IL-4 were determined in bronchoalveolar lavage fluid and serum of 20 CAP patients upon admission and 10 healthy individuals. Systemic cytokine levels were also measured on days 7 and 30.

In bronchoalveolar lavage fluid of CAP patients, levels of IL-6, IL-8 and IFN-γ were significantly increased compared with healthy individuals, but no correlations with disease severity were found. Systemic levels of IL-6, IL-10 and IFN-γ were significantly higher in severe CAP patients than in nonsevere CAP patients and healthy individuals. Moreover, these cytokines showed a significant correlation with the pneumonia severity index. In the total group of CAP patients, systemic IL-8 and IL-22 levels were also increased compared with healthy individuals.

We therefore conclude that IL-6, IL-10 and IFN-γ are important cytokines in CAP, although differences in disease severity upon admission are only reflected by systemic levels of these cytokines.
High prevalence of occult left heart disease in scleroderma-pulmonary hypertension
Authors: Fox Benjamin D. , Shimony Avi , Langleben David , Hirsch Andrew , Rudski Lawrence , Schlesinger Robert , Eisenberg Mark J. , Joyal Dominique , Hudson Marie , Boutet Kim , Serban Alexandrina , Masetto Ariel , Baron Murray
Published: December 2012

Our study aimed to determine the prevalence of occult left-heart disease in patients with scleroderma and pulmonary hypertension. In patients with pulmonary hypertension (mean pulmonary artery pressure (mean PAP) ≥25 mmHg), differentiation between pre- and post-capillary pulmonary hypertension has been made according to pulmonary artery wedge pressure (PAWP) less than or more than 15 mmHg, respectively.

We performed a retrospective chart review of 107 scleroderma patients. All patients with suspected pulmonary hypertension had routine right or left heart catheterisation with left ventricular end-diastolic pressure (LVEDP) measurement pre-/post-fluid challenge. We extracted demographic, haemodynamic and echocardiographic data. Patients were classified into one of four groups: haemodynamically normal (mean PAP<25 mmHg); pulmonary venous hypertension (PVH) (mean PAP≥25 mmHg, PAWP>15 mmHg); occult PVH (mean PAP≥25 mmHg, PAWP≤15 mmHg, LVEDP>15 mmHg before or after fluid challenge); and pulmonary arterial hypertension (PAH) (mean PAP≥25 mmHg, PAWP≤15 mmHg and LVEDP≤15 mmHg before or after fluid challenge).

53 out of 107 patients had pulmonary hypertension. Based on the PAWP-based definition, 29 out of 53 had PAH and 24 out of 53 had PVH. After considering the resting and post-fluid-challenge LVEDP, 11 PAH patients were reclassified as occult PVH. The occult PVH group was haemodynamically, echocardiographically and demographically closer to the PVH group than the PAH group.

PVH had high prevalence in our scleroderma-pulmonary hypertension population. Distinguishing PAH from PVH with only PAWP may result in some PVH patients being misclassified as having PAH.
Physical activity in COPD patients: patterns and bouts
Authors: Donaire-Gonzalez David , Gimeno-Santos Elena , Balcells Eva , Rodríguez Diego A. , Farrero Eva , de Batlle Jordi , Benet Marta , Ferrer Antoni , Barberà Joan A. , Gea Joaquim , Rodriguez-Roisin Robert , Antó Josep M. , Garcia-Aymerich Judith
Published: December 2012

The present study aims to describe the pattern of physical activity and the frequency, duration and intensity of physical activity bouts in patients with chronic obstructive pulmonary disease (COPD), to assess how these patterns differ according to COPD severity, and to explore whether these patients meet the general guidelines for physical activity for older adults.

177 patients (94% male, mean±sdage 71±8 years and forced expiratory volume in 1 s 52±16% predicted) wore the SenseWear Pro2Armband accelerometer for eight consecutive days. Physical activity bouts were defined as periods of ≥10 min above 1.5 metabolic equivalent tasks and classified according to their median intensity.

Patients engaged in activity a median of 153 min·day−1and 57% of that time was spent in bouts. Median frequencies of bouts per day were four and three for all and moderate-to-vigorous intensities, respectively. With increasing COPD severity, time in physical activity, proportion of time in bouts and frequency of bouts decreased. 61% of patients fulfilled the recommended physical activity guidelines.

In conclusion, COPD patients of all spirometric severity stages engage in physical activity bouts of moderate-to-vigorous intensities. Patients with severe and very severe COPD perform their daily activities in fewer and shorter bouts than those in mild and moderate stages.
Risk of deep vein thrombosis and pulmonary embolism in asthma
Authors: Majoor Christof J. , Kamphuisen Pieter W. , Zwinderman Aeilko H. , ten Brinke Anneke , Amelink Marijke , Rijssenbeek-Nouwens Lucia , Sterk Peter J. , Büller Harry R. , Bel Elisabeth H.
Published: December 2012

Increasing evidence suggests that patients with asthma have activated coagulation within the airways. Whether this leads to an increase in venous thromboembolic events is unknown. We therefore assessed the incidence of venous thromboembolic events in patients with mild-to-moderate and severe asthma as compared with an age- and sex-matched reference population.

648 patients with asthma (283 with severe and 365 patients with mild-to-moderate asthma) visiting three Dutch outpatient asthma clinics were studied. All patients completed a questionnaire about a diagnosis of deep vein thrombosis and pulmonary embolism in the past, their risk factors, history of asthma and medication use. All venous thromboembolic events were objectively verified.

In total, 35 venous thromboembolic events (16 deep vein thrombosis and 19 pulmonary embolism) occurred at a median age of 39 (range 20–63) years. The incidence of pulmonary embolism in patients with severe asthma was 0.93 (95% CI 0.42–1.44) per 1000 person-years, 0.33 (95% CI 0.07–0.60) in mild-to-moderate asthma and 0.18 (95% CI 0.03–0.33) in the general population, respectively. Severe asthma and oral corticosteroid use were independent risk factors of pulmonary embolism (hazard ratios 3.33 (1.16–9.93) and 2.82 (1.09–7.30), respectively). Asthma was not associated with deep vein thrombosis.

Severe asthma greatly enhances the risk of pulmonary embolism, particularly if chronic corticosteroids are used.
Welding, longitudinal lung function decline and chronic respiratory symptoms: a systematic review of cohort studies
Authors: Szram Joanna , Schofield Susie J. , Cosgrove Martin P. , Cullinan Paul
Published: December 2012

While the acute respiratory risks of welding are well characterised, more chronic effects, including those on lung function, are less clear. We carried out a systematic review of published longitudinal studies of lung function decline in welders.

Original cohort studies documenting two or more sequential measurements of lung function were reviewed. Meta-analysis was carried out on studies with suitable data on forced expiratory volume in 1 s (FEV1).

Seven studies were included; their quality (measured on the Newcastle–Ottawa scale) was good, although exposure assessment was limited and the studies showed significant heterogeneity. Five had data suitable for meta-analysis; the pooled estimate of the difference in FEV1decline between welders and nonwelders was -9.0 mL·year−1(95% CI -22.5–4.5; p=0.193). The pooled estimates of difference in annual FEV1decline between welders and referents who smoked was -13.7 mL·year−1(95% CI -33.6–6.3; p=0.179). For welders and referents who did not smoke the estimated difference was -3.8 mL·year−1(95% CI -20.2–12.6; p=0.650). Symptom prevalence data were mainly narrative; smoking appeared to have the greatest effect on symptom evolution.

Collectively, available longitudinal data on decline of lung function in welders and respiratory symptoms suggest a greater effect in those who smoke, supporting a focus on smoking cessation as well as control of fume exposure in this trade. Further prospective studies are required to confirm these findings.
Protein interface classification by evolutionary analysis
Authors: Duarte Jose M , Srebniak Adam , Schärer Martin A , Capitani Guido
Published: December 2012

Background

Distinguishing biologically relevant interfaces from lattice contacts in protein crystals is a fundamental problem in structural biology. Despite efforts towards the computational prediction of interface character, many issues are still unresolved.

Results

We present here a protein-protein interface classifier that relies on evolutionary data to detect the biological character of interfaces. The classifier uses a simple geometric measure, number of core residues, and two evolutionary indicators based on the sequence entropy of homolog sequences. Both aim at detecting differential selection pressure between interface core and rim or rest of surface. The core residues, defined as fully buried residues (>95% burial), appear to be fundamental determinants of biological interfaces: their number is in itself a powerful discriminator of interface character and together with the evolutionary measures it is able to clearly distinguish evolved biological contacts from crystal ones. We demonstrate that this definition of core residues leads to distinctively better results than earlier definitions from the literature. The stringent selection and quality filtering of structural and sequence data was key to the success of the method. Most importantly we demonstrate that a more conservative selection of homolog sequences - with relatively high sequence identities to the query - is able to produce a clearer signal than previous attempts.

Conclusions

An evolutionary approach like the one presented here is key to the advancement of the field, which so far was missing an effective method exploiting the evolutionary character of protein interfaces. Its coverage and performance will only improve over time thanks to the incessant growth of sequence databases. Currently our method reaches an accuracy of 89% in classifying interfaces of the Ponstingl 2003 datasets and it lends itself to a variety of useful applications in structural biology and bioinformatics. We made the corresponding software implementation available to the community as an easy-to-use graphical web interface at http://www.eppic-web.org.
Evolutionary relationships between miRNA genes and their activity
Authors: Zhu Yan , Skogerbø Geir , Ning Qianqian , Wang Zhen , Li Biqing , Yang Shuang , Sun Hong , Li Yixue
Published: December 2012

Background

The emergence of vertebrates is characterized by a strong increase in miRNA families. MicroRNAs interact broadly with many transcripts, and the evolution of such a system is intriguing. However, evolutionary questions concerning the origin of miRNA genes and their subsequent evolution remain unexplained.

Results

In order to systematically understand the evolutionary relationship between miRNAs gene and their function, we classified human known miRNAs into eight groups based on their evolutionary ages estimated by maximum parsimony method. New miRNA genes with new functional sequences accumulated more dynamically in vertebrates than that observed in Drosophila. Different levels of evolutionary selection were observed over miRNA gene sequences with different time of origin. Most genic miRNAs differ from their host genes in time of origin, there is no particular relationship between the age of a miRNA and the age of its host genes, genic miRNAs are mostly younger than the corresponding host genes. MicroRNAs originated over different time-scales are often predicted/verified to target the same or overlapping sets of genes, opening the possibility of substantial functional redundancy among miRNAs of different ages. Higher degree of tissue specificity and lower expression level was found in young miRNAs.

Conclusions

Our data showed that compared with protein coding genes, miRNA genes are more dynamic in terms of emergence and decay. Evolution patterns are quite different between miRNAs of different ages. MicroRNAs activity is under tight control with well-regulated expression increased and targeting decreased over time. Our work calls attention to the study of miRNA activity with a consideration of their origin time.
Structural analysis of the genome of breast cancer cell line ZR-75-30 identifies twelve expressed fusion genes
Authors: Schulte Ina , Batty Elizabeth M , Pole Jessica CM , Blood Katherine A , Mo Steven , Cooke Susanna L , Ng Charlotte , Howe Kevin L , Chin Suet-Feung , Brenton James D , Caldas Carlos , Howarth Karen D , Edwards Paul AW
Published: December 2012

Background

It has recently emerged that common epithelial cancers such as breast cancers have fusion genes like those in leukaemias. In a representative breast cancer cell line, ZR-75-30, we searched for fusion genes, by analysing genome rearrangements.

Results

We first analysed rearrangements of the ZR-75-30 genome, to around 10kb resolution, by molecular cytogenetic approaches, combining array painting and array CGH. We then compared this map with genomic junctions determined by paired-end sequencing. Most of the breakpoints found by array painting and array CGH were identified in the paired end sequencing—55% of the unamplified breakpoints and 97% of the amplified breakpoints (as these are represented by more sequence reads). From this analysis we identified 9 expressed fusion genes: APPBP2-PHF20L1, BCAS3-HOXB9, COL14A1-SKAP1, TAOK1-PCGF2, TIAM1-NRIP1, TIMM23-ARHGAP32, TRPS1-LASP1, USP32-CCDC49 and ZMYM4-OPRD1. We also determined the genomic junctions of a further three expressed fusion genes that had been described by others, BCAS3-ERBB2, DDX5-DEPDC6/DEPTOR and PLEC1-ENPP2. Of this total of 12 expressed fusion genes, 9 were in the coamplification. Due to the sensitivity of the technologies used, we estimate these 12 fusion genes to be around two-thirds of the true total. Many of the fusions seem likely to be driver mutations. For example, PHF20L1, BCAS3, TAOK1, PCGF2, and TRPS1 are fused in other breast cancers. HOXB9 and PHF20L1 are members of gene families that are fused in other neoplasms. Several of the other genes are relevant to cancer—in addition to ERBB2, SKAP1 is an adaptor for Src, DEPTOR regulates the mTOR pathway and NRIP1 is an estrogen-receptor coregulator.

Conclusions

This is the first structural analysis of a breast cancer genome that combines classical molecular cytogenetic approaches with sequencing. Paired-end sequencing was able to detect almost all breakpoints, where there was adequate read depth. It supports the view that gene breakage and gene fusion are important classes of mutation in breast cancer, with a typical breast cancer expressing many fusion genes.
Membranoproliferative glomerulonephritis complicating Waldenström’s macroglobulinemia
Authors: Kratochvil David , Amann Kerstin , Bruck Heike , Büttner Maike
Published: December 2012

Background

Lymphoproliferative disorders causing paraproteinemia can be associated with various kidney injuries including the deposition of monoclonal immunoglobulins (Ig). A known glomerular manifestation of Waldenström’s macroglobulinemia is characterized by prominent intracapillary hyaline thrombi and lack of conspicuous glomerular proliferation. The present case was special in 2 aspects: 1. the diagnosis of glomerulonephritis was unexpected before renal biopsy, 2. the prominent glomerular proliferation paired with large intracapillary hyaline thrombi is uncommon in Waldenström’s macroglobulinemia-associated glomerulonephritis.

Case presentation

A 73-year-old Caucasian woman with a long-standing history of rheumatoid arthritis and Waldenström’s macroglobulinemia was admitted for acute renal failure (ARF), which initially was presumed to be the consequence of extrarenal causes. Proteinuria and hematuria were only mild. In renal core biopsy, a membranoproliferative glomerulonephritis (MPGN) and prominent intracapillary hyaline monoclonal IgM thrombi were found in addition to acute tubular necrosis. Of note, the patient’s history was positive for purpuric skin changes, suspicious for cryoglobulinemia. However, serological tests for cryoglobulins were repeatedly negative. The ARF resolved before the start of immunomodulatory therapy for Waldenström’s macroglobulinemia.

Conclusion

The presence of MPGN with prominent hyaline thrombi in the context of Waldenström’s macroglobulinemia is uncommon and can be oligosymptomatic. We discuss this case in the context of previous literature and classifications suggested for monoclonal Ig-related renal pathologies.
Disseminated tumor cells as selection marker and monitoring tool for secondary adjuvant treatment in early breast cancer. Descriptive results from an intervention study
Authors: Synnestvedt Marit , Borgen Elin , Wist Erik , Wiedswang Gro , Weyde Kjetil , Risberg Terje , Kersten Christian , Mjaaland Ingvil , Vindi Lise , Schirmer Cecilie , Nesland Jahn Martin , Naume Bjørn
Published: December 2012

Background

Presence of disseminated tumor cells (DTCs) in bone marrow (BM) after completion of systemic adjuvant treatment predicts reduced survival in breast cancer. The present study explores the use of DTCs to identify adjuvant insufficiently treated patients to be offered secondary adjuvant treatment intervention, and as a surrogate marker for therapy response.

Methods

A total of 1121 patients with pN1-3 or pT1c/T2G2-3pN0-status were enrolled. All had completed primary surgery and received 6 cycles of anthracycline-containing chemotherapy. BM-aspiration was performed 8-12 weeks after chemotherapy (BM1), followed by a second BM-aspiration 6 months later (BM2). DTC-status was determined by morphological evaluation of immunocytochemically detected cytokeratin-positive cells. If DTCs were present at BM2, docetaxel (100 mg/m2, 3qw, 6 courses) was administered, followed by DTC-analysis 1 month (BM3) and 13 months (BM4) after the last docetaxel infusion.

Results

Clinical follow-up (FU) is still ongoing. Here, the descriptive data from the study are presented. Of 1085 patients with a reported DTC result at both BM1 and BM2, 94 patients (8.7%) were BM1 positive and 83 (7.6%) were BM2 positive. The concordance between BM1 and BM2 was 86.5%. Both at BM1 and BM2 DTC-status was significantly associated with lobular carcinomas (p = 0.02 and p = 0.03, respectively; chi-square). In addition, DTC-status at BM2 was also associated with pN-status (p = 0.009) and pT-status (p = 0.03). At BM1 28.8% and 12.8% of the DTC-positive patients had ≥2 DTCs and ≥3 DTCs, respectively. At BM2, the corresponding frequencies were 47.0% and 25.3%. Of 72 docetaxel-treated patients analyzed at BM3 and/or BM4, only 15 (20.8%) had persistent DTCs. Of 17 patients with ≥3 DTCs before docetaxel treatment, 12 patients turned negative after treatment (70.6%). The change to DTC-negativity was associated with the presence of ductal carcinoma (p = 0.009).

Conclusions

After docetaxel treatment, the majority of patients experienced disappearance of DTCs. As this is not a randomized trial, the results can be due to effects of adjuvant (docetaxel/endocrine/trastuzumab) treatment and/or limitations of the methodology. The clinical significance of these results awaits mature FU data, but indicates a possibility for clinical use of DTC-status as a residual disease-monitoring tool and as a surrogate marker of treatment response.

Trial registration

Clin Trials Gov NCT00248703
Personal characteristics related to the risk of adolescent internet addiction: a survey in Shanghai, China
Authors: Xu Jian , Shen Li-xiao , Yan Chong-huai , Hu Howard , Yang Fang , Wang Lu , Kotha Sudha Rani , Zhang Li-na , Liao Xiang-peng , Zhang Jun , Ouyang Feng-xiu , Zhang Jin-song , Shen Xiao-ming
Published: December 2012

Background

Paralleling the rapid growth in computers and internet connections, adolescent internet addiction (AIA) is becoming an increasingly serious problem, especially in developing countries. This study aims to explore the prevalence of AIA and associated symptoms in a large population-based sample in Shanghai and identify potential predictors related to personal characteristics.

Methods

In 2007, 5,122 adolescents were randomly chosen from 16 high schools of different school types (junior, senior key, senior ordinary and senior vocational) in Shanghai with stratified-random sampling. Each student completed a self-administered and anonymous questionnaire that included DRM 52 Scale of Internet-use. The DRM 52 Scale was adapted for use in Shanghai from Young’s Internet Addiction Scale and contained 7 subscales related to psychological symptoms of AIA. Multiple linear regression and logistic regression were both used to analyze the data.

Results

Of the 5,122 students, 449 (8.8%) were identified as internet addicts. Although adolescents who had bad (vs. good) academic achievement had lower levels of internet-use (p< 0.0001), they were more likely to develop AIA (odds ratio 4.79, 95% CI: 2.51-9.73,p< 0.0001) and have psychological symptoms in 6 of the 7 subscales (not in Time-consuming subscale). The likelihood of AIA was higher among those adolescents who were male, senior high school students, or had monthly spending >100 RMB (allp-values <0.05). Adolescents tended to develop AIA and show symptoms in all subscales when they spent more hours online weekly (however, more internet addicts overused internet on weekends than on weekdays,p< 0.0001) or when they used the internet mainly for playing games or real-time chatting.

Conclusions

This study provides evidence that adolescent personal factors play key roles in inducing AIA. Adolescents having aforementioned personal characteristics and online behaviors are at high-risk of developing AIA that may compound different psychological symptoms associated with AIA. Spending excessive time online is not in itself a defining symptom of AIA. More attention is needed on adolescent excessive weekend internet-use in prevention of potential internet addicts.
Angiotensin II type 1 and type 2 receptor expression in circulating monocytes of diabetic and hypercholesterolemic patients over 3-month rosuvastatin treatment
Authors: Marino Franca , Maresca Andrea Maria , Cosentino Marco , Castiglioni Luana , Rasini Emanuela , Mongiardi Christian , Maio Ramona C , Legnaro Massimiliano , Schembri Laura , Dentali Francesco , Grandi Anna Maria , Guasti Luigina
Published: December 2012

Background

In diabetes, a variety of pro-inflammatory cellular changes has been found in various cell types, including monocytes which are known to be involved in all the phases of atherogenesis. Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the pro-atherogenic effects of Ang II whereas the type 2 receptor (AT2R) seems associated with atheroprotection. We sought to investigate the potential changes of AT1R-AT2R expression in human monocytes of type 2 diabetic- hypercholesterolemic patients and in hypercholesterolemic subjects, upon clinical treatment with rosuvastatin.

Methods

The AT1R membrane protein and mRNA AT1R and AT2R expression in monocytes were investigated in 10 type 2 diabetic-hypercholesterolemic patients and in 10 hypercholesterolemic subjects, before and after 3-month rosuvastatin treatment. Moreover, the serum cytokine levels of interferon-γ (IFN-γ) and interleukin-4 (IL-4) were detected.

Results

As expected, rosuvastatin was associated with a change in the lipid profile in the two groups. Both the membrane protein (P = 0.008) and the AT1R mRNA expression (P = 0.038) were significantly reduced during treatment in the absence of AT2R expression change in diabetic-hypercholesterolemic patients whereas no significant difference was observed in hypercholesterolemic subjects. The serum IL-4 levels were increased during treatment whereas no change was observed in IFN-γ in diabetic-hypercholesterolemic patients. No cytokine change was observed in hypercholesterolemic subjects.

Conclusions

Our study on monocytes of diabetic-hypercholesterolemic patients, showing a reduced AT1R but not AT2R expression during rosuvastatin treatment, suggests that statin therapy may modulate favorably the AT1-AT2 receptor balance in subjects with coexistent type 2 diabetes.
Bioinformatic identification of Mycobacterium tuberculosis proteins likely to target host cell mitochondria: virulence factors?
Authors: Moreno-Altamirano María Maximina Bertha , Paredes-González Iris Selene , Espitia Clara , Santiago-Maldonado Mauricio , Hernández-Pando Rogelio , Sánchez-García Francisco Javier
Published: December 2012

Background

M. tuberculosis infection either induces or inhibits host cell death, depending on the bacterial strain and the cell microenvironment. There is evidence suggesting a role for mitochondria in these processes.

On the other hand, it has been shown that several bacterial proteins are able to target mitochondria, playing a critical role in bacterial pathogenesis and modulation of cell death. However, mycobacteria–derived proteins able to target host cell mitochondria are less studied.

Results

A bioinformaic analysis based on available genomic sequences of the common laboratory virulent reference strain Mycobacterium tuberculosis H37Rv, the avirulent strain H37Ra, the clinical isolate CDC1551, and M. bovis BCG Pasteur strain 1173P2, as well as of suitable bioinformatic tools (MitoProt II, PSORT II, and SignalP) for the in silico search for proteins likely to be secreted by mycobacteria that could target host cell mitochondria, showed that at least 19 M. tuberculosis proteins could possibly target host cell mitochondria. We experimentally tested this bioinformatic prediction on four M. tuberculosis recombinant proteins chosen from this list of 19 proteins (p27, PE_PGRS1, PE_PGRS33, and MT_1866). Confocal microscopy analyses showed that p27, and PE_PGRS33 proteins colocalize with mitochondria.

Conclusions

Based on the bioinformatic analysis of whole M. tuberculosis genome sequences, we propose that at least 19 out of 4,246 M. tuberculosis predicted proteins would be able to target host cell mitochondria and, in turn, control mitochondrial physiology. Interestingly, such a list of 19 proteins includes five members of a mycobacteria specific family of proteins (PE/PE_PGRS) thought to be virulence factors, and p27, a well known virulence factor. P27, and PE_PGRS33 proteins experimentally showed to target mitochondria in J774 cells. Our results suggest a link between mitochondrial targeting of M. tuberculosis proteins and virulence.
Screening of recombinant proteins as antigens in indirect ELISA for diagnosis of bovine tuberculosis
Authors: Souza Ingrid IF , Melo Elaine SP , Ramos Carlos AN , Farias Thaís A , Osório Ana Luiza AR , Jorge Klaudia SG , Vidal Carlos ES , Silva Altino S , Silva Márcio R , Pellegrin Aiesca O , Araújo Flábio R
Published: December 2012

Bovine tuberculosis is an important infectious disease caused by Mycobacterium bovis, which is responsible for considerable economic losses. This disease constitutes a serious public health problem. Control programs in most countries, including Brazil, are based on the identification and slaughter of infected animals, as defined by the skin tuberculin test, which has its constraints. In the present study, the recombinant proteins CFP-10, ESAT-6, Mb0143, MPB83, PE5, PE13, TB10.4, TB15.3 and a chimera of ESAT-6/MPB70/MPB83 (fusion protein) were tested as ELISA antigens for the diagnosis of bovine tuberculosis. The proteins were produced in Escherichia coli, purified and tested in ELISAs with sera from 126 cattle having tested negative in the comparative intradermal tuberculin test (CITT) and 107 sera from cattle having tested positive in the CITT. Also, 236 sera from two BTB-free beef cattle herds were tested. Among the proteins tested, only the ESAT-6/MPB70/MPB83 chimera demonstrated satisfactory agreement with the CITT (kappa index: 0.688), reflecting in 83.2% sensitivity and 86.5% specificity. The ELISA absorbances of the cattle sera from BTB-free herds showed similar levels to those of CITT positive cattle, probably as the result of successive skin tuberculinizations to define the BTB-free status of the herds. However, the ELISA with the ESAT-6/MPB70/MPB83 chimera was useful to discriminate BTB positive and negative cattle in herds prior to the tuberculin skin test.
Semi-analytic algorithms for the electrohydrodynamic flow equation
Authors: Pandey Ram K , Baranwal Vipul K , Singh Chandra S , Singh Om P
Published: December 2012

In this paper, we consider the nonlinear boundary value problem for the electrohydrodynamic (EHD) flow of a fluid in an ion-drag configuration in a circular cylindrical conduit. This phenomenon is governed by a nonlinear second-order differential equation. The degree of nonlinearity is determined by a nondimensional parameter α. We present two semi-analytic algorithms to solve the EHD flow equation for various values of relevant parameters based on optimal homotopy asymptotic method (OHAM) and optimal homotopy analysis method. In 1999, Paullet has shown that for large α, the solutions are qualitatively different from those calculated by Mckee in 1997. Both of our solutions obtained by OHAM and optimal homotopy analysis method are qualitatively similar with Paullet’s solutions.
Genomic vulnerability to LINE-1 hypomethylation is a potential determinant of the clinicogenetic features of multiple myeloma
Authors: Aoki Yuka , Nojima Masanori , Suzuki Hiromu , Yasui Hiroshi , Maruyama Reo , Yamamoto Eiichiro , Ashida Masami , Itagaki Mitsuhiro , Asaoku Hideki , Ikeda Hiroshi , Hayashi Toshiaki , Imai Kohzoh , Mori Mitsuru , Tokino Takashi , Ishida Tadao , Toyota Minoru , Shinomura Yasuhisa
Published: December 2012

Background

The aim of this study was to clarify the role of global hypomethylation of repetitive elements in determining the genetic and clinical features of multiple myeloma (MM).

Methods

We assessed global methylation levels using four repetitive elements (long interspersed nuclear element-1 (LINE-1), Alu Ya5, Alu Yb8, and Satellite-α) in clinical samples comprising 74 MM samples and 11 benign control samples (7 cases of monoclonal gammopathy of undetermined significance (MGUS) and 4 samples of normal plasma cells (NPC)). We also evaluated copy-number alterations using array-based comparative genomic hybridization, and performed methyl-CpG binding domain sequencing (MBD-seq).

Results

Global levels of the repetitive-element methylation declined with the degree of malignancy of plasma cells (NPC>MGUS>MM), and there was a significant inverse correlation between the degree of genomic loss and the LINE-1 methylation levels. We identified 80 genomic loci as common breakpoints (CBPs) around commonly lost regions, which were significantly associated with increased LINE-1 densities. MBD-seq analysis revealed that average DNA-methylation levels at the CBP loci and relative methylation levels in regions with higher LINE-1 densities also declined during the development of MM. We confirmed that levels of methylation of the 5' untranslated region of respective LINE-1 loci correlated strongly with global LINE-1 methylation levels. Finally, there was a significant association between LINE-1 hypomethylation and poorer overall survival (hazard ratio 2.8, P = 0.015).

Conclusion

Global hypomethylation of LINE-1 is associated with the progression of and poorer prognosis for MM, possibly due to frequent copy-number loss.
Beclin 1 Enhances Proteasome Inhibition-Mediated Cytotoxicity of Thyroid Cancer Cells in Macroautophagy-Independent Manner
Authors: Zhang Hai-Yan , Du Zhen-Xian , Meng Xin , Zong Zhi-Hong , Wang Hua-Qin
Published: December 2012

Context:

The ubiquitin–proteasome system and macroautophagy are two major pathways for intracellular protein degradation. Emerging lines of evidence have shown that blockade of ubiquitin–proteasome system by proteasome inhibitors activates macroautophagy.

Objective:

The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors.

Design:

Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy, as well as LC3-II transition using Western blot. To ascertain the effect of Beclin 1, cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1. Cell viability and apoptotic cells were measured using MTT assay and flow cytometry, respectively.

Results:

Proteasome inhibitors decreased Beclin 1 expression. In addition, treatment with PI3K inhibitors 3-MA or wortmannin, as well as knockdown of Beclin 1 expression, was unable to affect autophagic responses mediated by proteasome inhibitors. Overexpression of Beclin 1 enhanced proteasome inhibitor–mediated cytotoxicity of thyroid cancer cells via suppression of survivin.

Conclusions:

Proteasome inhibitors cause Beclin 1–independent macroautophagic responses of thyroid cancer cells in a Beclin 1–independent manner. Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors.
Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS
Authors: Agrawal Nishant , Jiao Yuchen , Sausen Mark , Leary Rebecca , Bettegowda Chetan , Roberts Nicholas J. , Bhan Sheetal , Ho Allen S. , Khan Zubair , Bishop Justin , Westra William H. , Wood Laura D. , Hruban Ralph H. , Tufano Ralph P. , Robinson Bruce , Dralle Henning , Toledo Sergio P. A. , Toledo Rodrigo A. , Morris Luc G. T. , Ghossein Ronald A. , Fagin James A. , Chan Timothy A. , Velculescu Victor E. , Vogelstein Bert , Kinzler Kenneth W. , Papadopoulos Nickolas , Nelkin Barry D. , Ball Douglas W.
Published: December 2012

Context:

Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome.

Objective:

To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs.

Patients and Design:

We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC.

Results:

We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons.

Conclusions:

Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.
The June Surprises: Balls, Strikes, and the Fog of War
Authors: Fried Charles
Published: December 2012

At first, few constitutional experts took seriously the argument that the Patient Protection and Affordable Care Act exceeded Congress's power under the commerce clause. The highly political opinions of two federal district judges — carefully chosen by challenging plaintiffs — of no particular distinction did not shake that confidence that the act was constitutional. This disdain for the challengers' arguments was only confirmed when the act was upheld by two highly respected conservative court of appeals judges in two separate circuits. But after the hostile, even mocking questioning of the government's advocate in the Supreme Court by the five Republican-appointed justices, the expectation was that the act would indeed be struck down on that ground. So it came as no surprise when the five opined the act did indeed exceed Congress's commerce clause power. But it came as a great surprise when Chief Justice John Roberts, joined by the four Democrat-appointed justices, ruled that the act could be sustained as an exercise of Congress's taxing power — a ground urged by the government almost as an afterthought. It was further surprising, even shocking, that Justices Antonin Scalia, Anthony Kennedy, Clarence Thomas, and Samuel Alito not only wrote a joint opinion on the commerce clause virtually identical to that of their chief, but that in writing it they did not refer to or even acknowledge his opinion. Finally surprising was the fact that Justices Ruth Bader Ginsburg and Stephen Breyer joined the chief in holding that aspects of the act's Medicaid expansion were unconstitutional. This essay ponders and tries to unravel some of these puzzles.
Legal, Imagined, and Real Worlds: Reflections on National Federation of Independent Business V. Sebelius
Authors: Mashaw Jerry L.
Published: December 2012

Chief Justice John Roberts's opinion upholding the individual mandate in the Patient Protection and Affordable Care Act has been hailed as an act of judicial statesmanship that saved the Supreme Court from serious criticism as a partisan, political institution. This article argues that any such praise should be tempered by an understanding of just how far outside mainstream legal understandings the chief justice's opinion strayed when considering constitutional issues that were unnecessary to the decision of the case and, in one instance, not ripe for judicial review. Except in its narrow result upholding the mandate, the chief justice's opinion is heedless of long-standing precedent, aggressive in creating novel grounds for judicial second-guessing of legislative judgments, cavalier with factual assertions, and disrespectful of the position of other governmental institutions.
Motherhood Preconceived: The Emergence of the Preconception Health and Health Care Initiative
Authors: Waggoner Miranda R.
Published: December 2012

Since the 1980s, maternal and child health experts have sought to redefine maternity care to include the period prior to pregnancy, essentially by expanding the concept of prenatal care to encompass the time before conception. In 2004, the Centers for Disease Control and Prevention endorsed and promoted this new definition when it launched the Preconception Health and Health Care Initiative. In arguing that prenatal care was often too little too late, a group of maternal and child health experts in the United States attempted to spur improvements in population health and address systemic problems in health care access and health disparities. By changing the terms of pregnancy risk and by using maternalism as a social policy strategy, the preconception health and health care paradigm promoted an ethic of anticipatory motherhood and conflated women's health with maternal health, sparking public debate about the potential social and clinical consequences of preconception care. This article tracks the construction of this policy idea and its ultimate potential utility in health and health policy discussions.
The Heart of Patient-Centered Care
Authors: Grob Rachel
Published: December 2012

This article examines the multiple aspirations and practices subsumed under the rubric “patient-centered care.” Clarifying the term's meaning is essential to understanding its impact on policy discourse and health care.