bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of seasonal vitamin D deficiency and respiratory acidosis on bone metabolism markers in submarine crewmembers during prolonged patrols
Authors: Holy Xavier , Collombet Jean-Marc , Labarthe Frédéric , Granger-Veyron Nicolas , Bégot Laurent
Published: December 2011

The aim of the study was to determine the seasonal influence of vitamin D status on bone metabolism in French submariners over a 2-mo patrol. Blood samples were collected as follows: prepatrol and patrol days 20, 41, and 58 on crewmembers from both a winter (WP; n = 20) and a summer patrol (SP; n = 20), respectively. Vitamin D status was evaluated for WP and SP. Moreover, extended parameters for acid-base balance (Pco2, pH, and bicarbonate), bone metabolism (bone alkaline phosphatase and COOH-terminal telopeptide of type I collagen), and mineral homeostasis (parathyroid hormone, ionized calcium and phosphorus) were scrutinized. As expected, SP vitamin D status was higher than WP vitamin D status, regardless of the considered experimental time. A mild chronic respiratory acidosis (CRA) was identified in both SP and WP submariners, up to patrol day 41. Such an occurrence paired up with an altered bone remodeling coupling (decreased bone alkaline phosphatase-to-COOH-terminal telopeptide of type I collagen ratio). At the end of the patrol ( day 58), a partial compensation of CRA episode, combined with a recovered normal bone remodeling coupling, was observed in SP, not, however, in WP submariners. The mild CRA episode displayed over the initial 41-day submersion period was mainly induced by a hypercapnia resulting from the submarine-enriched CO2 level. The correlated impaired bone remodeling may imply a physiological attempt to compensate this acidosis via bone buffering. On patrol day 58, the discrepancy observed in terms of CRA compensation between SP and WP may result from the seasonal influence on vitamin D status.
Asymmetric deformation of contracting human gastrocnemius muscle
Authors: Kinugasa Ryuta , Hodgson John A. , Edgerton V. Reggie , Sinha Shantanu
Published: December 2011

Muscle fiber deformation is related to its cellular structure, as well as its architectural arrangement within the musculoskeletal system. While playing an important role in aponeurosis displacement, and efficiency of force transmission to the tendon, such deformation also provides important clues about the underlying mechanical structure of the muscle. We hypothesized that muscle fiber cross section would deform asymmetrically to satisfy the observed constant volume of muscle during a contraction. Velocity-encoded, phase-contrast, and morphological magnetic resonance imaging techniques were used to measure changes in fascicle length, pinnation angle, and aponeurosis separation of the human gastrocnemius muscle during passive and active eccentric ankle joint movements. These parameters were then used to subsequently calculate the in-plane muscle area subtended by the two aponeuroses and fascicles and to calculate the in-plane (dividing area by fascicle length), and through-plane (dividing muscle volume by area) thicknesses. Constant-volume considerations of the whole-muscle geometry require that, as fascicle length increases, the muscle fiber cross-sectional area must decrease in proportion to the length change. Our empirical findings confirm the definition of a constant-volume rule that dictates that changes in the dimension perpendicular to the plane, i.e., through-plane thickness, (−6.0% for passive, −3.3% for eccentric) equate to the reciprocal of the changes in area (6.8% for passive, 3.7% for eccentric) for both exercise paradigms. The asymmetry in fascicle cross-section deformation for both passive and active muscle fibers is established in this study with a ∼22% in-plane and ∼6% through-plane fascicle thickness change. These fiber deformations have functional relevance, not only because they affect the force production of the muscle itself, but also because they affect the characteristics of adjacent muscles by deflecting their line of pull.
Novel whole body plethysmography system for the continuous characterization of sleep and breathing in a mouse
Authors: Hernandez A. B. , Kirkness J. P. , Smith P. L. , Schneider H. , Polotsky M. , Richardson R. A. , Hernandez W. C. , Schwartz A. R.
Published: December 2011

Sleep is associated with marked alterations in ventilatory control that lead to perturbations in respiratory timing, breathing pattern, ventilation, pharyngeal collapsibility, and sleep-related breathing disorders (SRBD). Mouse models offer powerful insight into the pathogenesis of SRBD; however, methods for obtaining the full complement of continuous, high-fidelity respiratory, electroencephalographic (EEG), and electromyographic (EMG) signals in unrestrained mice during sleep and wake have not been developed. We adapted whole body plethysmography to record EEG, EMG, and respiratory signals continuously in unrestrained, unanesthetized mice. Whole body plethysmography tidal volume and airflow signals and a novel noninvasive surrogate for respiratory effort (respiratory movement signal) were validated against simultaneously measured gold standard signals. Compared with the gold standard, we validated 1) tidal volume (correlation, R2= 0.87, P < 0.001; and agreement within 1%, P < 0.001); 2) inspiratory airflow (correlation, R2= 0.92, P < 0.001; agreement within 4%, P < 0.001); 3) expiratory airflow (correlation, R2= 0.83, P < 0.001); and 4) respiratory movement signal (correlation, R2= 0.79–0.84, P < 0.001). The expiratory airflow signal, however, demonstrated a decrease in amplitude compared with the gold standard. Integrating respiratory and EEG/EMG signals, we fully characterized sleep and breathing patterns in conscious, unrestrained mice and demonstrated inspiratory flow limitation in a New Zealand Obese mouse. Our approach will facilitate studies of SRBD mechanisms in inbred mouse strains and offer a powerful platform to investigate the effects of environmental and pharmacological exposures on breathing disturbances during sleep and wakefulness.
Cerebrovascular and corticomotor function during progressive passive hyperthermia in humans
Authors: Ross Emma Z. , Cotter James D. , Wilson Luke , Fan Jui-Lin , Lucas Samuel J. E. , Ainslie Philip N.
Published: December 2011

The present study examined the integrative effects of passive heating on cerebral perfusion and alterations in central motor drive. Eight participants underwent passive hyperthermia [0.5°C increments in core temperature (Tc) from normothermia (37 ± 0.3°C) to their limit of thermal tolerance (T-LIM; 39.0 ± 0.4°C)]. Blood flow velocity in the middle cerebral artery (CBFv) and respiratory responses were measured continuously. Arterial blood gases and blood pressure were obtained intermittently. At baseline and each Tc level, supramaximal femoral nerve stimulation and transcranial magnetic stimulation (TMS) were performed to assess neuromuscular and cortical function, respectively. At T-LIM, measures were (in a randomized order) also made during a period of breathing 5% CO2 gas to restore eucapnia (+5% CO2). Mean heating time was 179 ± 51 min, with each 0.5°C increment in Tc taking 40 ± 10 min. CBFv was reduced by ∼20% below baseline from +0.5°C until T-LIM. Maximal voluntary contraction (MVC) of the knee extensors was decreased at T-LIM (−9 ± 10%; P < 0.05), and cortical voluntary activation (VA), assessed by TMS, was decreased at +1.5°C and T-LIM by 11 ± 8 and 22 ± 23%, respectively ( P < 0.05). Corticospinal excitability (measured as the EMG response produced by TMS) was unaltered. Reductions in cortical VA were related to changes in ventilation (V̇e; R 2 = 0.76; P < 0.05) and partial pressure of end-tidal CO2 (PetCO2; R 2 = 0.63; P < 0.05) and to changes in CBFv ( R 2 = 0.61; P = 0.067). Interestingly, although CBFv was not fully restored, MVC and cortical VA were restored towards baseline values during inhalation of 5% CO2. These results indicate that descending voluntary drive becomes progressively impaired as Tc is increased, presumably due, in part, to reductions in CBFv and to hyperthermia-induced hyperventilation and subsequent hypocapnia.
Human muscle length-dependent changes in blood flow
Authors: McDaniel John , Ives Stephen J. , Richardson Russell S.
Published: December 2011

Although a multitude of factors that influence skeletal muscle blood flow have been extensively investigated, the influence of muscle length on limb blood flow has received little attention. Thus the purpose of this investigation was to determine if cyclic changes in muscle length influence resting blood flow. Nine healthy men (28 ± 4 yr of age) underwent a passive knee extension protocol during which the subjects' knee joint was passively extended and flexed through 100–180° knee joint angle at a rate of 1 cycle per 30 s. Femoral blood flow, cardiac output (CO), heart rate (HR), stroke volume (SV), and mean arterial pressure (MAP) were continuously recorded during the entire protocol. These measurements revealed that slow passive changes in knee joint angle did not have a significant influence on HR, SV, MAP, or CO; however, net femoral blood flow demonstrated a curvilinear increase with knee joint angle ( r2 = 0.98) such that blood flow increased by ∼90% (125 ml/min) across the 80° range of motion. This net change in blood flow was due to a constant antegrade blood flow across knee joint angle and negative relationship between retrograde blood flow and knee joint angle ( r2 = 0.98). Thus, despite the absence of central hemodynamic changes and local metabolic factors, blood flow to the leg was altered by changes in muscle length. Therefore, when designing research protocols, researchers need to be cognizant of the fact that joint angle, and ultimately muscle length, influence limb blood flow.
Mechanical effect of rat flexor carpi ulnaris muscle after tendon transfer: does it generate a wrist extension moment?
Authors: Maas Huub , Huijing Peter A.
Published: December 2011

The mechanical effect of a muscle following agonist-to-antagonist tendon transfers does not always meet the surgeon's expectations. We tested the hypothesis that after flexor carpi ulnaris (FCU) to extensor carpi radialis (ECR) tendon transfer in the rat, the direction (flexion or extension) of the muscle's joint moment is dependent on joint angle. Five weeks after recovery from surgery (tendon transfer group) and in a control group, wrist angle-moment characteristics of selectively activated FCU muscle were assessed for progressive stages of dissection: 1) with minimally disrupted connective tissues, 2) after distal tenotomy, and 3) after maximal tendon and muscle belly dissection, but leaving blood supply and innervations intact. In addition, force transmission from active FCU onto the distal tendon of passive palmaris longus (PL) muscle (a wrist flexor) was assessed. Excitation of control FCU yielded flexion moments at all wrist angles tested. Tenotomy decreased peak FCU moment substantially (by 93%) but not fully. Only after maximal dissection, FCU wrist moment became negligible. The mechanical effect of transferred FCU was bidirectional: extension moments in flexed wrist positions and flexion moments in extended wrist positions. Tenotomy decreased peak extension moment (by 33%) and increased peak flexion moment of transferred FCU (by 41%). Following subsequent maximal FCU dissection, FCU moments decreased to near zero at all wrist angles tested. We confirmed that, after transfer of FCU towards a wrist extensor insertion, force can be transmitted from active FCU to the distal tendon of passive PL. We conclude that mechanical effects of a muscle after tendon transfer to an antagonistic site can be quite different from those predicted based solely on the sign of the new moment arm at the joint.
New Method to Disaggregate and Analyze Single Isolated Helminthes Cells Using Flow Cytometry: Proof of Concept
Authors: Nava-Castro Karen , Hernández-Bello Romel , Muñiz-Hernández Saé , Escobedo Galileo , Morales-Montor Jorge
Published: December 2011

In parasitology, particularly in helminthes studies, several methods have been used to look for the expression of specific molecules, such as RT‐PCR, western blot, 2D‐electrophoresis, and microscopy, among others. However, these methods require homogenization of the whole helminth parasite, preventing evaluation of individual cells or specific cell types in a given parasite tissue or organ. Also, the extremely high interaction between helminthes and host cells (particularly immune cells) is an important point to be considered. It is really hard to obtain fresh parasites without host cell contamination. Then, it becomes crucial to determine that the analyzed proteins are exclusively from parasitic origin, and not a consequence of host cell contamination. Flow cytometry is a fluorescence‐based technique used to evaluate the expression of extra‐and intracellular proteins in different type cells, including protozoan parasites. It also allows the isolation and recovery of single‐cell populations. Here, we describe a method to isolate and obtain purified helminthes cells.
Strong Laws of Large Numbers for Arrays of Rowwise NA and LNQD Random Variables
Authors: Wang Jiangfeng , Wu Qunying
Published: December 2011

Some strong laws of large numbers and strong convergence properties for arrays of rowwise negatively associated and linearly negative quadrant dependent random variables are obtained. The results obtained not only generalize the result of Hu and Taylor to negatively associated and linearly negative quadrant dependent random variables, but also improve it.
Optimization of Liposomal Lipid Composition for a New, Reactive Sulfur Donor, andIn VivoEfficacy Studies on Mice to Antagonize Cyanide Intoxication
Authors: Petrikovics Ilona , Jayanna Prashanth , Childress Jonathan , Budai Marianna , Martin Sarah , Kuzmitcheva Galina , Rockwood Gary
Published: December 2011

Present studies have focused on a novel cyanide antidotal system, on the coencapsulation of a new sulfur donor DTO with rhodanese within sterically stabilized liposomes. The optimal lipid composition for coencapsulation of DTO with rhodanese is the combination of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, cholesterol, cationic lipid (DOTAP), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] ammonium salt (with molar ratios of 82.7 : 9.2 : 3.0 : 5.1). With the optimized compositions, prophylactic and therapeuticin vivoefficacy studies were carried out in a mice model. When DTO was coencapsulated with rhodanese and thiosulfate the prophylactic antidotal protection was4.9×LD50. Maximum antidotal protection against cyanide intoxication (15×LD50) was achieved with coencapsulated rhodanese and DTO/thiosulfate in combination with sodium nitrite. When applied therapeutically, 100% survival rate (6/6) was achieved at 20 mg/kg cyanide doses with the encapsulated DTO-rhodanese-thiosulfate antidotal systems with and without sodium nitrite. These data are indicating that the appropriately formulated DTO is a promising sulfur donor for cyanide antagonism.
Demersal Assemblages on the Soft Bottoms off the Catalan-Levante Coast of the Spanish Mediterranean
Authors: García-Rodríguez Mariano , Abelló Pere , Fernández Angel , Esteban Antonio
Published: December 2011

The analysis of 255 bottom trawl samples obtained in annual experimental surveys (2007–2010) along the western Mediterranean shows the existence of five well-defined demersal assemblages that follow a depth distribution: (a) upper shelf assemblages, including two assemblages differentiated by the type of substrate (sand-muddy and terrigenous muddy bottoms); (b) a middle shelf assemblage; (c) an upper slope assemblage; (d) a middle slope assemblage. Faunally, they are dominated by fish (37% of 452 total species), followed by crustaceans (22%), molluscs (17%), echinoderms (9%), and other invertebrates (15%). The assemblages identified showed major alterations on the shelf and shelf edge and less pronounced ones on the upper and middle slope. The average diversity values were more or less high, evidencing the high species richness in the western Mediterranean. The identified assemblages may facilitate future multispecies fisheries management based on an ecosystem approach.
Date Fruit Extract Is a Neuroprotective Agent in Diabetic Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats: A Multimodal Analysis
Authors: Zangiabadi Nasser , Asadi-Shekaari Majid , Sheibani Vahid , Jafari Mandana , Shabani Mohammad , Asadi Ali Reza , Tajadini Hale , Jarahi Morteza
Published: December 2011

Background. To study the effects of an aqueous extract of date fruit (Phoenix dactyliferaL. Arecaceae) diet on diabetic polyneuropathy (DPN) in streptozotocin- (STZ-) induced diabetic rats.Methods. The effects of a date fruit extract (DFE) diet on diabetic neuropathy in STZ-induced diabetic rats were evaluated and compared with a nondiabetic control group, diabetic control group (sham), and vehicle group with respect to the following parameters: open field behavioral test, motor nerve conduction velocity (MNCV), and morphological observations.Results. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 6 weeks with DFE counteracted the impairment of the explorative activity of the rats in an open field behavioral test and of the conduction velocity of the sciatic nerve (MNCV). In addition, pretreatment with DFE significantly reversed each nerve diameter reduction in diabetic rats.Conclusion. DFE treatment shows efficacy for preventing diabetic deterioration and for improving pathological parameters of diabetic neuropathy in rats, as compared with control groups.
Metric Characterizations of α‐Well‐Posedness for a System ofMixed Quasivariational‐Like Inequalities in Banach Spaces
Authors: Ceng L. C. , Lin Y. C.
Published: December 2011

The purpose of this paper is to investigate the problems of the well‐posedness
for a system of mixed quasivariational‐like inequalities in Banach spaces. First, we generalize the concept of α‐well‐posedness to the system of mixed quasivariational‐like inequalities,
which includes symmetric quasi‐equilibrium problems as a special case. Second, we establish
some metric characterizations of α‐well‐posedness for the system of mixed quasivariational‐like
inequalities. Under some suitable conditions, we prove that the α‐well‐posedness is equivalent to the existence and uniqueness of solution for the system of mixed quasivariational‐like
inequalities. The corresponding concept of α‐well‐posedness in the generalized sense is also
considered for the system of mixed quasivariational‐like inequalities having more than one
solution. The results presented in this paper generalize and improve some known results in
the literature.
Sperm DNA Integrity Assessment: A New Tool in Diagnosis and Treatment of Fertility
Authors: Bungum Mona
Published: December 2011

Infertility affects 15% of all couples. Although male infertility factors with reduced semen quality are contributing to about half of all involuntary childlessness, the value of standard semen parameters in prediction of fertilityin vivoand choice of proper method for assisted reproduction is limited. In the search for better markers of male fertility, during the last 10 years, assessment of sperm DNA integrity has emerged as a strong new biomarker of semen quality that may have the potential to discriminate between infertile and fertile men. Sperm DNA Fragmentation Index (DFI) as assessed by the flow cytometric Sperm Chromatin Structure Assay (SCSA) can be used for evaluation of sperm chromatin integrity. The biological background for abnormal DFI is not completely known, but clinical data show that DFI above 30% is associated with very low chance for achieving pregnancy in natural way or by insemination, but notin vitro. Already when the DFI is above 20%, the chance of natural pregnancy may be reduced, despite other sperm parameters being normal. Thus this method may explain a significant proportion of cases of unexplained infertility and can be beneficial in counselling involuntary childless couples need ofin vitrofertilisation.
Pathogenesis of Preeclampsia: The Genetic Component
Authors: Valenzuela Francisco J. , Pérez-Sepúlveda Alejandra , Torres María J. , Correa Paula , Repetto Gabriela M. , Illanes Sebastián E.
Published: December 2011

Preeclampsia (PE) is one of the main causes of maternal and fetal morbidity and mortality in the world, causing nearly 40% of births delivered before 35 weeks of gestation. PE begins with inadequate trophoblast invasion early in pregnancy, which produces an increase in oxidative stress contributing to the development of systemic endothelial dysfunction in the later phases of the disease, leading to the characteristic clinical manifestation of PE. Numerous methods have been used to predict the onset of PE with different degrees of efficiency. These methods have used fetal/placental and maternal markers in different stages of pregnancy. From an epidemiological point of view, many studies have shown that PE is a disease with a strong familiar predisposition, which also varies according to geographical, socioeconomic, and racial features, and this information can be used in the prediction process. Large amounts of research have shown a genetic association with a multifactorial polygenic inheritance in the development of this disease. Many biological candidate genes and polymorphisms have been examined in their relation with PE. We will discuss the most important of them, grouped by the different pathogenic mechanisms involved in PE.
The Impact of the Organism on Its Descendants
Authors: Bateson Patrick
Published: December 2011

Historically, evolutionary
biologists have taken the view that an understanding
of development is irrelevant to theories of evolution.
However, the integration of several disciplines in
recent years suggests that this position is wrong. The
capacity of the organism to adapt to challenges from
the environment can set up conditions that affect the
subsequent evolution of its descendants. Moreover,
molecular events arising from epigenetic processes can
be transmitted from one generation to the next and
influence genetic mutation. This in turn can
facilitate evolution in the conditions in which
epigenetic change was first initiated.
Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease
Authors: Berk Camryn , Sabbagh Marwan
Published: December 2011

Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.
Depression in Temporal Lobe Epilepsy: A Review of Prevalence, Clinical Features, and Management Considerations
Authors: Garcia C. S.
Published: December 2011

Depression in temporal lobe epilepsy has been established as a frequent occurrence, and various possible mechanisms for this significant comorbidity have been posited. However, there is still little to guide a clinician in the recognition and management of depression in patients with temporal lobe epilepsy. This is in part due to the lack of consistent findings in earlier studies, which was likely partly due to variabilities in methodology, sampling, and diagnosis of both temporal lobe epilepsy and depression. However, in recent years, significant effort has been made to address these issues and provide a framework for diagnosis and management of depression in this population. The following is a review of the literature, with special emphasis on clinical phenomenology of depressive symptoms, described bidirectional risk between depression and temporal lobe epilepsy, and treatment strategies in the context of potential drug interactions with antiepileptic drugs.
Demographic Predictors of Peanut, Tree Nut, Fish, Shellfish, and Sesame Allergy in Canada
Authors: Ben-Shoshan M. , Harrington D. W. , Soller L. , Fragapane J. , Joseph L. , Pierre Y. St. , Godefroy S. B. , Elliott S. J. , Clarke A. E.
Published: December 2011

Background. Studies suggest that the rising prevalence of food allergy during recent decades may have stabilized. Although genetics undoubtedly contribute to the emergence of food allergy, it is likely that other factors play a crucial role in mediating such short-term changes.
Objective. To identify potential demographic predictors of food allergies. Methods. We performed a cross-Canada, random telephone survey. Criteria for food allergy were self-report of convincing symptoms and/or physician diagnosis of allergy. Multivariate logistic regressions were used to assess potential determinants. Results. Of 10,596 households surveyed in 2008/2009, 3666 responded, representing 9667 individuals. Peanut, tree nut, and sesame allergy were more common in children (odds ratio (OR) 2.24 (95% CI, 1.40, 3.59), 1.73 (95% CI, 1.11, 2.68), and 5.63 (95% CI, 1.39, 22.87), resp.) while fish and shellfish allergy were less common in children (OR 0.17 (95% CI, 0.04, 0.72) and 0.29 (95% CI, 0.14, 0.61)). Tree nut and shellfish allergy were less common in males (OR 0.55 (95% CI, 0.36, 0.83) and 0.63 (95% CI, 0.43, 0.91)). Shellfish allergy was more common in urban settings (OR 1.55 (95% CI, 1.04, 2.31)). There was a trend for most food allergies to be more prevalent in the more educated (tree nut OR 1.90 (95% CI, 1.18, 3.04)) and less prevalent in immigrants (shellfish OR 0.49 (95% CI, 0.26, 0.95)), but wide CIs preclude definitive conclusions for most foods. Conclusions. Our results reveal that in addition to age and sex, place of residence, socioeconomic status, and birth place may influence the development of food allergy.
Immunomodulation of Curcumin on Adoptive Therapy with T Cell Functional Imaging in Mice
Authors: Chang Ya-Fang , Chuang Hui-Yen , Hsu Chien-Hui , Liu Ren-Shyan , Gambhir Sanjiv Sam , Hwang Jeng-Jong
Published: December 2011

Adoptive T-cell therapy involves the ex vivo expansion and subsequent transfusion of tumor-specific T lymphocytes to eliminate tumors. Using immune modulators to block immunosuppressive factors in the tumor microenvironment has emerged as a promising strategy to enhance T-cell–mediated tumor regression. Curcumin, a major component of turmeric, has been shown to possess antitumor and immunomodulatory effects by regulating a diverse range of molecular targets. Thus, we hypothesize that these beneficial effects of curcumin may improve the therapeutic efficacy of adoptive therapy. Here, we have shown that curcumin enhances cytotoxicity of CD8+ T cells toward tumors via alteration of the tumor microenvironment when combined with adoptive therapy. We found that T-cell accumulation and function were increased in combined treatment due to the blockade of different immunosuppressors, including TGF-β, indoleamine 2,3-dioxygenase, and regulatory T cells. Furthermore, bioluminescent imaging with a granzyme B promoter–conjugated optical reporter also reflected improved cytotoxicity of antigen-specific CD8+ T cells in tumor-bearing mice during treatment. These findings suggest that combination of multitargeting drugs, such as curcumin, with adoptive therapy may have potential for clinical application. In addition, using a granzyme B–specific imaging reporter to assess T-cell function may also be applied for the development and therapeutic evaluation of new immunotherapy in preclinical studies. Cancer Prev Res; 5(3); 444–52. ©2011 AACR.
Nuclear Receptors as Modulators of the Tumor Microenvironment
Authors: Sherman Mara H. , Downes Michael , Evans Ronald M.
Published: December 2011

Over the past several decades of cancer research, the inherent complexity of tumors has become increasingly appreciated. In addition to acquired cell-intrinsic properties, tumor initiation and growth is supported by an abundance of parenchymal, inflammatory, and stromal cell types, which infiltrate and surround the tumor. Accumulating evidence shows that numerous components of this supportive milieu, referred to collectively as the tumor microenvironment, are indeed critical during the process of multistep tumorigenesis. These findings highlight the important interplay between neoplastic cells and tumor-associated cell types, and suggest that therapy should target both neoplastic cells and supportive stromal cells to effectively attenuate tumor growth. The nuclear receptor superfamily encompasses a druggable class of molecules expressed in numerous stromal and parenchymal cell types, whose established physiologic roles suggest their potential as therapeutic and preventive targets in the context of the reactive tumor microenvironment. In this minireview, we discuss recent evidence that tumor-associated inflammation, angiogenesis, and fibrosis can be modulated at the transcriptional level by nuclear receptors and their ligands. As these processes have been widely implicated in cancer initiation, progression, and resistance to current therapy, nuclear receptor ligands targeting the tumor microenvironment may be potent antitumor agents in combination therapies, including for preventing cancer development within high-risk populations. Cancer Prev Res; 5(1); 3–10. ©2011 AACR.
Diet-Dependent Net Endogenous Acid Load of Vegan Diets in Relation to Food Groups and Bone Health-Related Nutrients: Results from the German Vegan Study
Authors: Ströhle Alexander , Waldmann Annika , Koschizke Jochen , Leitzmann Claus , Hahn Andreas
Published: December 2011

Background/Aims:Dietary composition has been shown to affect acid-base homeostasis and bone health in humans. We investigated the potential renal acid load (PRAL) and the estimated diet-dependent net acid load (net endogenous acid production, NEAP) in adult vegans and evaluated the relationships between NEAP, food groups and intake of bone health-related nutrients. Methods: The German Vegan Study (GVS) is a cross-sectional study. Data from healthy men (n = 67) and women (n = 87), aged 21–75 years, who fulfilled the study criteria (vegan diet for ≧1 year prior to study start; age ≧18 years, and no pregnancy/childbirth during the last 12 months) were included in the analysis. NEAP values were calculated from diet composition using two models: one based on the protein/potassium quotient and another taking into account an anthropometry-based loss of urinary organic anions. Results:Mean daily intakes of phosphorus, potassium, sodium, magnesium and vitamin C were above, and vitamin D and calcium below Dietary Reference Intake (DRI). Regardless of the model used, the diet in the GVS was characterized by a nearly neutral NEAP. A strong correlation was observed between the NEAP values of the two models (rs = 0.873, p < 0.001). Only the consumption of fruits decreased constantly across the increasing quartiles of NEAP. Conclusions: It can be hypothesized that vegan diets do not affect acid-base homeostasis. With respect to bone health, the significance of this finding needs further investigation.
Upregulation of Hepatic 11β-Hydroxysteroid Dehydrogenase-1 Expression in Calcium-Deficient Rats
Authors: Takaya Junji , Iharada Anna , Okihana Hiroyuki , Kaneko Kazunari
Published: December 2011

Background: Many epidemiologic studies have reported a link between calcium (Ca) deficiency and metabolic syndrome. In this study, we examine Ca deficiency in rats and whether changes in glucocorticoid metabolism are induced. Methods: Twelve-week-old female Wistar rats were weaned onto a very-low-Ca diet (low-Ca group) or a control diet (control group) for 2 weeks. Quantitative real-time PCR was used to assess mRNA for 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1), 11β-HSD2, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor-α, and glucocorticoid receptor in the liver. Concentrations of adiponectin, leptin, corticosterone, intact parathyroid hormone, asymmetrical dimethylarginine and insulin in fasting serum were determined using a rat-specific enzyme-linked immunosorbent assay. Glucose concentrations were measured using a glucose oxidase system. Serum ionized Ca levels were measured with an automatic ion-selective electrode analyzer. Serum nitrite/nitrate levels were measured using a colorimetric assay kit. Results: After 2 weeks, no differences in serum glucose, corticosterone or insulin levels were observed. The low-Ca group rats showed higher homeostasis model assessment insulin resistance, lower adiponectin and higher intact parathyroid hormone levels. Serum nitrite/nitrate and asymmetrical dimethylarginine were significantly higher in the low-Ca group than in the control group. The expression of hepatic 11β-HSD1 mRNA was upregulated, while hepatic phosphoenolpyruvate carboxykinase expression was downregulated in the low-Ca group. Glucocorticoid receptor, peroxisome proliferator-activated receptor-α and 11β-HSD2 expression levels showed a similar tendency. Conclusion: A low-Ca diet alters glucocorticoid metabolism, which leads to hepatic upregulation of 11β-HSD1, and is possibly a key mechanism inducing the metabolic complications of Ca deficiency.
Cardioprotective Effect of a Hemoglobin-Based Oxygen Carrier on Cold Ischemia/Reperfusion Injury
Authors: Wei Li , Wu Ruo-Bin , Yang Cheng-Min , Zheng Shao-Yi , Yu Xi-Yong
Published: December 2011

Objectives: The etiology of myocardial ischemia/reperfusion (I/R) injury is multifactorial, but activation of the innate immune system and the resulting inflammatory response are important components of I/R injury. The aim of this study was to investigate the protective effect of a hemoglobin-based oxygen carrier (HBOC) on cold I/R heart and to explore the underlying mechanisms. Methods: Isolated Sprague-Dawley rat hearts were perfused in the Langendorff mode. After 30 min of basal perfusion, rat hearts were arrested with histidine-tryptophan-ketoglutarate solution (HTKs) with or without an HBOC and hypothermically stored (4°C) for 9 or 14 h, followed by 2 h of reperfusion. Results: Compared with HTKs alone, the HBOC in HTKs greatly improved heart contraction and decreased infarct size, necrosis and apoptosis, which was related to the reduced expression of Toll-like receptor 2 (TLR 2), TLR 4, TNF-α, IL-1β and nuclear factor-ĸB (NF-ĸB) activation. Conclusions: Our results demonstrated that the HBOC protected isolated rat heart from cold I/R injury and this protection was associated with attenuation of the expression of the TLR 2 and TLR 4/NF-ĸB signaling pathway, which may down-regulate the inflammatory response.
Tailor-Made Therapy for Viral Hepatitis: Recent Advances
Authors: Kudo Masatoshi
Published: December 2011

Combination therapy of pegylated interferon-α with ribavirin (PEG-IFN/RBV) is a standard of care for chronic hepatitis C (CHC). The majority of CHC patients are infected with HCV genotype I. The recent discovery revealed by a genome-wide association study technology provides the important role of interleukin-28B (IL28B) and inosine triphosphatase (ITPA) in HCV infection. In addition, response to PEG-IFN/RBV therapy is correlated with insulin resistance, hepatic steatosis, and hepatic fibrosis in CHC patients. Double-filtration plasmapheresis together with IFN therapy has proved to be effective in the reduction of viral load during the early stage of treatment. In CHC patients, not only IL28B status, but also the treatment period of PEG-IFN/RBV is important. Even when new polymerase/protease inhibitors are introduced in the treatment of CHC, tailor-made treatment for CHC using IL28B, inosine triphosphatase testing or double-filtration plasmapheresis treatment prolonged treatment strategy is highly recommended. The relative etiologic role of prior hepatitis B virus infection in the development of non-B non-C hepatocellular carcinoma is also known in hepatitis B-endemic areas.
Correlation between Insulin Resistance and Outcome of Pegylated Interferon and Ribavirin Therapy, Hepatic Steatosis, Hepatic Fibrosis in Chronic Hepatitis C-1b and High Viral Load
Authors: Kim Soo Ryang , Saito Jun , Imoto Susumu , Komaki Takamitsu , Nagata Yoshiaki , Nakajima Taisuke , Ando Kenji , Fukuda Katsumi , Otono Yumi , Kim Ke Ih , Ohtani Aya , Sugimoto Kayo , Hasegawa Yutaka , Fujinami Aya , Ohta Mitsuhiro , Hotta Hak , Maekawa Yoko , Hayashi Yoshitake , Kudo Masatoshi
Published: December 2011

Background/Aims: Insulin resistance (IR) has been reported to be an independent predictor of treatment outcome in chronic hepatitis C patients. Methods: We analyzed the relationship between IR and the outcome of pegylated interferon and ribavirin (PEG-IFN/RBV) therapy, taking into account host factors of body mass index and histological index, such as rate of fatty change and fibrosis. Japanese patients (n = 30; 19 men and 11 women; median age 60.0 ± 8.7 years) with chronic hepatitis C-1b with a high viral load were treated with PEG-IFN-α2b/RBV for 48 weeks. Results: Sustained virological response (SVR) was seen in 60% (18/30) and non-SVR in 40% (12/30). HOMA-IR (homeostasis model of assessment-insulin resistance index) at the start and at 24 weeks of treatment showed no statistical difference between SVR and non-SVR. Correlation was observed between HOMA-IR and body mass index (r = 0.45, p = 0.013). Among 20 patients, steatosis and fibrosis were assessed by biopsy. Correlation was observed between HOMA-IR and steatosis (r = 0.57, p = 0.0093), whereas no correlation was observed between HOMA-IR and fibrosis. Conclusion: A larger prospective study is needed to clarify the role of IR in the outcome of PEG-IFN/RBV combination therapy and hepatic fibrosis in Japanese patients.
Association of Interleukin-28B and Hepatitis C Genotype 1 with a High Viral Load and Response to Pegylated Interferon plus Ribavirin Therapy
Authors: Takita Masahiro , Hagiwara Satoru , Arizumi Tadaaki , Hayaishi Sousuke , Ueda Taisuke , Kitai Satoshi , Yada Norihisa , Inoue Tatsuo , Minami Yasunori , Chung Hobyung , Ueshima Kazuomi , Sakurai Toshiharu , Kudo Masatoshi
Published: December 2011

Background: Pegylated interferon (PEG-IFN) plus ribavirin therapy is the current standard treatment for chronic hepatitis C (CHC) genotype 1 with high viral load. A common genetic variation near the IL28B gene has been found to affect the response to PEG-IFN plus ribavirin therapy for CHC. The aims of this study were to analyze the association between the rs8099917 genotype and treatment response in a cohort study of CHC. Methods: This study evaluated clinical and laboratory parameters retrospectively in a cohort of 122 patients with chronic hepatitis C with genotype 1 and a high viral load who received PEG-IFN plus ribavirin therapy. We carried out univariate and multivariate statistical analyses of parameters and clinical responses. Results: Sixty-three of 122 patients (51.6%) had sustained virological responses (SVRs). Patients with the rs8099917 genotype TT achieved significantly higher SVR rates (p < 0.01). Univariate analysis revealed that SVRs were associated with BMI, fibrosis, albumin, total cholesterol, PEG-IFN dose, ribavirin dose and the rs8099917 genotype. Multivariate analysis revealed that the rs8099917 genotype (odds ratio 7.434, 95% CI 2.278–24.257, p = 0.001) and total PEG-IFN dose (odds ratio 7.162, 95% CI 1.565–18.15, p = 0.007) were significant factors. Conclusions: The rs8099917 genotype and total PEG-IFN dose were associated with SVR in patients with hepatitis C virus genotype 1.
HLA-DRB1*010101 Allele Is Closely Associated with Poor Virological Response to Lamivudine Therapy in Patients with Chronic Hepatitis B
Authors: Jin Young-Joo , Shim Ju Hyun , Chung Young-Hwa , Kim Jeong A. , Choi Jong Gi , Park Won Hyung , Lee Danbi , Kim Sung Eun , Lee Yoon Seon , Kim Sung Hoon , Yang Soo Hyun
Published: December 2011

Background/Aims: We intended to evaluate the association between specific human leukocyte antigen (HLA)-DRB1 gene polymorphism and antiviral response to lamivudine (LAM) therapy in chronic hepatitis B (CHB) patients. Methods: Six-digit HLA-DRB1 genotypes were determined using sequence-based typing in 334 CHB patients initially treated with LAM for at least 12 months. Antiviral response was evaluated every 3–6 months during LAM therapy. Results: Median age of the subjects was 43 years (range, 16–72). Median duration of LAM therapy was 69 months (range, 13–140). Median baseline serum hepatitis B virus (HBV DNA) level was 7.0 log10 copies/ml (range, 5.5–9.1). At 12 months of LAM therapy, serum HBV DNA was undetectable by solution hybridization method in 308 (88%) patients. Among 25 HLA-DRB1 alleles identified, HLA-DRB1*090102, *080302, and *070101 were the most frequent alleles (>10%). HLA-DRB1*010101 was identified in 5.4% (18/334). The frequency of the HLA-DRB1*010101 allele was significantly lower in patients with virological response at 12 months of LAM therapy than in patients without it (4.2 vs. 19.2%, p = 0.025). The other HLA-DRB1 alleles were not associated with virological response. HBeAg loss/seroconversion and alanine aminotransferase normalization were not associated with HLA-DRB1 alleles. Conclusion: The HLA-DRB1*010101 allele is closely associated with poor virological response to initial LAM therapy in CHB patients.
Effect of Selenium Supplementation on Glutathione Peroxidase and Catalase Activities in Senescent Cultured Human Fibroblasts
Authors: Ghneim Hazem K. , Al-Sheikh Yazeed A.
Published: December 2011

Aims: To investigate the effect of senescence and selenium supplementation on glutathione peroxidase (cGPx) and catalase (CAT) activities, and concurrent hydrogen peroxide (H2O2) generation in subcultured human fibroblasts. Methods: cGPx and CAT activities and H2O2 levels were assayed in presenescent passage 5 and 10 cells, and in senescent passage 20, 25, 30 and 35 cells cultured in routine medium (MEM1) and supplemented media MEM2 and MEM3 containing normal and triple human plasma levels of Se, respectively. Senescent cells were identified by studying their growth and replication states, and by monitoring their activity of key glucose and glycogen degradative enzymes. Results: cGPx activity showed moderate increases in senescent cells at passages 20–35 subcultured in MEM1 or MEM2. This activity underwent highly significant progressive increases in the same senescent cells subcultured in MEM3. In contrast, CAT activity showed progressive, highly significant increases in senescent cells at passages 20–35 regardless of the culture medium type. Concurrent H2O2 generation was significantly increased in passage 15–25 cells and peaked to higher levels in passage 30 and 35 cells cultured in MEM1 or MEM2. These rates, however, were significantly reduced in senescent passage 20–35 cells cultured in MEM3. Conclusions: The highest cGPx activity and coupled lower H2O2 generation were achieved in senescent cells cultured in MEM3.
The Association of Serum Sialic Acid with Carotid Intima-Media Thickness and Anthropometric and Metabolic Parameters in Obese Children and Adolescents
Authors: Akın Leyla , Kurtoglu Selim , Muhtaroğlu Sabahattin , Yikilmaz Ali , Kendirci Mustafa , Mazicioglu Mümtaz
Published: December 2011

Background: Sialic acid (SA) has been shown to be a strong predictor of cardiovascular mortality in adults. No study in children regarding the association of SA with cardiovascular risks exists in the literature. Aim: We aimed to investigate the association of SA with anthropometric and metabolic parameters and its correlation with metabolic syndrome (MS) and carotid intima-media thickness (IMT) in obese children. Methods: A total of 154 obese children were included in the study (74 females, 80 males; mean age 11.3 ± 2.6 years). Anthropometric measurements including body fat percentage (BFP) were recorded. Fasting lipids and SA levels were measured. The carotid IMT was evaluated with ultrasonography. Results: We found a significant correlation between serum total SA (TSA) levels and BFP (r = 0.25, p = 0.01 in the whole group; r = 0.43, p = 0.00 in girls). The group with BFP ≧95th percentile had higher TSA levels than the group with BFP <95th percentile (p = 0.04). TSA and carotid IMT were weakly correlated (r = 0.20, p = 0.01), but the significance was lost after correcting for BFP. No correlations were found between TSA and other anthropometric measurements. TSA did not correlate with serum fasting glucose, lipids, insulin or homeostasis model assessment-insulin resistance. TSA levels were not different between children with or without MS. Conclusion: Serum TSA levels are significantly correlated with BFP in obese children.
Hepatitis B Virus Serology to Predict Antiviral Response in Chronic Hepatitis B
Authors: Kim Beom Kyung , Han Kwang-Hyub , Ahn Sang Hoon
Published: December 2011

Since active replication of hepatitis B virus is strongly associated with the development of cirrhosis, hepatocellular carcinoma, and liver-related mortality, antiviral therapy is aimed at maximal viral suppression. However, as no antiviral therapy is perfect due to the emergence of resistant strains and suboptimal efficacy in some patients, modifying the treatment strategies for certain patients in advance is important through prediction of treatment responses. Recently, along with serial monitoring of hepatitis B virus DNA level, quantitative analysis of the serologic markers HBsAg (qHBsAg) and HBeAg (qHBeAg) has been used to predict responses to antiviral therapy. The clinical usefulness of both pretreatment qHBsAg and decline in qHBsAg during treatment was assessed in patients treated with pegylated interferon, suggesting that they might be used as another criterion to identify good and poor responders. Similarly, in patients treated with oral nucleos(t)ide analogues (NAs), the clinical significance of qHBsAg has been reported in some studies. However, as the decline in qHBsAg is much slower during NA therapy and the data on the use of qHBsAg to predict response to NA treatment are very preliminary, its wide application remains to be determined. Another serologic marker (qHBeAg) measured at baseline and during treatment might be applied for identifying good or poor responders to antiviral therapy. Unfortunately, measurement of qHBeAg has not been widely used because it is expensive, nonstandardized, and unavailable in patients with HBeAg-negative chronic hepatitis B (CHB). In conclusion, serologic markers may be potential predictors of response to antiviral therapy in CHB, allowing delivery of the most appropriate treatments to the most suitable patients. Further investigations into the universal clinical usefulness of such markers are needed.