bluuebunny/crossref_metadata_2025 huggingface dataset:
Global similarity and local divergence in human and mouse gene co-expression networks
Authors: Tsaparas Panayiotis , Mariño-Ramírez Leonardo , Bodenreider Olivier , Koonin Eugene V , Jordan I King
Published: September 2006

Background

A genome-wide comparative analysis of human and mouse gene expression patterns was performed in order to evaluate the evolutionary divergence of mammalian gene expression. Tissue-specific expression profiles were analyzed for 9,105 human-mouse orthologous gene pairs across 28 tissues. Expression profiles were resolved into species-specific coexpression networks, and the topological properties of the networks were compared between species.

Results

At the global level, the topological properties of the human and mouse gene coexpression networks are, essentially, identical. For instance, both networks have topologies with small-world and scale-free properties as well as closely similar average node degrees, clustering coefficients, and path lengths. However, the human and mouse coexpression networks are highly divergent at the local level: only a small fraction (<10%) of coexpressed gene pair relationships are conserved between the two species. A series of controls for experimental and biological variance show that most of this divergence does not result from experimental noise. We further show that, while the expression divergence between species is genuinely rapid, expression does not evolve free from selective (functional) constraint. Indeed, the coexpression networks analyzed here are demonstrably functionally coherent as indicated by the functional similarity of coexpressed gene pairs, and this pattern is most pronounced in the conserved human-mouse intersection network. Numerous dense network clusters show evidence of dedicated functions, such as spermatogenesis and immune response, that are clearly consistent with the coherence of the expression patterns of their constituent gene members.

Conclusion

The dissonance between global versus local network divergence suggests that the interspecies similarity of the global network properties is of limited biological significance, at best, and that the biologically relevant aspects of the architectures of gene coexpression are specific and particular, rather than universal. Nevertheless, there is substantial evolutionary conservation of the local network structure which is compatible with the notion that gene coexpression networks are subject to purifying selection.
Incidence of epidural haematoma and neurological injury in cardiovascular patients with epidural analgesia/anaesthesia: systematic review and meta-analysis
Authors: Ruppen Wilhelm , Derry Sheena , McQuay Henry J , Moore R Andrew
Published: September 2006

Background

Epidural anaesthesia is used extensively for cardiothoracic and vascular surgery in some centres, but not in others, with argument over the safety of the technique in patients who are usually extensively anticoagulated before, during, and after surgery. The principle concern is bleeding in the epidural space, leading to transient or persistent neurological problems.

Methods

We performed an extensive systematic review to find published cohorts of use of epidural catheters during vascular, cardiac, and thoracic surgery, using electronic searching, hand searching, and reference lists of retrieved articles.

Results

Twelve studies included 14,105 patients, of whom 5,026 (36%) had vascular surgery, 4,971 (35%) cardiac surgery, and 4,108 (29%) thoracic surgery. There were no cases of epidural haematoma, giving maximum risks following epidural anaesthesia in cardiac, thoracic, and vascular surgery of 1 in 1,700, 1 in 1,400 and 1 in 1,700 respectively. In all these surgery types combined the maximum expected rate would be 1 in 4,700. In all these patients combined there were eight cases of transient neurological injury, a rate of 1 in 1,700 (95% confidence interval 1 in 3,300 to 1 in 850). There were no cases of persistent neurological injury (maximum expected rate 1 in 4,600).

Conclusion

These estimates for cardiothoracic epidural anaesthesia should be the worst case. Limitations are inadequate denominators for different types of surgery in anticoagulated cardiothoracic or vascular patients more at risk of bleeding.
Efficacy and clinical effectiveness of influenza vaccines in HIV-infected individuals: a meta-analysis
Authors: Atashili Julius , Kalilani Linda , Adimora Adaora A
Published: September 2006

Background

Though influenza vaccines are the cornerstone of medical interventions aimed at protecting individuals against epidemic influenza, their effectiveness in HIV infected individuals is not certain. With the recent detection of influenza strains in countries with high HIV prevalence rates, we aimed at evaluating the current evidence on the efficacy and clinical effectiveness of influenza vaccines in HIV-infected individuals.

Methods

We used electronic databases to identify studies assessing efficacy or effectiveness of influenza vaccines in HIV patients. We included studies that compared the incidence of culture- or serologically-confirmed influenza or clinical influenza-like illness in vaccinated to unvaccinated HIV infected individuals. Characteristics of study participants were independently abstracted and the risk difference (RD), the number needed to vaccinate to prevent one case of influenza (NNV) and the vaccine effectiveness (VE) computed.

Results

We identified six studies that assessed the incidence of influenza in vaccinated HIV-infected subjects. Four of these studies compared the incidence in vaccinated versus unvaccinated subjects. These involved a total of 646 HIV-infected subjects. In all the 4 studies, the incidence of influenza was lower in the vaccinated compared to unvaccinated subjects with RD ranging from -0.48 (95% CI: -0.63, -0.34) to -0.15 (95% CI: -0.25, 0.05); between 3 and 7 people would need to be vaccinated to prevent one case of influenza. Vaccine effectiveness ranged from 27% to 78%. A random effects model was used to obtain a summary RD of -0.27 (95%CI: -0.42, -0.11). There was no evidence of publication bias.

Conclusion

Current evidence, though limited, suggests that influenza vaccines are moderately effective in reducing the incidence of influenza in HIV-infected individuals. With the threat of a global influenza pandemic, there is an urgent need to evaluate the effectiveness of influenza vaccines in trials with a larger number of representative HIV-infected persons.
Echocardiographic partition values and prevalence of left ventricular hypertrophy in hypertensive Nigerians
Authors: Adebiyi Adewole A , Ogah Okechukwu S , Aje Akinyemi , Ojji Dike B , Adebayo Adedeji K , Oladapo Olulola O , Falase Ayodele O
Published: September 2006

Background

Left ventricular hypertrophy (LVH) is a well known independent risk factor for cardiovascular events. It has been shown that combination of left ventricular mass (LVM) and relative wall thickness (RWT) can be used to identify different forms of left ventricular (LV) geometry. Prospective studies have shown that LV geometric patterns have prognostic implications, with the worst prognosis associated with concentric hypertrophy. The methods for the normalization or indexation of LVM have also recently been shown to confer some prognostic value especially in obese population. We sought to determine the prevalence of echocardiographic lLVH using eight different and published cut-off or threshold values in hypertensive subjects seen in a developing country's tertiary centre.

Methods

Echocardiography was performed in four hundred and eighty consecutive hypertensive subjects attending the cardiology clinic of the University college Hospital Ibadan, Nigeria over a two-year period.

Results

Complete data was obtained in 457 (95.2%) of the 480 subjects (48.6% women). The prevalence of LVH ranged between 30.9–56.0%. The highest prevalence was when LVM was indexed to the power of 2.7 with a partition value of 49.2 g/ht2.7 in men and 46.7 g/ht2.7 in women. The lowest prevalence was observed when LVM was indexed to body surface area (BSA) and a partition value of 125 g/m2 was used for both sexes. Abnormal LV geometry was present in 61.1%–74.0% of our subjects and commoner in women.

Conclusion

The prevalence of LVH hypertensive patients is strongly dependent on the cut-off value used to define it. Large-scale prospective study will be needed to determine the prognostic implications of the different LV geometry in native Africans.
Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8
Authors: De Bortoli Massimiliano , Castellino Robert C , Lu Xin-Yan , Deyo Jeffrey , Sturla Lisa Marie , Adesina Adekunle M , Perlaky Laszlo , Pomeroy Scott L , Lau Ching C , Man Tsz-Kwong , Rao Pulivarthi H , Kim John YH
Published: September 2006

Background

Medulloblastoma is the most common malignant brain tumor of childhood. Improvements in clinical outcome require a better understanding of the genetic alterations to identify clinically significant biological factors and to stratify patients accordingly. In the present study, we applied cytogenetic characterization to guide the identification of biologically significant genes from gene expression microarray profiles of medulloblastoma.

Methods

We analyzed 71 primary medulloblastomas for chromosomal copy number aberrations (CNAs) using comparative genomic hybridization (CGH). Among 64 tumors that we previously analyzed by gene expression microarrays, 27 were included in our CGH series. We analyzed clinical outcome with respect to CNAs and microarray results. We filtered microarray data using specific CNAs to detect differentially expressed candidate genes associated with survival.

Results

The most frequent lesions detected in our series involved chromosome 17; loss of 16q, 10q, or 8p; and gain of 7q or 2p. Recurrent amplifications at 2p23-p24, 2q14, 7q34, and 12p13 were also observed. Gain of 8q is associated with worse overall survival (p = 0.0141), which is not entirely attributable to MYC amplification or overexpression. By applying CGH results to gene expression analysis of medulloblastoma, we identified three 8q-mapped genes that are associated with overall survival in the larger group of 64 patients (p < 0.05): eukaryotic translation elongation factor 1D (EEF1D), ribosomal protein L30 (RPL30), and ribosomal protein S20 (RPS20).

Conclusion

The complementary use of CGH and expression profiles can facilitate the identification of clinically significant candidate genes involved in medulloblastoma growth. We demonstrate that gain of 8q and expression levels of three 8q-mapped candidate genes (EEF1D, RPL30, RPS20) are associated with adverse outcome in medulloblastoma.
Breast cancer risk associated with different HRT formulations: a register-based case-control study
Authors: Dinger Juergen C , Heinemann Lothar AJ , Möhner Sabine , Thai Do Minh , Assmann Anita
Published: September 2006

Background

Previous epidemiological studies have inconsistently shown a modestly increased breast cancer risk associated with hormone replacement therapy (HRT). Limited information is available about different formulations – particularly concerning different progestins.

Methods

A case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched breast cancer cases. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to compare the risk of different estrogens, progestins, and combinations.

Results

A total of 3593 cases of breast cancer were identified and compared with 9098 controls. The adjusted overall risk estimate for breast cancer (BC) associated with current or past use of HRT was 1.2 (1.1–1.3), and almost identical for lag times from 6 months to 6 years prior to diagnosis. No significant trend of increasing BC risk was found with increasing duration of HRT use, or time since first or last use in aggregate. Many established BC risk factors significantly modified the effect of HRT on BC risk, particularly first-degree family history of BC, higher age, lower education, higher body mass index (BMI), and never having used oral contraceptives (OCs) during lifetime.

Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT formulation groups (estrogens, progestins, and combinations) were too small for strong conclusions. Nevertheless, the BC risk seems not to vary much across HRT formulation subgroups. In particular, no substantial difference in BC risk was observed between HRT containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe.

Conclusion

The BC risk of HRT use is rather small. Low risk estimates for BC and a high potential for residual confounding and bias in this observational study do not permit causal conclusions. Apparently, there is not much variation of the BC risk across HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of some of the subgroups suggest cautious interpretation.
Oxygen cost of dynamic or isometric exercise relative to recruited muscle mass
Authors: Elder Christopher P , Mahoney Edward T , Black Christopher D , Slade Jill M , Dudley Gary A
Published: September 2006

Background

Oxygen cost of different muscle actions may be influenced by different recruitment and rate coding strategies. The purpose of this study was to account for these strategies by comparing the oxygen cost of dynamic and isometric muscle actions relative to the muscle mass recruited via surface electrical stimulation of the knee extensors.

Methods

Comparisons of whole body pulmonary ΔV˙MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWGwbGvgaGaaaaa@2DEA@O2were made in seven young healthy adults (1 female) during 3 minutes of dynamic or isometric knee extensions, both induced by surface electrical stimulation. Recruited mass was quantified in T2weighted spin echo magnetic resonance images.

Results

The ΔV˙MathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuWGwbGvgaGaaaaa@2DEA@O2for dynamic muscle actions, 242 ± 128 ml • min-1(mean ± SD) was greater (p = 0.003) than that for isometric actions, 143 ± 99 ml • min-1. Recruited muscle mass was also greater (p = 0.004) for dynamic exercise, 0.716 ± 282 versus 0.483 ± 0.139 kg. The rate of oxygen consumption per unit of recruited muscle (V˙O2RMMathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuqGwbGvgaGaaiabb+eapnaaBaaaleaacqaIYaGmdaahaaadbeqaaiabbkfasjabb2eanbaaaSqabaaaaa@32B0@) was similar in dynamic and isometric exercise (346 ± 162 versus 307 ± 198 ml • kg-1• min-1; p = 0.352), but theV˙O2RMMathType@MTEF@5@5@+=feaafiart1ev1aaatCvAUfKttLearuWrP9MDH5MBPbIqV92AaeXatLxBI9gBaebbnrfifHhDYfgasaacH8akY=wiFfYdH8Gipec8Eeeu0xXdbba9frFj0=OqFfea0dXdd9vqai=hGuQ8kuc9pgc9s8qqaq=dirpe0xb9q8qiLsFr0=vr0=vr0dc8meaabaqaciaacaGaaeqabaqabeGadaaakeaacuqGwbGvgaGaaiabb+eapnaaBaaaleaacqaIYaGmdaahaaadbeqaaiabbkfasjabb2eanbaaaSqabaaaaa@32B0@calculated relative to initial knee extensor torque was significantly greater during dynamic exercise 5.1 ± 1.5 versus 3.6 ± 1.6 ml • kg-1• Nm-1• min-1(p = 0.019).

Conclusion

These results are consistent with the view that oxygen cost of dynamic and isometric actions is determined by different circumstances of mechanical interaction between actin and myosin in the sarcomere, and that muscle recruitment has only a minor role.
Role of metabolically active hormones in the insulin resistance associated with short-term glucocorticoid treatment
Authors: Patel Jeetesh V , Cummings David E , Girod John P , Mascarenhas Alwin V , Hughes Elizabeth A , Gupta Manjula , Lip Gregory YH , Reddy Sethu , Brotman Daniel J
Published: September 2006

Background

The mechanisms by which glucocorticoid therapy promotes obesity and insulin resistance are incompletely characterized. Modulations of the metabolically active hormones, tumour necrosis factor alpha (TNF alpha), ghrelin, leptin and adiponectin are all implicated in the development of these cardiovascular risk factors. Little is known about the effects of short-term glucocorticoid treatment on levels of these hormones.

Research methods and procedures

Using a blinded, placebo-controlled approach, we randomised 25 healthy men (mean (SD) age: 24.2 (5.4) years) to 5 days of treatment with either placebo or oral dexamethasone 3 mg twice daily. Fasting plasma TNFα, ghrelin, leptin and adiponectin were measured before and after treatment.

Results

Mean changes in all hormones were no different between treatment arms, despite dexamethasone-related increases in body weight, blood pressure, HDL cholesterol and insulin. Changes in calculated indices of insulin sensitivity (HOMA-S, insulin sensitivity index) were strongly related to dexamethasone treatment (p < 0.001).

Discussion

Our data do not support a role for TNF alpha, ghrelin, leptin or adiponectin in the insulin resistance associated with short-term glucocorticoid treatment.
Correlation of symptom clusters of schizophrenia with absolute powers of main frequency bands in quantitative EEG
Authors: Gross Andres , Joutsiniemi Sirkka-Liisa , Rimon Ranan , Appelberg Björn
Published: September 2006

Background

Research of QEEG activity power spectra has shown intriguing results in patients with schizophrenia. Different symptom clusters have been correlated to QEEG frequency bands. The findings have been to some extent inconsistent. Replication of the findings of previous research is thus an important task. In the current study we investigated the correlations between the absolute powers of delta, theta, alpha, and beta frequency bands over the fronto-central scalp area (FC) with the PANSS subscales and the Liddle's factors in 16 patients with schizophrenia.

The authors hypothesised a priori the correlations reported by Harris et al (1999) of PANSS negative subscale with delta power, Liddle's psychomotor poverty with delta and beta powers, disorganisation with delta power and reality distortion with alpha power on the midline FC.

Methods

The sample consisted of 16 patients with chronic schizophrenia considered as having insufficient clinical response to conventional antipsychotic treatment and evidencing a relapse. The correlations between quantitative electroencephalography (QEEG) absolute powers of delta (1.5–3.0 Hz), theta (3.0–7.5 Hz), alpha (7.5–12.5 Hz), and beta (12.5–20.0 Hz) frequency bands over the fronto-central scalp area (FC) with PANSS subscales and Liddle's factors (reality distortion, disorganisation, psychomotor poverty) were investigated.

Results

Significant positive correlations were found between the beta and psychomotor poverty (p < 0.05). Trends towards positive correlations (p < 0.1) were observed between delta and PANSS negative subscale and psychomotor poverty. Alpha did not correlate with reality distortion and delta did not correlate with disorganisation.

Post hoc analysis revealed correlations of the same magnitude between beta and psychopathology generally over FC.

Conclusion

The a priori hypothesis was partly supported by the correlation of the beta and psychomotor poverty. Liddle's factors showed correlations of the same magnitude with PANSS subscales. Supplementary analysis showed beta frequency correlating non-specifically over FC with a wide range of psychiatric symptomatology in patients with schizophrenia having a relapse.
The toxicity of cadmium and resulting hazards for human health
Authors: Godt Johannes , Scheidig Franziska , Grosse-Siestrup Christian , Esche Vera , Brandenburg Paul , Reich Andrea , Groneberg David A
Published: September 2006

Cadmium (Cd) has been in industrial use for a long period of time. Its serious toxicity moved into scientific focus during the middle of the last century. In this review, we discuss historic and recent developments of toxicological and epidemiological questions, including exposition sources, resorption pathways and organ damage processes.
Cdc45-MCM-GINS, a new power player for DNA replication
Authors: Aparicio Tomás , Ibarra Arkaitz , Méndez Juan
Published: September 2006

The identity of the DNA helicase(s) involved in eukaryotic DNA replication is still a matter of debate, but the mini-chromosome maintenance (MCM) proteins are the chief candidate. Six conserved MCM proteins, Mcm2–7, are essential for the initiation and elongation stages of DNA replication, contain ATP binding pockets and can form a hexameric structure resembling that of known prokaryotic and viral helicases. However, biochemical proof of their presumed function has remained elusive. Several recent reports confirm that the MCM complex is part of the cellular machine responsible for the unwinding of DNA during S phase. In one of these reports, the helicase activity of Mcm2–7 is finally revealed, when they are purified in association with two partners: initiation factor Cdc45 and a four-subunit complex called GINS. The Cdc45-MCM-GINS complex could constitute the core of a larger macromolecular structure that has been termed the "replisome progression complex".
Fatal stroke after completion pneumonectomy for torsion of left upper lobe following left lower lobectomy
Authors: Apostolakis Efstratios , Koletsis Efstratios N , Panagopoulos Nikolaos , Prokakis Christos , Dougenis Dimitrios
Published: September 2006

Background

The lobar torsion after lung surgery is a rare complication with an incidence of 0.09 to 0.4 %. It may occur after twisting of the bronchovascular pedicle of the remaining lobe after lobectomy, usually on the right side. The 180-degree rotation of the pedicle produces an acute obstruction of the lobar bronchus (atelectasis) and of the lobar vessels as well. Without prompt treatment it progresses to lobar ischemia, pulmonary infarction and finally fatal gangrene.

Case Presentation

A 62 years old female patient was admitted for surgical treatment of lung cancer. She underwent elective left lower lobectomy for squamous cell carcinoma (pT2 N0). The operation was unremarkable, and the patient was extubated in the operating room. After eight hours the patient established decrease of pO2 and chest x-ray showed atelectasis of the lower lobe. To establish diagnosis, bronchoscopy was performed, demonstrating obstructed left lobar bronchus. The patient was re-intubated, and admitted to the operating room where reopening of the thoracotomy was performed. Lobar torsion was diagnosed, with the diaphragmatic surface of the upper lobe facing in an anterosuperior orientation. A completion pneumonectomy was performed. At the end of the procedure the patient developed a right pupil dilatation, presumably due to a cerebral embolism. A subsequent brain angio-CT scan established the diagnosis. She died at the intensive care unit 26 days later.

Conclusion

The thoracic surgeon should suspect this rare early postoperative complication after any thoracic operation in every patient with atelectasis of the neighboring lobe. High index of suspicion and prompt diagnosis may prevent catastrophic consequences, such as, infarction or gangrene of the pulmonary lobe. During thoracic operations, especially whenever the lung or lobe hilum is full mobilized, fixation of the remaining lobe may prevent this life threatening complication.
Presence of antibodies against cyclic citrullinated peptides in patients with 'rhupus': a cross-sectional study
Authors: Amezcua-Guerra Luis M , Springall Rashidi , Marquez-Velasco Ricardo , Gómez-García Lorena , Vargas Angélica , Bojalil Rafael
Published: September 2006

'Rhupus' is a rare condition sharing features of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). If rhupus is a distinctive entity, an overlap between RA and SLE or a subset of SLE is currently debated. This study was performed to explore the prevalence of antibodies against cyclic citrullinated peptides (anti-CCP antibodies) in rhupus. Patients meeting American College of Rheumatology criteria for RA, SLE, or both were included. Clinical and radiographic features were recorded and sera were searched for anti-CCP antibodies, rheumatoid factor, antinuclear antibodies, anti-extractable nuclear antigens, and antibodies against double-stranded DNA (anti-dsDNA antibodies). Seven patients for each group were included. Clinical and serological features for RA or SLE were similar between rhupus and RA patients, and between rhupus and SLE patients, respectively. Values for anti-CCP antibodies obtained were significantly (p < 0.05) higher in RA (6/7) and rhupus (4/7) than in SLE patients (0/7) and healthy subjects (0/7). Our data support the possibility that rhupus is an overlap between RA and SLE, because highly specific autoantibodies for RA (anti-CCP) and for SLE (anti-dsDNA and anti-Sm) are detected in coexistence.
Follow-up of newborns treated with extracorporeal membrane oxygenation: a nationwide evaluation at 5 years of age
Authors: Hanekamp Manon N , Mazer Petra , van der Cammen-van Zijp Monique HM , van Kessel-Feddema Boudien JM , Nijhuis-van der Sanden Maria WG , Knuijt Simone , Zegers-Verstraeten Jessica LA , Gischler Saskia J , Tibboel Dick , Kollée Louis AA
Published: September 2006

Introduction

Extracorporeal membrane oxygenation (ECMO) is a supportive cardiopulmonary bypass technique for babies with acute reversible cardiorespiratory failure. We assessed morbidity in ECMO survivors at the age of five years, when they start primary school and major decisions for their school careers must be made.

Methods

Five-year-old neonatal venoarterial-ECMO survivors from the two designated ECMO centres in The Netherlands (Erasmus MC – Sophia Children's Hospital in Rotterdam, and University Medical Center Nijmegen) were assessed within the framework of an extensive follow-up programme. The protocol included medical assessment, neuromotor assessment, and psychological assessment by means of parent and teacher questionnaires.

Results

Seventeen of the 98 children included in the analysis (17%) were found to have neurological deficits. Six of those 17 (6% of the total) showed major disability. Two of those six children had a chromosomal abnormality. Three were mentally retarded and profoundly impaired. The sixth child had a right-sided hemiplegia. These six children did not undergo neuromotor assessment. Twenty-four of the remaining 92 children (26%) showed motor difficulties: 15% actually had a motor problem and 11% were at risk for this. Cognitive delay was identified in 11 children (14%). The mean IQ score was within the normal range (IQ = 100.5).

Conclusion

Neonatal ECMO in The Netherlands was found to be associated with considerable morbidity at five years of age. It appeared feasible to have as many as 87% of survivors participate in follow-up assessment, due to cooperation between two centres and small travelling distances. Objective evaluation of the long-term morbidity associated with the application of this highly invasive technology in the immediate neonatal period requires an interdisciplinary follow-up programme with nationwide consensus on timing and actual testing protocol.
Myocardial injury in infants ventilated on the paediatric intensive care unit: a case control study
Authors: Clark Simon J , Eisenhut Michael , Sidaras Dorothea , Hancock Stephen W , Newland Paul , Thorburn Kent
Published: September 2006

Introduction

Cardiac troponin T (cTnT) has been used to assess prevalence of myocardial injury in critically ill children. The majority of studies investigated patients undergoing cardiac surgery. Myocardial injury has been associated with increased mortality. Our objectives were to investigate whether cTnT levels are elevated in infants without congenital heart disease admitted to the paediatric intensive care unit (PICU) and whether levels are associated with increased disease severity.

Methods

We measured cTnT in consecutive infants (<12 months old) without congenital heart disease admitted to the PICU and healthy infants. The Paediatric Index of Mortality (PIM) score was determined in patients on the PICU.

Results

We recruited 107 infants: 47 infants admitted to the PICU and 60 healthy controls. Controls were, with a median (interquartile range (IQR)) age of 20 (12 to 34) weeks, significantly older than cases, with a median age of 6.5 (0.3 to 20.6) weeks. CTnT levels were, with a median (IQR) of 18 (10 to 60) pg/ml, significantly higher in admissions to the PICU than in controls, with a median level of 10 (10 to 10) pg/ml (95th centile of 20 pg/ml) (p < 0.001). There was a significant positive correlation (r = 0.41, p = 0.004) between PIM score and cTnT levels. Admissions under one month old had higher cTnT levels than older patients (p = 0.013) but the PIM score was not significantly different between them. When corrected for age and weight the correlation of PIM and cTnT was no longer significant.

Conclusion

Infants on the PICU in the neonatal period have higher cTnT levels compared to older infants despite not having more severe disease.
High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin
Authors: Yang De , Chen Qian , Yang Huan , Tracey Kevin J , Bustin Michael , Oppenheim Joost J
Published: September 2006

High mobility group box-1 (HMGB1) protein is a nonhistone, DNA-binding protein that plays a critical role in regulating gene transcription. Recently, HMGB1 has also been shown to act as a late mediator of endotoxic shock and to exert a variety of proinflammatory, extracellular activities. Here, we report that HMGB1 simultaneously acts as a chemoattractant and activator of dendritic cells (DCs). HMGB1 induced the migration of monocyte-derived, immature DCs (Mo-iDCs) but not mature DCs. The chemotactic effect of HMGB1 on iDCs was pertussis toxin-inhibitable and also inhibited by antibody against the receptor of advanced glycation end products (RAGE), suggesting that HMGB1 chemoattraction of iDCs is mediated by RAGE in a Gi protein-dependent manner. In addition, HMGB1 treatment of Mo-iDCs up-regulated DC surface markers (CD80, CD83, CD86, and HLA-A, B,C), enhanced DC production of cytokines (IL-6, CXCL8, IL-12p70, and TNF-α), switched DC chemokine responsiveness from CCL5-sensitive to CCL21-sensitive, and acquired the capacity to stimulate allogeneic T cell proliferation. Based on its dual DC-attracting and -activating activities as well as its reported capacity to promote an antigen-specific immune response, we consider HMGB1 to have the properties of an immune alarmin.
IRF-1 deficiency skews the differentiation of dendritic cells toward plasmacytoid and tolerogenic features
Authors: Gabriele L , Fragale A , Borghi P , Sestili P , Stellacci E , Venditti M , Schiavoni G , Sanchez M , Belardelli F , Battistini A
Published: September 2006

Members of the IFN regulatory factors (IRFs) family are transcriptional regulators that play essential roles in the homeostasis and function of the immune system. Recent studies indicate a direct involvement of some members of the family in the development of different subsets of dendritic cells (DC). Here, we report that IRF-1 is a potent modulator of the development and functional maturation of DC. IRF-1-deficient mice (IRF-1−/−) exhibited a predominance of plasmacytoid DC and a selective reduction of conventional DC, especially the CD8α+ subset. IRF-1−/− splenic DC were markedly impaired in their ability to produce proinflammatory cytokines such as IL-12. By contrast, they expressed high levels of IL-10, TGF-β, and the tolerogenic enzyme indoleamine 2,3 dioxygenase. As a consequence, IRF-1−/− DC were unable to undergo full maturation and retained plasmacytoid and tolerogenic characteristics following virus infection ex vivo and in vivo. Accordingly, DC from IRF-1−/− mice were less efficient in stimulating the proliferation of allogeneic T cells and instead, induced an IL-10-mediated, suppressive activity in allogeneic CD4+CD25+ regulatory T cells. Together, these results indicate that IRF-1 is a key regulator of DC differentiation and maturation, exerting a variety of effects on the functional activation and tolerogenic potential of these cells.
MicroRNA Expression Abnormalities in Pancreatic Endocrine and Acinar Tumors Are Associated With Distinctive Pathologic Features and Clinical Behavior
Authors: Roldo Claudia , Missiaglia Edoardo , Hagan John P. , Falconi Massimo , Capelli Paola , Bersani Samantha , Calin George Adrian , Volinia Stefano , Liu Chang-Gong , Scarpa Aldo , Croce Carlo M.
Published: September 2006

Purpose

We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies.

Materials and Methods

Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas.

Results

Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis.

Conclusion

These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.
Phase II Study of Belagenpumatucel-L, a Transforming Growth Factor Beta-2 Antisense Gene-Modified Allogeneic Tumor Cell Vaccine in Non–Small-Cell Lung Cancer
Authors: Nemunaitis John , Dillman Robert O. , Schwarzenberger Paul O. , Senzer Neil , Cunningham Casey , Cutler Jodi , Tong Alex , Kumar Padmasini , Pappen Beena , Hamilton Cody , DeVol Edward , Maples Phillip B. , Liu Lily , Chamberlin Terry , Shawler Daniel L. , Fakhrai Habib
Published: September 2006

Purpose

Belagenpumatucel-L is a nonviral gene-based allogeneic tumor cell vaccine that demonstrates enhancement of tumor antigen recognition as a result of transforming growth factor beta-2 inhibition.

Patients and Methods

We performed a randomized, dose-variable, phase II trial involving stages II, IIIA, IIIB, and IV non–small-cell lung cancer patients. Each patient received one of three doses (1.25, 2.5, or 5.0 × 107cells/injection) of belagenpumatucel-L on a monthly or every other month schedule to a maximum of 16 injections. Immune function, safety, and anticancer activity were monitored.

Results

Seventy-five patients (two stage II, 12 stage IIIA, 15 stage IIIB, and 46 stage IV patients) received a total of 550 vaccinations. No significant adverse events were observed. A dose-related survival difference was demonstrated in patients who received ≥ 2.5 × 107cells/injection (P = .0069). Focusing on the 61 late-stage (IIIB and IV) assessable patients, a 15% partial response rate was achieved. The estimated probabilities of surviving 1 and 2 years were 68% and 52%, respectively for the higher dose groups combined and 39% and 20%, respectively, for the low-dose group. Immune function was explored in the 61 advanced-stage (IIIB and IV) patients. Increased cytokine production (at week 12 compared with patients with progressive disease) was observed among clinical responders (interferon gamma, P = .006; interleukin [IL] -6, P = .004; IL-4, P = .007), who also displayed an elevated antibody-mediated response to vaccine HLAs (P = .014). Furthermore, positive enzyme-linked immunospot reactions to belagenpumatucel-L showed a correlation trend (P = .086) with clinical responsiveness in patients achieving stable disease or better.

Conclusion

Belagenpumatucel-L is well tolerated, and the survival advantage justifies further phase III evaluation.
Loss of Heterozygosity 1p36 and 19q13 Is a Prognostic Factor for Overall Survival in Patients With Diffuse WHO Grade 2 Gliomas Treated Without Chemotherapy
Authors: Mariani Luigi , Deiana Gianluca , Vassella Erik , Fathi Ali-Reza , Murtin Christine , Arnold Marlène , Vajtai Istvan , Weis Joachim , Siegenthaler Peter , Schobesberger Martina , Reinert Michael M.
Published: September 2006

Purpose

This study was conducted to elucidate the impact of loss of heterozygosity (LOH) for chromosomes 1p36 and 19q13 on the overall survival of patients with diffusely infiltrating WHO grade 2 gliomas treated without chemotherapy.

Patients and Methods

We assessed the LOH status of tumors from patients harboring WHO grade 2 gliomas diagnosed between 1991 and 2000. Patients were either followed after initial biopsy or treated by surgery and/or radiation therapy (RT). Overall survival, time to malignant transformation, and progression-free survival were last updated as of March 2005.

Results

Of a total of 79 patients, LOH 1p36 and LOH 19q13 could be assessed in 67 and 66 patients, respectively. The median follow-up after diagnosis was 6 years. Loss of either 1p or 19q, in particular codeletion(s) at both loci, was found to positively impact on both overall survival (log-rank P < .01), progression-free survival, and survival without malignant transformation (P < .05). Tumor volume (P < .0001), neurologic deficits at diagnosis (P < .01), involvement of more than one lobe (P < .01), and absence of an oligodendroglial component (P < .05) were also predictors of shorter overall survival. The extent of surgery was similar in patients with or without LOH 1p and/or 19q; RT was more frequently resorted to for patients without than for patients with LOH 1p/19q (30% v 60%).

Conclusion

The presence of LOH on either 1p36 or 19q13, and in particular codeletion of both loci is a strong, nontreatment-related, prognostic factor for overall survival in patients with diffusely infiltrating WHO grade 2 gliomas.
Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group
Authors: Bedikian Agop Y. , Millward Michael , Pehamberger Hubert , Conry Robert , Gore Martin , Trefzer Uwe , Pavlick Anna C. , DeConti Ronald , Hersh Evan M. , Hersey Peter , Kirkwood John M. , Haluska Frank G.
Published: September 2006

Purpose

Chemotherapy resistance in melanoma has been linked to antiapoptotic effects mediated by Bcl-2 protein. We evaluated whether targeting Bcl-2 using an antisense oligonucleotide (oblimersen sodium) could improve the efficacy of systemic chemotherapy in patients with advanced melanoma.

Patients and Methods

We randomly assigned chemotherapy-naïve patients with advanced melanoma to treatment with dacarbazine (1,000 mg/m2) alone or preceded by a 5-day continuous intravenous infusion of oblimersen sodium (7 mg/kg/d) every 3 weeks for up to eight cycles. Patients were stratified by Eastern Cooperative Oncology Group performance status, liver metastases, disease site, and serum lactate dehydrogenase (LDH). The primary efficacy end point was overall survival.

Results

Among 771 patients randomly assigned, the addition of oblimersen to dacarbazine yielded a trend toward improved survival at 24-month minimum follow-up (median, 9.0 v 7.8 months; P = .077) and significant increases in progression-free survival (median, 2.6 v 1.6 months; P < .001), overall response (13.5% v 7.5%; P = .007), complete response (2.8% v 0.8%), and durable response (7.3% v 3.6%; P = .03). A significant interaction between baseline serum LDH and treatment was observed; oblimersen significantly increased survival in patients whose baseline serum LDH was not elevated (median overall survival, 11.4 v 9.7 months; P = .02). Neutropenia and thrombocytopenia were increased in the oblimersen-dacarbazine group; however, there was no increase in serious infections or bleeding events.

Conclusion

The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.
Gemcitabine Plus Carboplatin Compared With Carboplatin in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: An Intergroup Trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG
Authors: Pfisterer Jacobus , Plante Marie , Vergote Ignace , du Bois Andreas , Hirte Hal , Lacave Angel J. , Wagner Uwe , Stähle Anne , Stuart Gavin , Kimmig Rainer , Olbricht Sigrid , Le Tien , Emerich Janusz , Kuhn Walther , Bentley James , Jackisch Christian , Lück Hans-Joachim , Rochon Justine , Zimmermann Annamaria Hayden , Eisenhauer Elizabeth
Published: September 2006

Purpose

Most patients with advanced ovarian cancer develop recurrent disease. For those patients who recur at least 6 months after initial therapy, paclitaxel platinum has shown a modest survival advantage over platinum without paclitaxel; however, many patients develop clinically relevant neurotoxicity, frequently resulting in treatment discontinuation. Thus, an alternative regimen without significant neurotoxicity was evaluated by comparing gemcitabine plus carboplatin with single-agent carboplatin in platinum-sensitive recurrent ovarian cancer patients.

Methods

Patients with platinum-sensitive recurrent ovarian cancer were randomly assigned to receive either gemcitabine plus carboplatin or carboplatin alone, every 21 days. The primary objective was to compare progression-free survival (PFS).

Results

Three hundred fifty-six patients (178 gemcitabine plus carboplatin; 178 carboplatin) were randomly assigned. Patients received a median of six cycles in both arms. With a median follow-up of 17 months, median PFS was 8.6 months (95% CI, 7.9 to 9.7 months) for gemcitabine plus carboplatin and 5.8 months (95% CI, 5.2 to 7.1 months) for carboplatin. The hazard ration (HR) for PFS was 0.72 (95% CI, 0.58 to 0.90; P = .0031). Response rate was 47.2% (95% CI, 39.9% to 54.5%) for gemcitabine plus carboplatin and 30.9% (95% CI, 24.1% to 37.7%) for carboplatin (P = .0016). The HR for overall survival was 0.96 (95% CI, 0.75 to1.23; P = .7349). While myelosuppression was significantly more common in the combination, sequelae such as febrile neutropenia or infections were uncommon. No statistically significant differences in quality of life scores between arms were noted.

Conclusion

Gemcitabine plus carboplatin significantly improves PFS and response rate without worsening quality of life for patients with platinum-sensitive recurrent ovarian cancer.
RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non–Small-Cell Lung Cancer
Authors: Bepler Gerold , Kusmartseva Irina , Sharma Swati , Gautam Ashish , Cantor Alan , Sharma Anupama , Simon George
Published: September 2006

Purpose

RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.

Patients and Methods

We constructed genetically modified lung cancer cell lines with increased and decreased RRM1 expression to investigate the in vitro 50% inhibitory concentration (IC50) for gemcitabine, cisplatin, and carboplatin. A prospective phase II clinical trial in patients with locally advanced non–small-cell lung cancer was conducted with pretreatment tumor collection for determination of RRM1 and ERCC1 expression by real-time reverse transcriptase polymerase chain reaction. The levels of gene expression were correlated with tumor response after two cycles of gemcitabine and carboplatin.

Results

In cell lines with a genetically engineered 15-fold RRM1 expression range, the gemcitabine IC50 had a 100-fold range, and the cisplatin and carboplatin IC50 had a two-fold range. They were highest in constructs with high RRM1 expression. In the prospective clinical trial, RRM1 expression was significantly (P = .002) and inversely correlated (r = −0.498) with disease response. ERCC1 expression showed a similar trend (P = .099).

Conclusion

The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.
Detection of Subclinical Systemic Disease in Primary CNS Lymphoma by Polymerase Chain Reaction of the Rearranged Immunoglobulin Heavy-Chain Genes
Authors: Jahnke Kristoph , Hummel Michael , Korfel Agnieszka , Burmeister Thomas , Kiewe Philipp , Klasen Hermann Ayke , Müller Hans-Henning , Stein Harald , Thiel Eckhard
Published: September 2006

Purpose

To search for subclinical systemic disease in bone marrow and peripheral blood in patients with primary CNS lymphoma (PCNSL) to elucidate whether extracerebral relapse may represent a sequel of initial occult systemic disease rather than true extracerebral spread.

Patients and Methods

Bone marrow and peripheral-blood specimens of 24 PCNSL patients were examined using polymerase chain reaction (PCR) for analysis of clonally rearranged immunoglobulin heavy-chain (IgH) genes.

Results

Identical dominant PCR products were found in bone marrow aspirates, blood samples, and tumor biopsy specimens of two patients, indicating that the same tumor cell population is present in the CNS and in extracerebral sites. Follow-up IgH PCR performed in one of these patients in complete remission 24 months after diagnosis yielded a persistent monoclonal product in the blood. An oligoclonal IgH rearrangement pattern was found in the tumor specimen of two other patients, whereas bone marrow and blood samples demonstrated the same dominant PCR products. Follow-up PCR showed a persistent monoclonal amplificate in blood in one of these patients 27 months after diagnosis.

Conclusion

It could be demonstrated for the first time that subclinical systemic disease can be present in PCNSL patients at initial diagnosis. Our findings may have an impact on the understanding of PCNSL pathogenesis and the extent of staging and treatment.
Perception of Auditory Motion Affects Language Processing
Authors: Kaschak Michael P. , Zwaan Rolf A. , Aveyard Mark , Yaxley Richard H.
Published: September 2006

Previous reports have demonstrated that the comprehension of sentences describing motion in a particular direction (toward, away, up, or down) is affected by concurrently viewing a stimulus that depicts motion in the same or opposite direction. We report 3 experiments that extend our understanding of the relation between perception and language processing in 2 ways. First, whereas most previous studies of the relation between perception and language processing have focused on visual perception, our data show that sentence processing can be affected by the concurrent processing of auditory stimuli. Second, it is shown that the relation between the processing of auditory stimuli and the processing of sentences depends on whether the sentences are presented in the auditory or visual modality.