bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of cytochromeP-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats
Authors: Sporková Alexandra , Kopkan Libor , Varcabová Šárka , Husková Zuzana , Hwang Sung Hee , Hammock Bruce D. , Imig John D. , Kramer Herbert J. , Červenka Luděk
Published: March 2011

Alterations in renal function contribute to Goldblatt two-kidney, one-clip (2K1C) hypertension. A previous study indicated that bioavailability of cytochrome P-450 metabolites epoxyeicosatrienoic acids (EETs) is decreased while that of 20-hydroxyeicosatetraenoic acids (20-HETE) is increased in this model. We utilized the inhibitor of soluble epoxide hydrolase cis-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid ( c-AUCB) and HET-0016, the inhibitor of 20-HETE production, to study the role of EETs and 20-HETE in the regulation of renal function. Chronic c-AUCB treatment significantly decreased systolic blood pressure (SBP) (133 ± 1 vs. 163 ± 3 mmHg) and increased sodium excretion (1.23 ± 0.10 vs . 0.59 ± 0.03 mmol/day) in 2K1C rats. HET-0016 did not affect SBP and sodium excretion. In acute experiments, renal blood flow (RBF) was decreased in 2K1C rats (5.0 ± 0.2 vs . 6.9 ± 0.2 ml·min−1·g−1). c-AUCB normalized RBF in 2K1C rats (6.5 ± 0.6 ml·min−1·g−1). HET-0016 also increased RBF in 2K1C rats (5.8 ± 0.2 ml·min−1·g−1). Although RBF and glomerular filtration rate (GFR) remained stable in normotensive rats during renal arterial pressure (RAP) reductions, both were significantly reduced at 100 mmHg RAP in 2K1C rats. c-AUCB did not improve autoregulation but increased RBF at all RAPs and shifted the pressure-natriuresis curve to the left. HET-0016-treated 2K1C rats exhibited impaired autoregulation of RBF and GFR. Our data indicate that c-AUCB displays antihypertensive properties in 2K1C hypertension that are mediated by an improvement of RBF and pressure natriuresis. While HET-0016 enhanced RBF, its anti-natriuretic effect likely prevented it from producing a blood pressure-lowering effect in the 2K1C model.
Effects of chronic weight perturbation on energy homeostasis and brain structure in mice
Authors: Ravussin Y. , Gutman R. , Diano S. , Shanabrough M. , Borok E. , Sarman B. , Lehmann A. , LeDuc C. A. , Rosenbaum M. , Horvath T. L. , Leibel R. L.
Published: March 2011

Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (−10–15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.
Measuring glomerular number and size in perfused kidneys using MRI
Authors: Beeman Scott C. , Zhang Min , Gubhaju Lina , Wu Teresa , Bertram John F. , Frakes David H. , Cherry Brian R. , Bennett Kevin M.
Published: March 2011

The goal of this work was to nondestructively measure glomerular (and thereby nephron) number in the whole kidney. Variations in the number and size of glomeruli have been linked to many renal and systemic diseases. Here, we develop a robust magnetic resonance imaging (MRI) technique based on injection of cationic ferritin (CF) to produce an accurate measurement of number and size of individual glomeruli. High-field (19 Tesla) gradient-echo MR images of perfused rat kidneys after in vivo intravenous injection of CF showed specific labeling of individual glomeruli with CF throughout the kidney. We developed a three-dimensional image-processing algorithm to count every labeled glomerulus. MRI-based counts yielded 33,786 ± 3,753 labeled glomeruli ( n = 5 kidneys). Acid maceration counting of contralateral kidneys yielded an estimate of 30,585 ± 2,053 glomeruli ( n = 6 kidneys). Disector/fractionator stereology counting yielded an estimate of 34,963 glomeruli ( n = 2). MRI-based measurement of apparent glomerular volume of labeled glomeruli was 4.89 × 10−4mm3( n = 5) compared with the average stereological measurement of 4.99 × 10−4mm3( n = 2). The MRI-based technique also yielded the intrarenal distribution of apparent glomerular volume, a measurement previously unobtainable in histology. This work makes it possible to nondestructively measure whole-kidney glomerular number and apparent glomerular volumes to study susceptibility to renal diseases and opens the door to similar in vivo measurements in animals and humans.
Pulmonary stretch receptor spike time precision increases with lung inflation amplitude and airway smooth muscle tension
Authors: Chen Yan , Marchenko Vitaly , Rogers Robert F.
Published: March 2011

Slowly adapting pulmonary stretch receptors (SARs) respond to different lung inflation volumes with distinct spike counts and patterns, conveying information regarding the rate and depth of breathing to the cardiovascular and respiratory control systems. Previous studies demonstrated that SARs respond to repetitions of the same lung inflation faithfully, suggesting the possibility of modeling an SAR's discrete response pattern to a stimulus using a statistically based method. Urethane-anesthetized rabbit SAR spike trains were recorded in response to repeated 9-, 12-, and 15-ml lung inflations, and used to construct model spike trains using K-means clustering. Analysis of the statistics of the responses to different lung inflation volumes revealed that SARs fire with more temporal precision in response to larger lung inflations, because the standard deviations of real spikes clustered around the modeled spike times of responses to 15-ml stimuli were smaller than those produced by 12 or 9 ml, even at the same absolute firing frequencies. This implied that the mechanical coupling of SAR endings with pulmonary tissue is critical in determining spike time reliability. To test this, we collected SAR responses during bronchial constriction, compared them with those produced by the same SARs under normal airway resistance, and found that their firing reliability improved during bronchial constriction. These results suggest that airway distension and mechanical coupling of the receptor endings with the airway wall (partially determined by smooth muscle tone) are important determinants of SAR spike time reliability.
Diverse Roles of Inhibitor of Differentiation 2 in Adaptive Immunity
Authors: Rankin Lucille , Belz Gabrielle T.
Published: March 2011

The helix-loop-helix (HLH) transcription factor inhibitor of DNA binding 2 (Id2) has been implicated as a regulator of hematopoiesis and embryonic development. While its role in early lymphopoiesis has been well characterized, new roles in adaptive immune responses have recently been uncovered opening exciting new directions for investigation. In the innate immune system, Id2 is required for the development of mature natural killer (NK) cells, lymphoid tissue-inducer (LTi) cells, and the recently identified interleukin (IL)-22 secreting nonconventional innate lymphocytes found in the gut. In addition, Id2 has been implicated in the development of specific dendritic cell (DC) subsets, decisions determining the formation ofαβandγδT-cell development, NK T-cell behaviour, and in the maintenance of effector and memory CD8+T cells in peripheral tissues. Here, we review the current understanding of the role of Id2 in lymphopoiesis and in the development of the adaptive immune response required for maintaining immune homeostasis and immune protection.
A Vector-Like Reconfigurable Floating-Point Unit for the Logarithm
Authors: Alachiotis Nikolaos , Stamatakis Alexandros
Published: March 2011

The use of reconfigurable computing for accelerating floating-point intensive codes is becoming common due to the availability of DSPs in new-generation FPGAs. We present the design of an efficient, pipelined floating-point datapath for calculating the logarithm function on reconfigurable devices. We integrate the datapath into a stand-alone LUT-based (Lookup Table) component, the LAU (Logarithm Approximation Unit). We extended the LAU, by integrating two architecturally independent, LAU-based datapaths into a larger component, the VLAU (vector-like LAU). The VLAU produces 2 results/cycle, while occupying the same amount of memory as the LAU. Under single precision, one LAU is 12 and 1.7 times faster than the GNU and Intel Math Kernel Library (MKL) implementations, respectively. The LAU is also 1.6 times faster than the FloPoCo reconfigurable logarithm architecture. Under double precision, one LAU is 20 and 2.6 times faster than the respective GNU and MKL functions and 1.4 times faster than the FloPoCo logarithm. The VLAU is approximately twice as fast as the LAU, both under single and double precision.
Depressive and Aggressive Responses to Frustration: Development of a Questionnaire and Its Validation in a Sample of Male Alcoholics
Authors: Baars M. Y. , Müller M. J. , Gallhofer B. , Netter P.
Published: March 2011

Since clinical and biochemical observations point to much overlap between depression and aggression, both characterised by intolerance to frustration, a questionnaire was developed to test if different patterns of depressive and aggressive reactions elicited by exposure to negative events and deprivation from expected positive ones in human and nonhuman conditions, respectively, would result in specific response patterns in depressive and aggressive persons. The questionnaire was tested for internal consistency in a pilot healthy sample and for correlations of responses with the personality factors of Aggression and Depression in 60 abstinent male alcoholics. Aggressive and depressive responses were highly correlated across all stimulus conditions, and not specifically but rather equally associated with the personality factors of Aggression and Depression, confirming the close association between these dimensions.
Dynamic Contrast Enhanced MRI Can Monitor the Very Early Inflammatory Treatment Response upon Intra-Articular Steroid Injection in the Knee Joint: A Case Report with Review of the Literature
Authors: Boesen Mikael , Kubassova Olga , Cimmino Marco A. , Østergaard Mikkel , Taylor Peter , Danneskiold-Samsoe Bente , Bliddal Henning
Published: March 2011

Dynamic contrast-enhanced MRI in inflammatory arthritis, especially in conjunction with computer-aided analysis using appropriate dedicated software, seems to be a highly sensitive tool for monitoring the early inflammatory treatment response in patients with rheumatoid arthritis. This paper gives a review of the current knowledge of the emerging technique. The potential of the technique is demonstrated and discussed in the context of a case report following the early effect of an intra-articular steroid injection in a patient with rheumatoid arthritis flare in the knee.
Methotrexate Toxicity in Growing Long Bones of Young Rats: A Model for Studying Cancer Chemotherapy‐Induced Bone Growth Defects in Children
Authors: Fan Chiaming , Georgiou Kristen R. , King Tristan J. , Xian Cory J.
Published: March 2011

The advancement and intensive use of chemotherapy in treating childhood cancers has led to a growing population of young cancer survivors who face increased bone health risks. However, the underlying mechanisms for chemotherapy‐induced skeletal defects remain largely unclear. Methotrexate (MTX), the most commonly used antimetabolite in paediatric cancer treatment, is known to cause bone growth defects in children undergoing chemotherapy. Animal studies not only have confirmed the clinical observations but also have increased our understanding of the mechanisms underlying chemotherapy‐induced skeletal damage. These models revealed that high‐dose MTX can cause growth plate dysfunction, damage osteoprogenitor cells, suppress bone formation, and increase bone resorption and marrow adipogenesis, resulting in overall bone loss. While recent rat studies have shown that antidote folinic acid can reduce MTX damage in the growth plate and bone, future studies should investigate potential adjuvant treatments to reduce chemotherapy‐induced skeletal toxicities.
A Novel Prodrug of Epigallocatechin-3-gallate: Differential Epigenetic hTERT Repression in Human Breast Cancer Cells
Authors: Meeran Syed M. , Patel Shweta N. , Chan Tak-Hang , Tollefsbol Trygve O.
Published: March 2011

Epigallocatechin-3-gallate (EGCG), a major component of green tea polyphenols (GTP), has been reported to downregulate telomerase activity in breast cancer cells thereby increasing cellular apoptosis and inhibiting cellular proliferation. However, the major concerns with GTPs are their bioavailability and stability under physiologic conditions. In the present study, we show that treatments with EGCG and a novel prodrug of EGCG (pro-EGCG or pEGCG) dose- and time-dependently inhibited the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells but not normal control MCF10A cells. Furthermore, both EGCG and pro-EGCG inhibited the transcription of hTERT (human telomerase reverse transcriptase), the catalytic subunit of telomerase, through epigenetic mechanisms in estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 cells. The downregulation of hTERT expression was found to be because of hTERT promoter hypomethylation and histone deacetylations, mediated at least partially through inhibition of DNA methyltransferase and histone acetyltransferase activities, respectively. In addition, we also observed that EGCG and pEGCG can remodel chromatin structures of the hTERT promoter by decreasing the level of acetyl-H3, acetyl-H3K9, and acetyl-H4 to the hTERT promoter. EGCG and pEGCG induced chromatin alterations that facilitated the binding of many hTERT repressors such as MAD1 and E2F-1 to the hTERT regulatory region. Depletion of E2F-1 and MAD1 by using siRNA reversed the pEGCG downregulated hTERT expression and associated cellular apoptosis differently in ER-positive and ER-negative breast cancer cells. Collectively, our data provide new insights into breast cancer prevention through epigenetic modulation of telomerase by using pro-EGCG, a more stable form of EGCG, as a novel chemopreventive compound. Cancer Prev Res; 4(8); 1243–54. ©2011 AACR.
Cyclosporine A for Chemotherapy-Resistant Subcutaneous Panniculitis-Like T Cell Lymphoma with Hemophagocytic Syndrome
Authors: Mizutani Shinsuke , Kuroda Junya , Shimura Yuji , Kobayashi Tsutomu , Tsutsumi Yasuhiko , Yamashita Mihoko , Yamamoto Mio , Ohshiro Muneo , Sasaki Nana , Kiyota Miki , Nakayama Ryuko , Uchiyama Hitoji , Matsumoto Yosuke , Horiike Shigeo , Nakamura Shigeo , Taniwaki Masafumi
Published: March 2011

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL.
Challenges for Allogeneic Hematopoietic Stem Cell Transplantation in Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors
Authors: Oyekunle Anthony , Klyuchnikov Evgeny , Ocheni Sunday , Kröger Nicolaus , Zander Axel R. , Baccarani Michele , Bacher Ulrike
Published: March 2011

Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in the treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (HSCT) scene in CML has changed dramatically. The number of patients receiving HSCT in first chronic phase (CP) has declined rapidly, as allogeneic HSCT in CP is now performed in these patients only in case of failure or intolerance of TKIs. Second, those CML patients who undergo allogeneic HSCT represent a selection of high-risk patients due to more advanced disease with high rates of accelerated or blast phase (being associated with an increased relapse risk), advanced age and relevant co-morbidities. Efforts at meeting these special challenges are being developed: treatment with TKIs aims to improve the pre-transplant remission status before HSCT. Dose-reduced conditioning protocols were introduced to decrease transplant-related mortality in patients with co-morbidities or older age. In the post-transplant period, TKIs may be administered for prophylaxis and for treatment of post-transplant relapse. Still, the outcome of patients in advanced CML phases remains guarded, and requires an improvement in current transplant strategies.
Clinical Characteristics of Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction
Authors: Thenappan Thenappan , Shah Sanjiv J. , Gomberg-Maitland Mardi , Collander Brett , Vallakati Ajay , Shroff Pranavkumar , Rich Stuart
Published: March 2011

Background—

Pulmonary vascular disease associated with left-side heart failure and preserved ejection fraction (PH-HFpEF) is an increasingly common cause of pulmonary hypertension. The distinction between PH-HFpEF and pulmonary arterial hypertension (PAH) is important because therapies indicated for PAH can be detrimental in HFpEF. The characteristic features of PH-HFpEF are understudied.

Methods and Results—

In a cross-sectional study, we compared the clinical, echocardiographic, and hemodynamic features of PH-HFpEF (n=100), with PAH (n=522), and HFpEF without pulmonary vascular disease (n=45). We determined the clinical characteristics that best differentiated PH-HFpEF from PAH. Compared with patients with PAH, patients with PH-HFpEF were older; had a higher prevalence of cardiovascular comorbidities; had worse exercise capacity and renal function; more frequently had left atrial enlargement; and less frequently had right atrial enlargement. PH was less severe in PH-HFpEF patients than in PAH patients (pulmonary vascular resistance 4.8 [interquartile range 3 to 8.4] versus 10.9 [interquartile range 7.4 to 15.7] Wood units;
P
<0.001). Old age, the presence of hypertension and coronary artery disease, the absence of right atrial enlargement, higher aortic systolic pressure, higher mean right atrial pressure, and higher cardiac output best differentiated PH-HFpEF from PAH (area under the receiver operating characteristics curve; curve 0.97). Compared with HFpEF patients without pulmonary hypertension, PH-HFpEF patients were often female and more symptomatic, more often had right ventricular hypertrophy and right atrial enlargement, and had higher right atrial pressure.

Conclusions—

These data should help better identify PH-HFpEF, an entity that has become increasingly recognized and difficult to treat.
In the Thick of It
Authors: Harris Samantha P. , Lyons Ross G. , Bezold Kristina L.
Published: March 2011

In the 20 years since the discovery of the first mutation linked to familial hypertrophic cardiomyopathy (HCM), an astonishing number of mutations affecting numerous sarcomeric proteins have been described. Among the most prevalent of these are mutations that affect thick filament binding proteins, including the myosin essential and regulatory light chains and cardiac myosin binding protein (cMyBP)-C. However, despite the frequency with which myosin binding proteins, especially cMyBP-C, have been linked to inherited cardiomyopathies, the functional consequences of mutations in these proteins and the mechanisms by which they cause disease are still only partly understood. The purpose of this review is to summarize the known disease-causing mutations that affect the major thick filament binding proteins and to relate these mutations to protein function. Conclusions emphasize the impact that discovery of HCM-causing mutations has had on fueling insights into the basic biology of thick filament proteins and reinforce the idea that myosin binding proteins are dynamic regulators of the activation state of the thick filament that contribute to the speed and force of myosin-driven muscle contraction. Additional work is still needed to determine the mechanisms by which individual mutations induce hypertrophic phenotypes.
Neuromodulation by soy diets or equol: Anti-depressive & anti-obesity-like influences, age- & hormone-dependent effects
Authors: Blake Crystal , Fabick Kimberly M , Setchell Kenneth DR , Lund Trent D , Lephart Edwin D
Published: March 2011

Background

Soy-derived isoflavones potentially protect against obesity and depression. In five different studies we examined the influence of soy-containing diets or equol injections on depression, serotonin levels, body weight gain (BW) and white adipose tissue (WAT) deposition in female Long-Evans rats at various stages of life [rats were intact, ovariectomized or experienced natural ovarian failure (NOF)].

Results

In general, animals fed a soy-rich diet (Phyto-600) and/or administered equol (@ 5 mg/kg/day) displayed significant decreases in BW and WAT compared to a low-soy diet. When equol was injected alone (5 mg/kg/day), experiments 1, 4, and 5 demonstrated that body weight was significantly decreased. Equol has body weight control effects in females that are dependent on ovarian status and/or age of diet initiation. Experiments 1-4 all displayed no significant differences in depressive-related behavior as measured by the Prosolt forced swim test (PFST) when soy-rich (Phyto-600) or low-soy diets (Phyto-low) or equol treatments (5 mg/kg/day) were tested in female rats at various ages or hormonal status. Results of all the experiments are not presented here due to space limitations, but data from experiment 5 are presented. From conception female rats were exposed to either: a) a soy-rich (Phyto-600) or b) low-soy diet (Phyto-low). After 290 days all rats experienced NOF. At 330 days-old the animals were examined in the Porsolt forced swim test (PFST). One month later a second PFST was performed [after Phyto-low fed animals were injected with equol (5 mg/kg/day) for one week prior to the second PFST]. At the first PFST, serotonin and mobility levels were significantly decreased in the Phyto-low fed animals compared to animals that consumed the Phyto-600 diet. After equol injections at the second PFST, mobility and serotonin levels significantly increased in aged NOF rats fed the Phyto-low diet (to levels comparable to Phyto-600 fed animals).

Conclusions

Consumption of dietary isoflavones or equol exposure in rats has body weight controlling effects and equol specifically may have antidepressant potential dependent upon diet initiation and/or dosage of treatments. The current study demonstrates that equol is able to decrease body weight, abdominal WAT, and depressive-related behavior. While other factors and mechanisms may play a role, in part, the present results provide a greater understanding of how isoflavonoid molecules modulate the brain's influence on behavior.
Safety of pull-type and introducer percutaneous endoscopic gastrostomy tubes in oncology patients: a retrospective analysis
Authors: Van Dyck Evi , Macken Elisabeth J , Roth Bernard , Pelckmans Paul A , Moreels Tom G
Published: March 2011

Background

Percutaneous endoscopic gastrostomy (PEG) allows long-term tube feeding. Safety of pull-type and introducer PEG placement in oncology patients with head/neck or oesophageal malignancies is unknown.

Methods

Retrospective analysis of 299 patients undergoing PEG tube placement between January 2006 and December 2008 revealed 57 oncology patients. All patients with head/neck or oesophageal malignancy were treated with chemo- and radiotherapy. In case of high-grade stenosis introducer Freka® Pexact PEG tube was placed (n = 24) and in all other patients (n = 33) conventional pull-type PEG tube. Short-term complications and mortality rates were compared.

Results

Patients' characteristics and clinical status were comparable in both groups. Short-term complications were encountered in 11/24 (48%) introducer PEG patients as compared to only 4/33 (12%) pull-type PEG patients (P < 0.05). Accidental removal of the introducer PEG tube occurred in 4/24 (17%) with need for surgical intervention in 1 vs. 0/33 (0%, P < 0.05). Wound infection occurred in 3/24 (12%) leading to septic shock and admission to intensive care unit (ICU) in 1 vs. 3/33 (9%, NS). Finally, 3/24 gastrointestinal perforations (12%) resulted from a difficult placement procedure vs. 1/33 (3%), leading to urgent surgical intervention and admission to ICU. Two introducer PEG patients died at ICU, resulting in an overall mortality rate of 8% vs. 0% (P = 0.091).

Conclusion

The introducer Freka® Pexact PEG procedure for long-term tube feeding may lead to significantly higher complication and mortality rates in patients with head/neck or oesophageal malignancies treated with chemo- and radiotherapy. It is suggested to use the conventional pull-type PEG tube placement in this group of patients, if possible.
Weak up-regulation of serum response factor in gastric ulcers in patients with co-morbidities is associated with increased risk of recurrent bleeding
Authors: Cheng Hsiu-Chi , Yang Hsiao-Bai , Chang Wei-Lun , Yeh Yi-Chun , Tsai Yu-Ching , Sheu Bor-Shyang
Published: March 2011

Background

Serum response factor (SRF) is crucial for gastric ulcer healing process. The study determined if gastric ulcer tissues up-regulate SRF and if such up-regulation correlated with co-morbidities and the risk of recurrent bleeding.

Methods

Ulcer and non-ulcer tissues were obtained from 142 patients with active gastric ulcers for SRF expression assessed by immunohistochemistry. Based on the degree of SRF expression between these two tissue types, SRF up-regulation was classified as strong, intermediate, and weak patterns. The patients were followed-up to determine if SRF up-regulation correlated to recurrent bleeding.

Results

Gastric ulcer tissues had higher SRF expression than non-ulcer tissues (p < 0.05). Patients with strong SRF up-regulation had lower rates of stigmata of recent hemorrhage (SRH) on the ulcer base than the others (p < 0.05). Multivariate logistic regression confirmed that co-morbidities and weak SRF up-regulation were two independent factors of recurrent gastric ulcer bleeding (p < 0.05). Combining both factors, there was an 8.29-fold (95% CI, 1.31~52.62; p = 0.03) higher risk of recurrent gastric ulcer bleeding.

Conclusions

SRF expression is higher in gastric ulcer tissues than in non-ulcer tissues. Weak SRF up-regulation, combined with the presence of co-morbidities, increase the risk of the recurrent gastric ulcer bleeding.
Variation in Uteroglobin-Related Protein 1 (UGRP1) gene is associated with Allergic Rhinitis in Singapore Chinese
Authors: Andiappan Anand Kumar , Yeo Wei Sheng , Parate Pallavi Nilkanth , Anantharaman Ramani , Suri Bani Kaur , Wang De Yun , Chew Fook Tim
Published: March 2011

Background

Uteroglobin-Related Protein 1 (UGRP1) is a secretoglobulin protein which has been suggested to play a role in lung inflammation and allergic diseases. UGRP1 has also been shown to be an important pneumoprotein, with diagnostic potential as a biomarker of lung damage. Previous genetic studies evaluating the association between variations on UGRP1 and allergic phenotypes have yielded mixed results. The aim of this present study was to identify genetic polymorphisms in UGRP1 and investigate if they were associated with asthma and allergic rhinitis in the Singapore Chinese population.

Methods

Resequencing of the UGRP1 gene was conducted on 40 randomly selected individuals from Singapore of ethnic Chinese origin. The polymorphisms identified were then tagged and genotyped in a population of 1893 Singapore Chinese individuals. Genetic associations were evaluated in this population comparing 795 individuals with allergic rhinitis, 718 with asthma (of which 337 had both asthma and allergic rhinitis) and 717 healthy controls with no history of allergy or allergic diseases.

Results

By resequencing the UGRP1 gene within our population, we identified 11 novel and 16 known single nucleotide polymorphisms (SNPs). TagSNPs were then genotyped, revealing a significant association between rs7726552 and allergic rhinitis (Odds Ratio: 0.81, 95% Confidence Interval: 0.66-0.98, P = 0.039). This association remained statistically significant when it was analyzed genotypically or when stratified according to haplotypes. When variations on UGRP1 were evaluated against asthma, no association was observed.

Conclusion

This study documents the association between polymorphisms in UGRP1 and allergic rhinitis, suggesting a potential role in its pathogenesis.
Postpartum behaviour as predictor of weight change from before pregnancy to one year postpartum
Authors: Althuizen Ellen , van Poppel Mireille NM , de Vries Jeanne H , Seidell Jacob C , van Mechelen Willem
Published: March 2011

Background

Postpartum weight retention affects many women and increases the risk of becoming overweight. The research objective was to study modifiable factors contributing to weight change at one year postpartum.

Methods

In this prospective cohort, postpartum behavior, such as physical activity, sedentary behavior, sleep, and intake of total energy, total fat and saturated fatty acids of 118 Dutch women were assessed in 2003/2004 by self-report at 6 weeks, 6 and 12 months postpartum. Mean postpartum scores were computed for the behavioral measures. In linear regression models it was determined which factors were associated with average weight change from before pregnancy to one year postpartum. Furthermore, factors associated with substantial postpartum weight retention (≥ 5 kg) were also studied in logistic regression models.

Results

At one year postpartum, the average weight of participants had increased by 0.9 kg (SD 4.4). Moreover, 20% of the women retained ≥ 5 kg. Women who perceived themselves more physically active than others were almost ten times less likely to retain ≥ 5 kg than women who perceived themselves equally active (OR = 0.11, 95%CI: 0.02 - 0.66). Exceeding the guideline for saturated fatty acid intake (OR = 3.40, 95%CI: 1.04 - 11.11), total gestational weight gain (OR = 1.14/kg, 95%CI: 1.01 - 1.27), and not having completed post high school education (OR = 5.13, 95%CI: 1.66 - 15.90) increased the odds of retaining ≥ 5 kg.

Conclusions

Since one in five women had substantial weight retention postpartum, effective interventions for the prevention of weight retention are much needed. Future studies should evaluate whether interventions focusing on the identified modifiable postpartum factors are successful in reducing weight retention after childbirth.
Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma
Authors: Parker Joseph M , Oh Chad K , LaForce Craig , Miller S David , Pearlman David S , Le Chenxiong , Robbie Gabriel J , White Wendy I , White Barbara , Molfino Nestor A ,   the MEDI-528 Clinical Trials Group
Published: March 2011

Background

Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics.

Methods

Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both.

Results

In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation.

Conclusions

In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma.

Trial registration

ClinicalTrials (NCT): NCT00507130 and ClinicalTrials (NCT): NCT00590720
A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers
Authors: Chilengi Roma , Juma Rashid , Abdallah Ahmed M , Bashraheil Mahfudh , Lodenyo Hudson , Nyakundi Priscilla , Anabwani Evelyn , Salim Amina , Mwambingu Gabriel , Wenwa Ednah , Jemutai Julie , Kipkeu Chemtai , Oyoo George O , Muchohi Simon N , Kokwaro Gilbert , Niehues Tim , Lang Trudie , Nzila Alexis
Published: March 2011

Background

Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers.

Methods

Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days.

Results

The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product) were reported. The maximum concentration (Cmax) was 160-200 nM and after 6 hours, the effective concentration (Ceff) was <150 nM.

Conclusion

Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceffof 250-400-nM required to clear malaria infectionin vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.
Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh
Authors: Rahman Shahedur , Parvez Anowar Khasru , Islam Rezuanul , Khan Mahboob Hossain
Published: March 2011

Background

Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates.

Methods

Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh.

Results

All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm).

Conclusion

Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary.
Engineering of the E. coli Outer Membrane Protein FhuA to overcome the Hydrophobic Mismatch in Thick Polymeric Membranes
Authors: Muhammad Noor , Dworeck Tamara , Fioroni Marco , Schwaneberg Ulrich
Published: March 2011

Background

Channel proteins like the engineered FhuA Δ1-159 often cannot insert into thick polymeric membranes due to a mismatch between the hydrophobic surface of the protein and the hydrophobic surface of the polymer membrane. To address this problem usually specific block copolymers are synthesized to facilitate protein insertion. Within this study in a reverse approach we match the protein to the polymer instead of matching the polymer to the protein.

Results

To increase the FhuA Δ1-159 hydrophobic surface by 1 nm, the last 5 amino acids of each of the 22 β-sheets, prior to the more regular periplasmatic β-turns, were doubled leading to an extended FhuA Δ1-159 (FhuA Δ1-159 Ext). The secondary structure prediction and CD spectroscopy indicate the β-barrel folding of FhuA Δ1-159 Ext. The FhuA Δ1-159 Ext insertion and functionality within a nanocontainer polymeric membrane based on the triblock copolymer PIB1000-PEG6000-PIB1000 (PIB = polyisobutylene, PEG = polyethyleneglycol) has been proven by kinetic analysis using the HRP-TMB assay (HRP = Horse Radish Peroxidase, TMB = 3,3',5,5'-tetramethylbenzidine). Identical experiments with the unmodified FhuA Δ1-159 report no kinetics and presumably no insertion into the PIB1000-PEG6000-PIB1000 membrane. Furthermore labeling of the Lys-NH2 groups present in the FhuA Δ1-159 Ext channel, leads to controllability of in/out flux of substrates and products from the nanocontainer.

Conclusion

Using a simple "semi rational" approach the protein's hydrophobic transmembrane region was increased by 1 nm, leading to a predicted lower hydrophobic mismatch between the protein and polymer membrane, minimizing the insertion energy penalty. The strategy of adding amino acids to the FhuA Δ1-159 Ext hydrophobic part can be further expanded to increase the protein's hydrophobicity, promoting the efficient embedding into thicker/more hydrophobic block copolymer membranes.
Lateral electrical transport, optical properties and photocurrent measurements in two-dimensional arrays of silicon nanocrystals embedded in SiO2
Authors: Gardelis Spiros , Manousiadis Pavlos , Nassiopoulou Androula G
Published: March 2011

In this study we investigate the electronic transport, the optical properties, and photocurrent in two-dimensional arrays of silicon nanocrystals (Si NCs) embedded in silicon dioxide, grown on quartz and having sizes in the range between less than 2 and 20 nm. Electronic transport is determined by the collective effect of Coulomb blockade gaps in the Si NCs. Absorption spectra show the well-known upshift of the energy bandgap with decreasing NC size. Photocurrent follows the absorption spectra confirming that it is composed of photo-generated carriers within the Si NCs. In films containing Si NCs with sizes less than 2 nm, strong quantum confinement and exciton localization are observed, resulting in light emission and absence of photocurrent. Our results show that Si NCs are useful building blocks of photovoltaic devices for use as better absorbers than bulk Si in the visible and ultraviolet spectral range. However, when strong quantum confinement effects come into play, carrier transport is significantly reduced due to strong exciton localization and Coulomb blockade effects, thus leading to limited photocurrent.
Genome-wide analysis of primary CD4+ and CD8+ T cell transcriptomes shows evidence for a network of enriched pathways associated with HIV disease
Authors: Wu Jing Qin , Dwyer Dominic E , Dyer Wayne B , Yang Yee Hwa , Wang Bin , Saksena Nitin K
Published: March 2011

Background

HIV preferentially infects CD4+ T cells, and the functional impairment and numerical decline of CD4+ and CD8+ T cells characterize HIV disease. The numerical decline of CD4+ and CD8+ T cells affects the optimal ratio between the two cell types necessary for immune regulation. Therefore, this work aimed to define the genomic basis of HIV interactions with the cellular transcriptome of both CD4+ and CD8+ T cells.

Results

Genome-wide transcriptomes of primary CD4+ and CD8+ T cells from HIV+ patients were analyzed at different stages of HIV disease using Illumina microarray. For each cell subset, pairwise comparisons were performed and differentially expressed (DE) genes were identified (fold change >2 and B-statistic >0) followed by quantitative PCR validation. Gene ontology (GO) analysis of DE genes revealed enriched categories of complement activation, actin filament, proteasome core and proton-transporting ATPase complex. By gene set enrichment analysis (GSEA), a network of enriched pathways functionally connected by mitochondria was identified in both T cell subsets as a transcriptional signature of HIV disease progression. These pathways ranged from metabolism and energy production (TCA cycle and OXPHOS) to mitochondria meditated cell apoptosis and cell cycle dysregulation. The most unique and significant feature of our work was that the non-progressing status in HIV+ long-term non-progressors was associated with MAPK, WNT, and AKT pathways contributing to cell survival and anti-viral responses.

Conclusions

These data offer new comparative insights into HIV disease progression from the aspect of HIV-host interactions at the transcriptomic level, which will facilitate the understanding of the genetic basis of transcriptomic interaction of HIVin vivoand how HIV subverts the human gene machinery at the individual cell type level.
ATF3, an HTLV-1 bZip factor binding protein, promotes proliferation of adult T-cell leukemia cells
Authors: Hagiya Keita , Yasunaga Jun-ichirou , Satou Yorifumi , Ohshima Koichi , Matsuoka Masao
Published: March 2011

Background

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+ T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 bZIP factor (HBZ) gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3) as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known.

Results

Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR), doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2) and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ.

Conclusions

Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system.
Complete genome sequence of a marine roseophage provides evidence into the evolution of gene transfer agents in alphaproteobacteria
Authors: Huang Sijun , Zhang Yongyu , Chen Feng , Jiao Nianzhi
Published: March 2011

Roseophage RDJLΦ1 is a siphovirus isolated from South China Sea on Roseobacter denitrificans OCh114. Its virion encapsulates 62.7 kb genome that encodes 87 gene products. RDJLΦ1 shares similar genome organization and gene content with the marine bacteriophage ΦJL001 and Pseudomonas phages YuA and M6, which are different from those of typical λ- or Mu-like phages. Four hallmark genes (ORFs 81 to 84) of RDJLΦ1 were highly homologous to RcGTA-like genes 12 to 15. The largest gene (ORF 84) was predicted to encode a tail fibre protein that could be involved in host recognition. Extended phylogenetic and comparative genomic analyses based on 77 RcGTA-like element-containing bacterial genomes revealed that RcGTA-like genes 12 to 15 together appear to be a conserved modular element that could also be found in some phage or prophage genomes. Our study suggests that RcGTA-like genes-containing phages and prophages and complete RcGTAs possibly descended from a same prophage ancestor that had diverged and then evolved vertically. The complete genome of RDJLΦ1 provides evidence into the hypothesis that extant RcGTA may be a prophage remnant.
Isolation of a novel monkey adenovirus reveals a new phylogenetic clade in the evolutionary history of simian adenoviruses
Authors: Maluquer de Motes Carlos , Hundesa Ayalkibet , Almeida Francisca C , Bofill-Mas Silvia , Girones Rosina
Published: March 2011

Adenoviruses of primates include human (HAdV) and simian (SAdV) isolates classified into 8 species (Human Adenovirus A to G, and Simian Adenovirus A). In this study, a novel adenovirus was isolated from a colony of cynomolgus macaques (Macaca fascicularis) and subcultured in VERO cells. Its complete genome was purified and a region encompassing the hexon gene, the protease gene, the DNA binding protein (DBP) and the 100 kDa protein was amplified by PCR and sequenced by primer walking. Sequence analysis of these four genes showed that the new isolate had 80% identity to other primate adenoviruses and lacked recombination events. The study of the evolutionary relationships of this new monkey AdV based on the combined sequences of the four genes supported a close relationship to SAdV-3 and SAdV-6, lineages isolated from Rhesus monkeys. The clade formed by these three types is separated from the remaining clades and establishes a novel branch that is related to species HAdV-A, F and G. However, the genetic distance corresponding to the newly isolated monkey AdV considerably differs from these as to belong to a new, not yet established species. Results presented here widen our knowledge on SAdV and represents an important contribution to the understanding of the evolutionary history of primate adenoviruses.