bluuebunny/crossref_metadata_2025 huggingface dataset:
Family therapy as a model for treating childhood obesity: Useful tools for clinicians
Authors: Nowicka Paulina , Flodmark Carl-Erik
Published: July 2010

More than 15 percent of children in Europe are overweight; another 5 percent are obese. The high prevalence of obesity emphasizes the necessity of developing evidence-based treatment programs that are useful in a clinical setting. Management of childhood obesity is commonly based on lifestyle interventions where nutrition, physical activity, and behavior modification are the main targets. To incorporate lifestyle interventions, many childhood obesity treatment models use different psychological models, such as behavior modification or cognitive behavior therapy. This paper presents the key lessons from a research program on an empirically supported family-therapy-based treatment, Standardized Obesity Family Therapy (SOFT). SOFT is based on systemic and solution-focused theories and has shown positive effects on the child with respect to degree of obesity, physical fitness, self-esteem, and family functioning in several studies. The distinguishing features of SOFT are the focus on family interactions as an important source for implementing and maintaining lifestyle changes, the multidisciplinary team approach, and a limited number of sessions (three to four per year). The main aim of this paper is to provide tools for clinicians in the field of obesity who work with families, alone or in a multidisciplinary team.
Socioeconomic differences in mortality among diabetic people in Finland
Authors: Forssas Erja , Arffman Martti , Koskinen Seppo , Reunanen Antti , Keskimäki Ilmo
Published: July 2010

Aims: A clear socioeconomic gradient in mortality emerged among diabetic people in Finland from the early 1980s to the early 1990s. The present study examines whether this development continued between 1991 and 2003. Methods: People with diabetes aged 30—79 in 1991—2002 were identified in the national registers, and followed up for mortality until 31 December 2003. The data comprised 1,407,025 person years and 59,917 deaths. Results: From 1991—1994 to 1995—1999, the all-cause mortality among diabetic people decreased 20% for men and 26% for women among non-manual workers compared with 14% and 19% respectively among manual workers. The socioeconomic differences increased particularly in mortality from coronary heart disease and causes related to smoking and excessive alcohol use. From 1995—1999 to 2000—2003 the socioeconomic mortality disparity remained stable except for emerging socioeconomic differences in neoplasm deaths among women. Persons with type 1 diabetes showed much larger socioeconomic differences in deaths from alcohol related diseases (RR: men 1.97, women 2.13) compared to persons with type 2 diabetes (RR: men 1.20, women 1.05). Conclusions: During the 1990s disparities in mortality between socioeconomic groups among diabetic people increased due to a more favourable trend among non-manual workers compared to manual workers in deaths from coronary heart disease and causes of death related to smoking and excessive alcohol use. From the late 1990s to 2000—2003, inequality in mortality remained stable except for emerging socioeconomic differences in neoplasm deaths among women.
The effect of detecting undetected common mental disorders on psychological distress and quality of life in long-term sickness absence: A randomised controlled trial
Authors: Søgaard Hans Jørgen , Bech Per
Published: July 2010

Background: The burden imposed by common mental disorders on individuals and society calls for interventions aimed at reducing psychological distress and improving quality of life. Aim: To study whether detection of mental disorders plus feedback to individuals and caregivers reduces psychological distress and improves quality of life in long-term sickness absence (LSA), defined as continuous sick-leave for more than 8 weeks. Mental disorders were detected by Present State Examination. Methods: The study population comprised 118,000 inhabitants. During 1 year, all incident individuals on LSA were identified from public registers regarding sickness transfer income. Common Mental Disorders Screening Questionnaire (CMD-SQ) (psychological distress) and SF-36 (quality of life) were sent to 2414 incident individuals on LSA, response rate 46.7%. In a randomised controlled trial for individuals with a certain level of psychological distress, 420 participants were allocated to an intervention group and 416 to a control group. The dropout at 12-months follow-up was 22.4% in the intervention group and 13.9% in the control group. Results: There were no significant effects for individuals sick-listed with a psychiatric sick-leave diagnosis. For individuals without a psychiatric sick-leave diagnosis, significant effects were seen in the subscales of CMD-SQ (effect sizes: 0.20—0.28) and in more subscales of SF-36 (effect sizes: 0.12-0.22). The effects varied according to socio-demographic characteristics and somatic sick-leave diagnoses. Conclusion: The intervention was most effective for individuals without a psychiatric sick-leave diagnosis sick-listed from full-time work. Thus, despite small effect sizes, the intervention may be efficient for large subgroups on LSA.
A Commentary on the Case Study of State-Owned Hotels in China
Authors: Hanson Bjorn
Published: July 2010

The comparison of Stephen Rushmore’s seven hotel valuation techniques provides a starting point for approaches to valuing government-owned hotels in the People’s Republic of China. Although the authors express concern because of a relative lack of published lodging valuation data for China, until relatively recently appraisals have been performed without third-party data even in the United States. In-person interviews almost always overcome any lack of published data. Hotel valuation relies on the skill of the researcher, especially because selection of discount and capitalization rates involves judgment.
Heat shock protein 90 regulates the expression of Wilms tumor 1 protein in myeloid leukemias
Authors: Bansal Hima , Bansal Sanjay , Rao Manjeet , Foley Kevin P. , Sang Jim , Proia David A. , Blackman Ronald K. , Ying Weiwen , Barsoum James , Baer Maria R. , Kelly Kevin , Swords Ronan , Tomlinson Gail E. , Battiwalla Minoo , Giles Francis J. , Lee Kelvin P. , Padmanabhan Swaminathan
Published: July 2010

The aberrant overexpression of Wilms tumor 1 (WT1) in myeloid leukemia plays an important role in blast cell survival and resistance to chemotherapy. High expression of WT1 is also associated with relapse and shortened disease-free survival in patients. However, the mechanisms by which WT1 expression is regulated in leukemia remain unclear. Here, we report that heat shock protein 90 (Hsp90), which plays a critical role in the folding and maturation of several oncogenic proteins, associates with WT1 protein and stabilizes its expression. Pharmacologic inhibition of Hsp90 resulted in ubiquitination and subsequent proteasome-dependant degradation of WT1. RNAi-mediated silencing of WT1 reduced the survival of leukemia cells and increased the sensitivity of these cells to chemotherapy and Hsp90 inhibition. Furthermore, Hsp90 inhibitors 17-AAG [17-(allylamino)-17-demethoxygeldanamycin] and STA-9090 significantly reduced the growth of myeloid leukemia xenografts in vivo and effectively down-regulated the expression of WT1 and its downstream target proteins, c-Myc and Bcl-2. Collectively, our studies identify WT1 as a novel Hsp90 client and support the crucial role for the WT1–Hsp90 interaction in maintaining leukemia cell survival. These findings have significant implications for developing effective therapies for myeloid leukemias and offer a strategy to inhibit the oncogenic func-tions of WT1 by clinically available Hsp90 inhibitors.
The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress
Authors: Auner Holger W. , Beham-Schmid Christine , Dillon Niall , Sabbattini Pierangela
Published: July 2010

Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress–induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.
Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma
Authors: Görgün Güllü , Calabrese Elisabetta , Soydan Ender , Hideshima Teru , Perrone Giulia , Bandi Madhavi , Cirstea Diana , Santo Loredana , Hu Yiguo , Tai Yu-Tzu , Nahar Sabikun , Mimura Naoya , Fabre Claire , Raje Noopur , Munshi Nikhil , Richardson Paul , Anderson Kenneth C.
Published: July 2010

The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing–MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.
Regional ventilation distribution in the first 6 months of life
Authors: Pham T.M.T. , Yuill M. , Dakin C. , Schibler A.
Published: July 2010

Electrical impedance tomography (EIT) has been used to study regional ventilation distribution in neonatal and paediatric lung disease; however, little information has been obtained in healthy newborns and infants.

Data on regional ventilation distribution and regional filling characteristics were obtained using EIT in the neonatal period, at 3 and 6 months of age, in spontaneously breathing infants during non-rapid eye movement sleep. Regional ventilation distribution was described using regional end-expiratory and end-inspiratory impedance amplitudes, and geometric centre of ventilation. Regional filling characteristics were described with the phase lag or lead of the regional impedance change in comparison to global impedance change.

32 infants were measured in the supine position. Regional impedance amplitudes increased with age but regional ventilation distribution remained unchanged in all infants at any age, with the dependent (posterior) lung always better ventilated. Regional filling characteristics showed that the dependent lung filled during inspiration before the nondependent lung during all follow-up measurements.

Regional ventilation distribution and regional filling characteristics remained unchanged over the first 6 months of life, and the results obtained on regional ventilation distribution are very similar to those in adult subjects.
Host defence duringKlebsiellapneumonia relies on haematopoietic-expressed Toll-like receptors 4 and 2
Authors: Wieland C.W. , van Lieshout M.H.P. , Hoogendijk A.J. , van der Poll T.
Published: July 2010

In this study, the relative roles of Toll-like receptor (TLR)2 and TLR4 were investigated independently and together. Moreover, we studied the role of haematopoietic compartment in anti-Klebsiellahost defence.

We infected TLR2 and TLR4 single-, and TLR2×4 double knockout (KO) animals with different doses ofKlebsiella pneumoniae. In addition, bone marrow chimeric mice were created and infected.

TLR4 played a more prominent role in antibacterial defence than TLR2, considering that only TLR4 KO mice demonstrated enhanced bacterial growth in lungs and spleen 24 h after infection with 3×103colony-forming units ofKlebsiellacompared with wild-type (WT) mice. In late-stage infection or after exposure to a higher infectious dose, bacterial counts in lungs of TLR2 KO animals were elevated compared with WT mice and TLR2×4 KO animals were more susceptible to infection than TLR4 KO mice. TLR signalling in cells of haematopoietic origin is of primary importance in host defence againstK. pneumoniae.

These data suggest that: 1) TLR4 drives the antibacterial host response after induction of pneumonia with relatively lowKlebsielladoses; 2) TLR2 becomes involved at a later phase of the infection and/or upon exposure to higher bacterial burdens; and 3) haematopoietic TLR2 and TLR4 are important for an adequate host response duringKlebsiellapneumonia.
Lymphatic and blood microvasculature organisation in pulmonary sarcoid granulomas
Authors: Kambouchner M. , Pirici D. , Uhl J-F. , Mogoanta L. , Valeyre D. , Bernaudin J-F.
Published: July 2010

Pulmonary sarcoid granulomas are characterised by their elective distribution along collecting lymphatics. However, relationships between granulomas and intralobular lymphatics or blood microvascularisation have not been investigated. Therefore, we undertook a specific analysis of blood capillaries and lymphatics supplying sarcoid granulomas to identify additional clues to understanding the pathophysiogenesis of these lesions.

Six pulmonary samples were immunolabelled with D2-40, anti-CD34 and anti-CD31 antibodies, paying particular attention to the relationships between lymphatics and granulomas, and the pattern of blood microvessels supplying sarcoid lesions. A morphometric study of granulomas included their distance to lymphatics and a three-dimensional reconstruction of a granuloma in its lymphatic context.

Intralobular granulomas were closely associated with lymphatics; apart from a few granulomas, blood capillaries stopped at the outer border of the fibrous ring surrounding granulomas, and perigranuloma capillaries were particularly scarce.

Our observations of the lymphatic and blood microvascular environment of intralobular pulmonary sarcoid granulomas provide evidence for the critical role of lymphatics in the emergence of these lesions. Moreover, pulmonary sarcoid lesions could be considered avascular structures, thereby providing new insights into the understanding of the granuloma physiology and the distribution of blood-borne therapeutic agents.
Dickkopf proteins influence lung epithelial cell proliferation in idiopathic pulmonary fibrosis
Authors: Pfaff E-M. , Becker S. , Günther A. , Königshoff M.
Published: July 2010

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with unknown pathogenesis. The WNT/β-catenin pathway has recently been reported to be operative in epithelial cells in IPF. Dickkopf (DKK) proteins are known to regulate WNT signallingviainteraction with Kremen (KRM) receptors, yet their expression and role in the adult lung and in IPF has not been addressed.

We analysed the expression, localisation and function of DKK and KRM proteins in IPF lungs using Western blotting, quantitative RT-PCR, immunohistochemistry, ELISA and functionalin vitrostudies.

Enhanced expression of DKK1 and DKK4 and KRM1 was detected in lung homogenates of IPF patients compared with transplant donors. Immunohistochemistry revealed that DKK1 was predominantly localised in basal bronchial epithelial cells. Furthermore, prominent expression of all proteins was observed in hyperplastic alveolar epithelial cells in IPF. Quantitative measurement of DKK1 revealed enhanced protein expression in the bronchoalveolar lumen of IPF patients. Finally, functional studies using human bronchial and alveolar epithelial cell lines demonstrated that WNT-induced epithelial cell proliferation is regulated by DKK1 in a dose-dependent fashion.

In summary, DKK proteins are expressed in the lung epithelium in IPF. DKK proteins influence epithelial cell proliferation and may, therefore, be suitable therapeutic targets for IPF.
Steroids induce a disequilibrium of secreted interleukin-1 receptor antagonist and interleukin-1β synthesis by human neutrophils
Authors: Langereis J.D. , Oudijk E-J.D. , Schweizer R.C. , Lammers J-W.J. , Koenderman L. , Ulfman L.H.
Published: July 2010

Chronic obstructive pulmonary disease (COPD) is characterised by neutrophilic inflammation in the airways and these neutrophils contribute to the production of inflammatory mediators. Dampening the production of proinflammatory mediators might be an important strategy to treat COPD and glucocorticosteroids are known to do soviainhibition of nuclear factor-κB. However, this pathway is important for the control of pro- and anti-inflammatory genes.

We studied the effects of dexamethasone on production and secretion of pro-inflammatory interleukin (IL)-1β and anti-inflammatory secreted IL-1 receptor antagonist (sIL-1Ra) by human neutrophils activated with tumor necrosis factor (TNF)-α.

In vitro, TNF-α-stimulated neutrophils produced significant amounts of IL-1β and sIL-1Ra; this production was inhibited by dexamethasone. However, synthesis and secretion of sIL-1Ra was inhibited at lower concentrations dexamethasone compared to IL-1β, which changed the IL-1β:sIL-1Ra ratio significantly. This altered ratio resulted in a more pro-inflammatory condition, as visualised by increased intercellular adhesion molecule-1 expression on human endothelial cells.In vivo, moderate-to-severe COPD patients using inhaled glucocorticosteroids have decreased plasma sIL-Ra levels compared with mild-to-moderate patients not on glucocorticosteroid treatment.

In conclusion, dexamethasone induces a pro-inflammatory shift in the IL-1β:sIL-1Ra cytokine balance in neutrophilsin vitro, which might contribute to a lack of endogenous anti-inflammatory signals to dampen inflammationin vivo.
Legionella pneumophila-induced IκBζ-dependent expression of interleukin-6 in lung epithelium
Authors: Lorenz J. , Zahlten J. , Pollok I. , Lippmann J. , Scharf S. , N'Guessan P.D. , Opitz B. , Flieger A. , Suttorp N. , Hippenstiel S. , Schmeck B.
Published: July 2010

Severe community- and hospital-acquired pneumonia is caused byLegionella pneumophila. Lung airway and alveolar epithelial cells comprise an important sentinel system in airborne infections. Although interleukin (IL)-6 is known as a central regulator of the immune response in pneumonia, its regulation in the lung is widely unknown.

Herein, we demonstrate that differentL. pneumophilastrains induce delayed expression of IL-6 in comparison with IL-8 by human lung epithelial cells. IL-6 expression depended, at early time points, on flagellin recognition by Toll-like receptor (TLR)5, activity of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1 and p38 mitogen-activated protein (MAP) kinase, and, at later time points, on the type-IV secretion system. In the same manner, but more rapidly, the recently described transcription factor IκBζ was induced byLegionellainfection and, binding to the nuclear factor (NF)-κB subunit p50 - recruited to theil6promoter together with CCAAT-enhancer-binding protein β and phosphorylated activator protein-1 subunit cJun. Similarly, histone modifications and NF-κB subunit p65/RelA appeared at theiκbζand subsequently at theil6gene promoter, thereby initiating gene expression. Gene silencing of IκBζ reducedLegionella-related IL-6 expression by 41%.

Overall, these data indicate a sequence of flagellin/TLR5- and type IV-dependent IκBζ expression, recruitment of IκBζ/p50 to theil6promoter, chromatin remodelling and subsequent IL-6 transcription inL. pneumophila-infected lung epithelial cells.
A comparison of internal validation techniques for multifactor dimensionality reduction
Authors: Winham Stacey J , Slater Andrew J , Motsinger-Reif Alison A
Published: July 2010

Background

It is hypothesized that common, complex diseases may be due to complex interactions between genetic and environmental factors, which are difficult to detect in high-dimensional data using traditional statistical approaches. Multifactor Dimensionality Reduction (MDR) is the most commonly used data-mining method to detect epistatic interactions. In all data-mining methods, it is important to consider internal validation procedures to obtain prediction estimates to prevent model over-fitting and reduce potential false positive findings. Currently, MDR utilizes cross-validation for internal validation. In this study, we incorporate the use of a three-way split (3WS) of the data in combination with a post-hoc pruning procedure as an alternative to cross-validation for internal model validation to reduce computation time without impairing performance. We compare the power to detect true disease causing loci using MDR with both 5- and 10-fold cross-validation to MDR with 3WS for a range of single-locus and epistatic disease models. Additionally, we analyze a dataset in HIV immunogenetics to demonstrate the results of the two strategies on real data.

Results

MDR with 3WS is computationally approximately five times faster than 5-fold cross-validation. The power to find the exact true disease loci without detecting false positive loci is higher with 5-fold cross-validation than with 3WS before pruning. However, the power to find the true disease causing loci in addition to false positive loci is equivalent to the 3WS. With the incorporation of a pruning procedure after the 3WS, the power of the 3WS approach to detect only the exact disease loci is equivalent to that of MDR with cross-validation. In the real data application, the cross-validation and 3WS analyses indicate the same two-locus model.

Conclusions

Our results reveal that the performance of the two internal validation methods is equivalent with the use of pruning procedures. The specific pruning procedure should be chosen understanding the trade-off between identifying all relevant genetic effects but including false positives and missing important genetic factors. This implies 3WS may be a powerful and computationally efficient approach to screen for epistatic effects, and could be used to identify candidate interactions in large-scale genetic studies.
Roles of the Anterior Cingulate Cortex and Medial Thalamus in Short-Term and Long-Term Aversive Information Processing
Authors: Chai Sin-Chee , Kung Jen-Chuang , Shyu Bai-Chuang
Published: July 2010

Background:

The anterior cingulate cortex (ACC) and medial thalamus (MT) are two of the main components of the medial pain pathway that subserve the affective aspect of pain. The hypothesis of the present study was that the ACC is involved in short-term aversive information processing and that the MT is critical for encoding unconditioned nociceptive information. The roles of these two components in short-term and long-term aversive information processing was investigated using a step-through inhibitory avoidance task.

Results:

Behavioral training began 1 week after surgery, in which radiofrequency lesions of the ACC or MT were performed. The retention tests were conducted 30 s (short-term) or 24 h (long-term) after training. Pretraining radiofrequency lesions of the ACC impaired performance in the 30 s, but not 24 h, retention test. Microinfusions of lidocaine into the ACC immediately after training impaired performance in the retention test conducted 10 min later. Pretraining radiofrequency lesions of the MT impaired performance in both the 30 s and 24 h retention tests. However, posttraining, but not pretest, microinfusions of lidocaine into the MT impaired performance in the 24 h retention test.

Conclusions:

These results suggest that the ACC may play an important role in short-term, but not long-term, nociceptive information processing. In contrast, the MT may be important for the consolidation of nociceptive information storage.
Is BDNF Sufficient for Information Transfer between Microglia and Dorsal Horn Neurons during the Onset of Central Sensitization?
Authors: Biggs James E , Van Lu B , Stebbing Martin J , Balasubramanyan Sridhar , Smith Peter A
Published: July 2010

Peripheral nerve injury activates spinal microglia. This leads to enduring changes in the properties of dorsal horn neurons that initiate central sensitization and the onset of neuropathic pain. Although a variety of neuropeptides, cytokines, chemokines and neurotransmitters have been implicated at various points in this process, it is possible that much of the information transfer between activated microglia and neurons, at least in this context, may be explicable in terms of the actions of brain derived neurotrophic factor (BDNF). Microglial-derived BDNF mediates central sensitization in lamina I by attenuating inhibitory synaptic transmission. This involves an alteration in the chloride equilibrium potential as a result of down regulation of the potassium-chloride exporter, KCC2. In lamina II, BDNF duplicates many aspects of the effects of chronic constriction injury (CCI) of the sciatic nerve on excitatory transmission. It mediates an increase in synaptic drive to putative excitatory neurons whilst reducing that to inhibitory neurons. CCI produces a specific pattern of changes in excitatory synaptic transmission to tonic, delay, phasic, transient and irregular neurons. A very similar ‘injury footprint’ is seen following long-term exposure to BDNF. This review presents new information on the action of BDNF and CCI on lamina II neurons, including the similarity of their actions on the kinetics and distributions of subpopulations of miniature excitatory postsynaptic currents (mEPSC). These findings raise the possibility that BDNF functions as a final common path for a convergence of perturbations that culminate in the generation of neuropathic pain.
The biomechanical analysis of three plating fixation systems for periprosthetic femoral fracture near the tip of a total hip arthroplasty
Authors: Lever James P. , Zdero Rad , Nousiainen Markku T. , Waddell James P. , Schemitsch Emil H.
Published: July 2010

Background

A variety of techniques are available for fixation of femoral shaft fractures following total hip arthroplasty. The optimal surgical repair method still remains a point of controversy in the literature. However, few studies have quantified the performance of such repair constructs. This study biomechanically examined 3 different screw-plate and cable-plate systems for fixation of periprosthetic femoral fractures near the tip of a total hip arthroplasty.

Methods

Twelve pairs of human cadaveric femurs were utilized. Each left femur was prepared for the cemented insertion of the femoral component of a total hip implant. Femoral fractures were created in the femurs and subsequently repaired with Construct A (Zimmer Cable Ready System), Construct B (AO Cable-Plate System), or Construct C (Dall-Miles Cable Grip System). Right femora served as matched intact controls. Axial, torsional, and four-point bending tests were performed to obtain stiffness values.

Results

All repair systems showed 3.08 to 5.33 times greater axial stiffness over intact control specimens. Four-point normalized bending (0.69 to 0.85) and normalized torsional (0.55 to 0.69) stiffnesses were lower than intact controls for most comparisons. Screw-plates provided either greater or equal stiffness compared to cable-plates in almost all cases. There were no statistical differences between plating systems A, B, or C when compared to each other (p > 0.05).

Conclusions

Screw-plate systems provide more optimal mechanical stability than cable-plate systems for periprosthetic femur fractures near the tip of a total hip arthroplasty.
Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality
Authors: Marchlik Erica , Thakker Paresh , Carlson Thaddeus , Jiang Zhaozhao , Ryan Mark , Marusic Suzana , Goutagny Nadege , Kuang Wen , Askew G Roger , Roberts Victoria , Benoit Stephen , Zhou Tianhui , Ling Vincent , Pfeifer Richard , Stedman Nancy , Fitzgerald Katherine A , Lin Lih-Ling , Hall J Perry
Published: July 2010

Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues, altered circulating immune cell compartments, and increased susceptibility to LPS-induced lethality.

TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1Δ allele encodes a truncated Tbk1Δ protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1Δ/Δ mice produce normal levels of proinflammatory cytokines (e.g., TNF-α), but IFN-β and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1Δ/Δ mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1+/+ and Tbk1+/Δ littermates. Skin from 2-week-old Tbk1Δ/Δ mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1Δ/Δ mice die more quickly and in greater numbers than their Tbk1+/+ and Tbk1+/Δ counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1Δ/Δ mice, including TNF-α, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1Δ/Δ mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.
Immune regulation by peripheral suppressor T cells induced upon homotypic T cell/T cell interactions
Authors: Thümmler Katja , Leipe Jan , Ramming Andreas , Schulze-Koops Hendrik , Skapenko Alla
Published: July 2010

Activated effector T cells induce the generation of suppressor T cells from bystander memory T cells via interactions involving LFA-1 and its receptors.

We have shown previously that homotypic interaction of resting memory CD4 T cells with activated T cells induces the production of cytokines with immunoregulatory potential (IL-10, IL-4) from the former. Here, we analyzed the effector functions of these T cells stimulated by homotypic T cell interaction. T cells induced upon homotypic T cell interaction expressed CD25 and reduced levels of CD127 and produced TGF-β. Functionally, homotypic T cell interaction-induced T cells were anergic and inhibited the proliferation of CD25-negative T cells as potently as naturally occurring CD25-positive Tregs in vitro. They also prevented clonotypic expansion of OVA TCR tg T cells in BALB/c mice upon antigenic challenge in vivo. The generation of suppressor T cells by homotypic T cell contact is anchored and tuned through interactions of LFA-1 and its ligands ICAM-1, ICAM-2, and ICAM-3. Together, the data suggest a negative-feedback mechanism of specific immunity involving bystander-activated memory T cells.
Does the number of pregnancies affect patterns of great saphenous vein reflux in women with varicose veins?
Authors: Engelhorn C A , Cassou M F , Engelhorn A L , Salles-Cunha S X
Published: July 2010

Objectives

Impact of pregnancies on great saphenous vein (GSV) reflux patterns deserves clarification. Which GSV segment is most affected? Is the saphenofemoral junction (SFJ) involved?

Methods

Colour-flow duplex ultrasonography was performed in 583 women extremities with primary varicose veins (clinical, aetiological, anatomical and pathological elements [CEAP C2]), without oedema, skin changes or ulcer. Women with previous thrombosis or varicose surgery were excluded. GSV reflux sources and drainage points were located at SFJ, thigh, knee and calf. Prevalence of most proximal reflux source was noted as a function of 0, 1, 2, 3 and 4 or more pregnancies. χ2 statistics was employed.

Results

Prevalence of GSV reflux was not dependent on 0, 1, 2, 3 or ≥4 pregnancies: 75%, 69%, 79%, 70% and 76% for right leg ( P = 0.79) and 78%, 81%, 82%, 79% and 73% for left leg ( P = 0.87), respectively. Prevalence of SFJ reflux and GSV reflux, starting at the thigh, knee or calf, was similar and showed no tendencies to increase with number of pregnancies.

Conclusions

Number of pregnancies did not influence GSV reflux patterns in women with primary varicose veins.
Functional implications of the emergence of alternative splicing in hnRNP A/B transcripts
Authors: Han Siew Ping , Kassahn Karin S. , Skarshewski Adam , Ragan Mark A. , Rothnagel Joseph A. , Smith Ross
Published: July 2010

The heterogeneous nuclear ribonucleoproteins (hnRNPs) A/B are a family of RNA-binding proteins that participate in various aspects of nucleic acid metabolism, including mRNA trafficking, telomere maintenance, and splicing. They are both regulators and targets of alternative splicing, and the patterns of alternative splicing of their transcripts have diverged between paralogs and between orthologs in different species. Surprisingly, the extent of this splicing variation and its implications for post-transcriptional regulation have remained largely unexplored. Here, we conducted a detailed analysis of hnRNP A/B sequences and expression patterns across six vertebrates. Alternative exons emerged via the introduction of new splice sites, changes in the strengths of existing splice sites, and the accumulation of auxiliary splicing regulatory motifs. Observed isoform expression patterns could be attributed to the frequency and strength of cis-elements. We found a trend toward increased splicing variation in mammals and identified novel alternatively spliced isoforms in human and chicken. Pulldown and translational assays demonstrated that the inclusion of alternative exons altered the affinity of hnRNP A/B proteins for their cognate nucleic acids and modified protein expression levels. As the hnRNPs A/B regulate several key steps in mRNA processing, the involvement of diverse hnRNP isoforms in multiple cellular contexts and species implies concomitant differences in the transcriptional output of these systems. We conclude that the emergence of alternative splicing in the hnRNPs A/B has contributed to the diversification of their roles in the regulation of alternative splicing and has thus added an unexpected layer of regulatory complexity to transcription in vertebrates.
Impact of Proton Pump Inhibitors on the Effectiveness of Clopidogrel After Coronary Stent Placement: The Clopidogrel Medco Outcomes Study
Authors: Kreutz Rolf P. , Stanek Eric J. , Aubert Ronald , Yao Jianying , Breall Jeffrey A. , Desta Zeruesenay , Skaar Todd C. , Teagarden J. Russell , Frueh Felix W. , Epstein Robert S. , Flockhart David A.
Published: July 2010

Study Objective. To investigate the potential impact of proton pump inhibitors (PPIs) on the effectiveness of clopidogrel in preventing recurrent ischemic events after percutaneous coronary intervention (PCI) with stent placement.

Design. Population‐based, retrospective cohort study.

Data Source. National medical and pharmacy benefit claims database comprising approximately 19 million members.

Patients. A total of 16,690 patients who had undergone PCI with stent placement and who were highly adherent to clopidogrel therapy alone (9862 patients) or to clopidogrel with a PPI (6828 patients) between October 1, 2005, and September 30, 2006.

Measurements and Main Results. The primary end point was the occurrence of a major adverse cardiovascular event during the 12 months after stent placement. These events were defined as hospitalization for a cerebrovascular event (stroke or transient ischemic attack), an acute coronary syndrome (myocardial infarction or unstable angina), coronary revascularization (PCI or coronary artery bypass graft), or cardiovascular death. A composite event rate was compared between patients who received clopidogrel alone and those who received concomitant clopidogrel‐PPI therapy. Baseline differences in covariates were adjusted by using Cox proportional hazards models. In the 9862 patients receiving clopidogrel alone, 1766 (17.9%) experienced a major adverse cardiovascular event compared with 1710 patients (25.0%) who received concomitant clopidogrel‐PPI therapy (adjusted hazard ratio 1.51, 95% confidence interval 1.39–1.64, p<0.0001). Similar associations of increased risk were observed for each PPI studied (omeprazole, esomeprazole, pantoprazole, and lansoprazole).

Conclusion. Concomitant use of a PPI and clopidogrel compared with clopidogrel alone was associated with a higher rate of major adverse cardiovascular events within 1 year after coronary stent placement.
Single‐Dose Pharmacokinetics and Tolerability of Telavancin in Elderly Men and Women
Authors: Goldberg Michael R. , Wong Shekman L. , Shaw Jeng‐Pyng , Kitt Michael M. , Barriere Steven L.
Published: July 2010

Study Objective. To assess the safety and tolerability, and the effect of sex on the pharmacokinetic disposition, of a single intravenous dose of telavancin 10 mg/kg in elderly (≥ 65 yrs) subjects.

Design. Phase I, open‐label, single‐dose, sex‐stratified study.

Setting. Clinical research unit.

Subjects. Eight healthy men and eight healthy women (mean ± SD ages 70.6 ± 6.1 and 70.8 ± 5.5 yrs, respectively).

Intervention. Each subject received a 60–minute intravenous infusion of telavancin 10 mg/kg.

Measurements and Main Results. For the pharmacokinetic analysis, blood samples were collected before drug administration and at regular intervals up to 48 hours after the start of the infusion. Telavancin plasma concentrations were determined by liquid chromatography with tandem mass spectrometric detection. Pharmacokinetic parameters of telavancin were determined by noncompartmental analysis. Standard clinical laboratory tests and electrocardiograms were used to assess safety and tolerability. The telavancin plasma concentration‐time curves and pharmacokinetic parameters for both sexes were comparable. Pooled mean ± SD clearance, half‐life, and volume of distribution at the steady state were 12.2 ± 1.4 ml/hour/kg, 9.3 ± 1.3 hours, and 156 ± 12 ml/kg, respectively. The pooled mean ± SD plasma concentration of telavancin 24 hours postdose was 10.8 ± 1.6 μg/ml, exceeding the telavancin minimum inhibitory concentration required to inhibit the growth of 90% of organisms for key gram‐positive pathogens (0.5 μg/ml). Ten (63%) of the 16 subjects reported at least one adverse event, most of which were mild; no serious adverse events were noted in this study. No clinically significant changes in vital signs, physical examinations, electrocardiograms, or clinical biochemistry profiles were observed.

Conclusion. The pharmacokinetic parameters of telavancin were similar between elderly men and women and comparable to historical results in healthy young subjects. No evidence was found to support telavancin dosage adjustment based on age or sex.
Effectiveness of Exogenous Albumin Administration for the Prevention of Ifosfamide‐Induced Encephalopathy
Authors: Kettle Jacob K. , Grauer Dennis , Folker Tanya L. , O'Neal Nyla , Henry David W. , Williams Casey B.
Published: July 2010

Study Objectives.To assess the effectiveness of prophylactic albumin for the prevention of ifosfamide‐induced encephalopathy (IIE), and to describe risk factors for IIE and investigate the predictive potential of a novel risk‐stratification model for IIE.

Design. Retrospective analysis.

Setting.Single academic medical center.

Patients.Forty‐one adults who received 93 chemotherapy cycles of regimens that included ifosfamide for the treatment of hematologic or solid tumor malignancy between November 2007 and November 2008. Patients were divided into two groups based on the use of albumin for IIE prophylaxis: albumin group (32 cycles) and no albumin group (61 cycles).

Measurements and Main Results. Overall occurrence of neurotoxicity during therapy served as the primary outcome measure. Proposed risk factors for IIE were assessed by conducting a subgroup analysis of patients who did and those who did not experience IIE. A novel risk‐stratification model was developed in an attempt to predict patients at risk for IIE. The validity of the scheme was assessed by comparing the occurrence of IIE among high‐ and low‐risk patients as identified by the model. Overall, among the 93 cycles, six cases of IIE (6.5%) were identified. The occurrence of IIE was more common in the albumin group compared with the no albumin group (15.6% [5/32] vs 1.6% [1/61], p=0.01). Baseline albumin level was significantly lower, and serum creatinine and aspartate and alanine aminotransferase concentrations were significantly higher among patients experiencing IIE. All cases of IIE occurred among patients identified as high risk according to the risk‐stratification model (p=0.01).

Conclusion. Prophylactic therapy with exogenous albumin is not an effective strategy for the prevention of IIE. The novel risk‐stratification model appears to be an effective method for predicting patients with the greatest potential for developing this adverse effect.
Management of Drug and Food Interactions with Azole Antifungal Agents in Transplant Recipients
Authors: Dodds‐Ashley Elizabeth
Published: July 2010

Azole antifungal agents are frequently used in hematopoietic stem cell and solid organ transplant recipients for prevention or treatment of invasive fungal infections. However, because of metabolism by or substrate activity for various isoenzymes of the cytochrome P450 system and/or P‐glycoprotein, azole antifungals have the potential to interact with many of the drugs commonly used in these patient populations. Thus, to identify drug interactions that may result between azole antifungals and other drugs, we conducted a literature search of the MEDLINE database (1966‐December 2009) for English‐language articles on drug interaction studies involving the azole antifungal agents fluconazole, itraconazole, voriconazole, and posaconazole. Another literature search between each of the azoles and the immunosuppressants cyclosporine, tacrolimus, and sirolimus, as well as the corticosteroids methylprednisolone, dexamethasone, prednisolone, and prednisone, was also conducted. Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity. The magnitude and duration of an interaction between azoles and immunosuppressants are not class effects of the azoles, but differ between drug combinations and are subject to interpatient variability. Drug interactions in the transplant recipient receiving azole therapy may also occur with antibiotics, chemotherapeutic agents, and acid‐suppressive therapies, among other drugs. Initiation of an azole antifungal in transplant recipients nearly ensures a drug‐drug interaction, but often these drugs are required. Management of these interactions first involves knowledge of the potential drug interaction, appropriate dosage adjustments when necessary, and therapeutic or clinical monitoring at an appropriate point in therapy to assess the drug‐drug interaction (e.g., immunosuppressive drug concentrations, signs and symptoms of toxicity). These aspects of drug interaction management are essential not only at the initiation of azole antifungal therapy, but also when these agents are removed from the regimen.
Historical and Cultural Forces Behind the Biopsychiatric Juggernaut
Authors: Galves Albert
Published: July 2010

What are the forces that have driven the dramatic increase in the use of psychotropic drugs by the American public? The most common candidates are the drive of the pharmaceutical companies to make money and mainstream psychiatrists to finally become “real medical practitioners.” This article suggests that there are larger historical and cultural forces that are behind this phenomenon, among them the following: the Age of Reason, the rise of scientism, the cult of professionalism, the industrial and technical revolutions, the myth of the heroic American, the myth of equal opportunity, and the myth of progress. The forces are briefly described, and an argument is made for addressing them.
Treatment of Chronic Periodontitis and Its Impact on Mastication
Authors: Pereira Luciano J. , Gazolla Cátia M. , Magalhães Isabela B. , Ramos‐Jorge Maria Letícia , Marques Leandro S. , Gameiro Gustavo H. , Fonseca Douglas C. , Castelo Paula M.
Published: July 2010

Background: The aim of the present study is to assess the impact of conventional periodontal treatment of chronic periodontitis on the perception of mastication.

Methods: The patients (n = 28; age range: 23 to 56 years, mean age: 37.9 years) were evaluated on two occasions (before and after treatment) with a 45‐day interval using the Oral Impact on Daily Performance questionnaire. An electromyography system was used for the determination of activity in muscles of mastication and bite force. Masticatory performance was assessed using a test material. The median particle size of the masticated material was determined using a sieve method and the Rosin‐Rammler equation. The clinical criteria were the number of teeth and probing depth, both determined by a single calibrated observer masked to the treatment phase. The data were analyzed in the pretreatment and post‐treatment periods using Wilcoxon test; Spearman correlation coefficient; and two multiple linear regression models (backward stepwise procedure).

Results: There was a significant negative correlation between the number of teeth (number of mastication units) and difficulty eating (P <0.05) before and after treatment. Probing depth had a positive relationship with the total Oral Impact on Daily Performance score before treatment (P <0.01).

Conclusions: The subjective perception of the impact of oral health on mastication diminished after periodontal treatment. The number of teeth had considerable importance in the perception of impact on mastication in the sample studied.