bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes
Authors: Tramonti Gianfranco , Xie Ping , Wallner Elisabeth I. , Danesh Farhad R. , Kanwar Yashpal S.
Published: October 2006

Renal mass reduction is associated with a compromise in renal excretion, and thus dosages of drugs need to be adjusted to avoid adverse reactions and to ensure their effectiveness. A prototypic example is patients who had undergone transplantation due to a variety of causes, including diabetic nephropathy; the latter appears to be the major cause of renal failure requiring hemodialysis and transplantation. Conceivably, hyperglycemia with reduced renal mass interferes in the delivery of xenobiotics handled by various tubular transporters. In this investigation, effect of renal mass reduction/hyperglycemia on gene and protein expression of P-glycoprotein (Pgp), PEPT1, and PEPT2 was assessed. Also, [H3]glycylsarcosine uptake, a prototype of dipeptide, was measured in various groups of rats: sham-operated, uninephrectomized, streptozotocin-induced diabetes, and diabetic + uninephrectomized. An increase in Pgp, PEPT1, and PEPT2 expression was observed in kidneys of uninephrectomy rats, the highest being in the Pgp. Similarly, an increase was observed in diabetic rats who had undergone uninephrectomy, although less than those with nephrectomy alone. No differences were observed between sham-operated and diabetic groups. Increased uptake of [H3]glycylsarcosine was also seen in uninephrectomised rats. A modest uptake was observed in diabetic rats who had undergone uninephrectomy. The data suggest that uninephrectomy induces an increase in the expression and activity of transporters localized to renal tubular epithelial brush border. The fact that upregulation and activity of the peptide transporters were less in kidneys of diabetic animals who had undergone uninephrectomy compared with uninephrectomy alone suggests that hyperglycemia interferes in their expression and activity during the compensatory phase.
Impact of sex and age on bone marrow immune responses in a murine model of trauma-hemorrhage
Authors: Schneider Christian P. , Schwacha Martin G. , Chaudry Irshad H.
Published: October 2006

Although studies have demonstrated that trauma markedly alters the bone marrow immune responses, sex and age are crucial determinants under such conditions and have not been extensively examined. To study this, 21- to 27-day-old (premature), 6- to 8-wk-old (mature), and 20- to 24-mo-old (aged) male and female (proestrus) C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30 ± 5 mmHg for 90 min) followed by fluid resuscitation. Twenty-four hours after resuscitation, bone marrow cells were harvested. Trauma-hemorrhage induced an increased number of the early pluripotent stem cell-associated bone marrow cell subsets (Sca1+CD34−CD117+/−lin+/−) in young mice. The CD117+proportion of these cell subsets increased in mature proestrus females, but not in males. Aged males displayed significant lower numbers of Sca1+CD34−CD117+/−lin+/−cells compared with young male mice. Trauma-hemorrhage also increased development of granulocyte/macrophage progenitor cells (CD11b+Gr-1+). Proliferative responses to granulocyte macrophage colony-stimulating factor were maintained in mature and aged proestrus females, but decreased in young mice and mature males. Augmented differentiation into monocyte/macrophage lineage in mature and aged proestrus females was observed and associated with the maintained release of TNF-α and IL-6. Conversely, increased IL-10 and PGE2production was observed in the male trauma-hemorrhage groups. Thus, sex- and age-specific effects in bone marrow differentiation and immune responses after trauma-hemorrhage occur, which are likely to contribute to the sex- and age-related differences in the systemic immune responses under such conditions.
Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness
Authors: Leaf David E. , Goldfarb David S.
Published: October 2006

Acetazolamide, a potent carbonic anhydrase (CA) inhibitor, is the most commonly used and best-studied agent for the amelioration of acute mountain sickness (AMS). The actual mechanisms by which acetazolamide reduces symptoms of AMS, however, remain unclear. Traditionally, acetazolamide's efficacy has been attributed to inhibition of CA in the kidneys, resulting in bicarbonaturia and metabolic acidosis. The result is offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Studies performed on both animals and humans, however, have shown that this explanation is unsatisfactory and that the efficacy of acetazolamide in the context of AMS is likely due to a multitude of effects. This review summarizes the known systemic effects of acetazolamide and incorporates them into a model encompassing several factors that are likely to play a key role in the drug's efficacy. Such factors include not only metabolic acidosis resulting from renal CA inhibition but also improvements in ventilation from tissue respiratory acidosis, improvements in sleep quality from carotid body CA inhibition, and effects of diuresis.
Haemostatic Factors and the Risk of Cardiovascular Death in Patients With Coronary Artery Disease
Authors: Morange P.E. , Bickel C. , Nicaud V. , Schnabel R. , Rupprecht H.J. , Peetz D. , Lackner K.J. , Cambien F. , Blankenberg S. , Tiret L.
Published: October 2006

Objective—

To get a better insight into the role of hemostasis in coronary artery disease (CAD), we assessed the impact of von Willebrand factor (vWF), fibrinogen, thrombin-antithrombin (TAT) complexes, D-dimers, and plasmin-antiplasmin (PAP) complexes on the risk of cardiovascular event in a prospective cohort of CAD patients.

Methods and Results—

The prospective Athero
gene
cohort includes 1057 individuals with an angiographically proven coronary artery disease at baseline. After a median follow-up of 6.6 years, 135 individuals died from a cardiovascular cause and 97 had a nonfatal cardiovascular event. Higher levels of all 5 hemostatic markers at baseline were associated with an increased risk of cardiovascular death, but not of nonfatal event. Except for vWF, these associations remained significant after adjustment for conventional cardiovascular risk factors and C-reactive protein (CRP) levels (
P
for trend according to increasing tertiles=0.20, 0.011, 0.026, 0.019, and 0.01 for vWF, fibrinogen, TAT, D-Dimer, and PAP, respectively). When including the 5 hemostatic markers in a stepwise Cox regression analysis where conventional risk factors and CRP were forced into the model, fibrinogen and D-dimers remained independently associated with the risk of cardiovascular death. Adjusted hazard ratios (95% CI) associated with one SD increase of fibrinogen and D-dimers were 1.27 (1.04 to 1.55) and 1.29 (1.09 to 1.53), respectively.

Conclusions—

In patients with coronary artery disease, fibrinogen and D-dimer levels are independent predictors of subsequent cardiovascular death. Our data support a role of impaired coagulation/fibrinolysis process in the complications of coronary artery disease.
Hydrogen Peroxide
Authors: Saitoh Shu-ichi , Zhang Cuihua , Tune Johnathan D. , Potter Barry , Kiyooka Takahiko , Rogers Paul A. , Knudson Jarrod D. , M. Dick Gregory , Swafford Albert , Chilian William M.
Published: October 2006

Objective—

We tested the hypothesis that hydrogen peroxide (H
2
O
2
), the dismutated product of superoxide (O
2
·−
), couples myocardial oxygen consumption to coronary blood flow. Accordingly, we measured O
2
·−
and H
2
O
2
production by isolated cardiac myocytes, determined the role of mitochondrial electron transport in the production of these species, and determined the vasoactive properties of the produced H
2
O
2
.

Methods and Results—

The production of O
2
·−
is coupled to oxidative metabolism because inhibition of complex I (rotenone) or III (antimycin) enhanced the production of O
2
·−
during pacing by about 50% and 400%, respectively; whereas uncoupling oxidative phosphorylation by decreasing the protonmotive force with carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP) decreased pacing-induced O
2
·−
production. The inhibitor of cytosolic NAD(P)H oxidase assembly, apocynin, did not affect O
2
·−
production by pacing. Aliquots of buffer from paced myocytes produced vasodilation of isolated arterioles (peak response 67±8% percent of maximal dilation) that was significantly reduced by catalase (5±0.5%,
P
<0.05) or the antagonist of Kv channels, 4-aminopyridine (18±4%,
P
<0.05). In intact animals, tissue concentrations of H
2
O
2
are proportionate to myocardial oxygen consumption and directly correlated to coronary blood flow. Intracoronary infusion of catalase reduced tissue levels of H
2
O
2
by 30%, and reduced coronary flow by 26%. Intracoronary administration of 4-aminopyridine also shifted the relationship between myocardial oxygen consumption and coronary blood flow or coronary sinus p
o
2
.

Conclusions—

Taken together, our results demonstrate that O
2
·−
is produced in proportion to cardiac metabolism, which leads to the production of the vasoactive reactive oxygen species, H
2
O
2
. Our results further suggest that the production of H
2
O
2
in proportion to metabolism couples coronary blood flow to myocardial oxygen consumption.
Impaired Diastolic Function After Exchange of Endogenous Troponin I With C-Terminal Truncated Troponin I in Human Cardiac Muscle
Authors: Narolska Nadiya A. , Piroddi Nicoletta , Belus Alexandra , Boontje Nicky M. , Scellini Beatrice , Deppermann Sascha , Zaremba Ruud , Musters Rene J. , dos Remedios Cris , Jaquet Kornelia , Foster D. Brian , Murphy Anne M. , van Eyk Jennifer E. , Tesi Chiara , Poggesi Corrado , van der Velden Jolanda , Stienen Ger J.M.
Published: October 2006

The specific and selective proteolysis of cardiac troponin I (cTnI) has been proposed to play a key role in human ischemic myocardial disease, including stunning and acute pressure overload. In this study, the functional implications of cTnI proteolysis were investigated in human cardiac tissue for the first time. The predominant human cTnI degradation product (cTnI
1–192
) and full-length cTnI were expressed in
Escherichia
coli
, purified, reconstituted with the other cardiac troponin subunits, troponin T and C, and subsequently exchanged into human cardiac myofibrils and permeabilized cardiomyocytes isolated from healthy donor hearts. Maximal isometric force and kinetic parameters were measured in myofibrils, using rapid solution switching, whereas force development was measured in single cardiomyocytes at various calcium concentrations, at sarcomere lengths of 1.9 and 2.2 μm, and after treatment with the catalytic subunit of protein kinase A (PKA) to mimic β-adrenergic stimulation. One-dimensional gel electrophoresis, Western immunoblotting, and 3D imaging revealed that approximately 50% of endogenous cTnI had been homogeneously replaced by cTnI
1–192
in both myofibrils and cardiomyocytes. Maximal tension was not affected, whereas the rates of force activation and redevelopment as well as relaxation kinetics were slowed down. Ca
2+
sensitivity of the contractile apparatus was increased in preparations containing cTnI
1–192
(pCa
50
: 5.73±0.03 versus 5.52±0.03 for cTnI
1–192
and full-length cTnI, respectively). The sarcomere length dependency of force development and the desensitizing effect of PKA were preserved in cTnI
1–192
-exchanged cardiomyocytes. These results indicate that degradation of cTnI in human myocardium may impair diastolic function, whereas systolic function is largely preserved.
Total Lightning Observations with the New and Improved Los Alamos Sferic Array (LASA)
Authors: Shao Xuan-Min , Stanley Mark , Regan Amy , Harlin Jeremiah , Pongratz Morrie , Stock Michael
Published: October 2006

Since 1998, Los Alamos National Laboratory (LANL) has deployed an array of fast electric field change sensors in New Mexico and Florida in support of LANL’s satellite lightning observations. In April 2004, all the sensors were significantly upgraded and improved, and a new array was deployed in north-central Florida. This paper describes the operations of the new array and reports the first 12 months of lightning observations. The new array is about 10 times more sensitive than the previous one and can capture millions of discharge events during a stormy day in Florida. In this paper, the array’s lightning location accuracy, minimum detectable peak current, and ratio of intracloud-to-cloud-to-ground flashes are analyzed. Some case studies that illustrate the storm evolution, lightning classification, and radar comparisons are presented. A new three-dimensional capability of the array is demonstrated.
A GPM Dual-Frequency Retrieval Algorithm: DSD Profile-Optimization Method
Authors: Rose C. R. , Chandrasekar V.
Published: October 2006

A new dual-frequency precipitation radar (DPR) will be included on the Global Precipitation Measurement (GPM) core satellite, which will succeed the highly successful Tropical Rainfall Measuring Mission (TRMM) satellite launched in 1997. New dual-frequency drop size distribution (DSD) and rain-rate estimation algorithms are being developed to take advantage of the enhanced capabilities of the DPR. It has been shown that the backward-iteration algorithm can be embedded within a single-loop (SL) feedback model. However, the SL model is unable to correctly estimate DSD profiles for a significant portion of global median volume diameter Do and normalized DSD intercept parameter Nw combinations in rain because of a multiple-value solution space. For the remaining Do, Nw pairs, another retrieval method is necessary. This paper proposes a supplementary profile-optimization technique to find those DSD profiles in the rain region that the SL model cannot correctly determine. The optimization method is based on a model that both Do and log(Nw) are linear vertical profiles, and that the profiles can be found using an optimization technique from the input reflectivity profiles. Using those assumptions, the optimization method finds the top and bottom Do, log(Nw) values such that a cost function related to the input-measured reflectivity is minimized. A random-restart method is used to generate random top-and-bottom DSD seed values for each optimization cycle. Example cases are shown to demonstrate the performance with and without error in the input reflectivity profiles. Limitations of the method are discussed, including its performance when the input reflectivity profiles are based on nonlinear DSD profiles and values of shape factor μ different than the algorithm assumed value.
Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation
Authors: Atanackovic Djordje , Arfsten Julia , Cao Yanran , Gnjatic Sacha , Schnieders Frank , Bartels Katrin , Schilling Georgia , Faltz Christiane , Wolschke Christine , Dierlamm Judith , Ritter Gerd , Eiermann Thomas , Hossfeld Dieter Kurt , Zander Axel R. , Jungbluth Achim A. , Old Lloyd J. , Bokemeyer Carsten , Kröger Nicolaus
Published: October 2006

Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n = 55) and healthy donors (n = 32) using reverse transcriptase–polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n = 66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1–specific CD4+ and CD8+ T-cell responses against peptide NY-ESO-151-62 and CD4+ responses against NY-ESO-1121-140 in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen–specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.
IL-7–induced proliferation of recent thymic emigrants requires activation of the PI3K pathway
Authors: Swainson Louise , Kinet Sandrina , Mongellaz Cedric , Sourisseau Marion , Henriques Telmo , Taylor Naomi
Published: October 2006

The IL-7 cytokine promotes the survival of a diverse T-cell pool, thereby ensuring an efficient immune response. Moreover, IL-7 induces the proliferation of recent thymic emigrants (RTEs) in neonates. Here, we demonstrate that the survival and proliferative effects of IL-7 on human RTEs can be distinguished on the basis of dose as well as duration of IL-7 administration. A dose of 0.1 ng/mL IL-7 is sufficient to promote viability, whereas cell-cycle entry is observed only at doses higher than 1 ng/mL. Moreover, a short 1-hour exposure to high-dose IL-7 (10 ng/mL) induces long-term survival but continuous IL-7 exposure is necessary for optimal cell-cycle entry and proliferation. We find that distinct signaling intermediates are activated under conditions of IL-7–induced survival and proliferation; STAT5 tyrosine phosphorylation does not correlate with proliferation, whereas up-regulation of the glucose transporter Glut-1 as well as increased glucose uptake are markers of IL-7–induced cell cycle entry. Glut-1 is directly regulated by PI3K and, indeed, inhibiting PI3K activity abrogates IL-7–induced proliferation. Our finding that the survival and proliferation of RTEs are differentially modulated by the dose and kinetics of exogenous IL-7 has important implications for the clinical use of this cytokine.
Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis
Authors: Zhan Fenghuang , Barlogie Bart , Arzoumanian Varant , Huang Yongsheng , Williams David R. , Hollmig Klaus , Pineda-Roman Mauricio , Tricot Guido , van Rhee Frits , Zangari Maurizio , Dhodapkar Madhav , Shaughnessy John D.
Published: October 2006

Monoclonal gammopathy of undetermined significance (MGUS) can progress to multiple myeloma (MM). Although these diseases share many of the same genetic features, it is still unclear whether global gene-expression profiling might identify prior genomic signatures that distinguish them. Through significance analysis of microarrays, 52 genes involved in important pathways related to cancer were differentially expressed in the plasma cells of healthy subjects (normal plasma-cell [NPC]; n = 22) and patients with stringently defined MGUS/smoldering MM (n = 24) and symptomatic MM (n = 351) (P < .001). Unsupervised hierarchical clustering of 351 patients with MM, 44 with MGUS (24 + 20), and 16 with MM from MGUS created 2 major cluster branches, one containing 82% of the MGUS patients and the other containing 28% of the MM patients, termed MGUS-like MM (MGUS-L MM). Using the same clustering approach on an independent cohort of 214 patients with MM, 27% were found to be MGUS-L. This molecular signature, despite its association with a lower incidence of complete remission (P = .006), was associated with low-risk clinical and molecular features and superior survival (P < .01). The MGUS-L signature was also seen in plasma cells from 15 of 20 patients surviving more than 10 years after autotransplantation. These data provide insight into the molecular mechanisms of plasma-cell dyscrasias.
Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl)
Authors: Podar Klaus , Raab Marc S. , Zhang Jing , McMillin Douglas , Breitkreutz Iris , Tai Yu-Tzu , Lin Boris K. , Munshi Nikhil , Hideshima Teru , Chauhan Dharminder , Anderson Kenneth C.
Published: October 2006

In multiple myeloma (MM) protein kinase C (PKC) signaling pathways have been implicated in cell proliferation, survival, and migration. Here we investigated the novel, orally available PKC-inhibitor enzastaurin for its anti-MM activity. Enzastaurin specifically inhibits phorbol ester–induced activation of PKC isoforms, as well as phosphorylation of downstream signaling molecules MARCKS and PKCμ. Importantly, it also inhibits PKC activation triggered by growth factors and cytokines secreted by bone marrow stromal cells (BMSCs), costimulation with fibronectin, vascular endothelial growth factor (VEGF), or interleukin-6 (IL-6), as well as MM patient serum. Consequently, enzastaurin inhibits proliferation, survival, and migration of MM cell lines and MM cells isolated from multidrug-resistant patients and overcomes MM-cell growth triggered by binding to BMSCs and endothelial cells. Importantly, strong synergistic cytotoxicity is observed when enzastaurin is combined with bortezomib and moderate synergistic or additive effects when combined with melphalan or lenalidomide. Finally, tumor growth, survival, and angiogenesis are abrogated by enzastaurin in an in vivo xenograft model of human MM. Our results therefore demonstrate in vitro and in vivo efficacy of the orally available PKC inhibitor enzastaurin in MM and strongly support its clinical evaluation, alone or in combination therapies, to improve outcome in patients with MM.
Coloring the Mu transpososome
Authors: Darcy Isabel K , Chang Jeff , Druivenga Nathan , McKinney Colin , Medikonduri Ram K , Mills Stacy , Navarra-Madsen Junalyn , Ponnusamy Arun , Sweet Jesse , Thompson Travis
Published: October 2006

Background

Tangle analysis has been applied successfully to study proteins which bind two segments of DNA and can knot and link circular DNA. We show how tangle analysis can be extended to model any stable protein-DNA complex.

Results

We discuss a computational method for finding the topological conformation of DNA bound within a protein complex. We use an elementary invariant from knot theory called colorability to encode and search for possible DNA conformations. We apply this method to analyze the experimental results of Pathania, Jayaram, and Harshey (Cell 2002). We show that the only topological DNA conformation bound by Mu transposase which is biologically likely is the five crossing solution found by Pathania et al (although other possibilities are discussed).

Conclusion

Our algorithm can be used to analyze the results of the experimental technique described in Pathania et al in order to determine the topological conformation of DNA bound within a stable protein-DNA complex.
Inhibition of prefrontal protein synthesis following recall does not disrupt memory for trace fear conditioning
Authors: Blum Sonja , Runyan Jason D , Dash Pramod K
Published: October 2006

Background

The extent of similarity between consolidation and reconsolidation is not yet fully understood. One of the differences noted is that not every brain region involved in consolidation exhibits reconsolidation. In trace fear conditioning, the hippocampus and the medial prefrontal cortex (mPFC) are required for consolidation of long-term memory. We have previously demonstrated that trace fear memory is susceptible to infusion of the protein synthesis inhibitor anisomycin into the hippocampus following recall. In the present study, we examine whether protein synthesis inhibition in the mPFC following recall similarly results in the observation of reconsolidation of trace fear memory.

Results

Targeted intra-mPFC infusions of anisomycin or vehicle were performed immediately following recall of trace fear memory at 24 hours, or at 30 days, following training in a one-day or a two-day protocol. The present study demonstrates three key findings: 1) trace fear memory does not undergo protein synthesis dependent reconsolidation in the PFC, regardless of the intensity of the training, and 2) regardless of whether the memory is recent or remote, and 3) intra-mPFC inhibition of protein synthesis immediately following training impaired remote (30 days) memory.

Conclusion

These results suggest that not all structures that participate in memory storage are involved in reconsolidation. Alternatively, certain types of memory-related information may reconsolidate, while other components of memory may not.
The PTI1-like kinase ZmPti1a from maize (Zea maysL.) co-localizes with callose at the plasma membrane of pollen and facilitates a competitive advantage to the male gametophyte
Authors: Herrmann Markus M , Pinto Sheena , Kluth Jantjeline , Wienand Udo , Lorbiecke René
Published: October 2006

Background

The tomato kinase Pto confers resistance to bacterial speck disease caused by Pseudomonas syringae pv. tomato in a gene for gene manner. Upon recognition of specific avirulence factors the Pto kinase activates multiple signal transduction pathways culminating in induction of pathogen defense. The soluble cytoplasmic serine/threonine kinase Pti1 is one target of Pto phosphorylation and is involved in the hypersensitive response (HR) reaction. However, a clear role of Pti1 in plant pathogen resistance is uncertain. So far, no Pti1 homologues from monocotyledonous species have been studied.

Results

Here we report the identification and molecular analysis of four Pti1-like kinases from maize (ZmPti1a, -b, -c, -d). These kinase genes showed tissue-specific expression and their corresponding proteins were targeted to different cellular compartments. Sequence similarity, expression pattern and cellular localization of ZmPti1b suggested that this gene is a putative orthologue of Pti1 from tomato. In contrast, ZmPti1a was specifically expressed in pollen and sequestered to the plasma membrane, evidently owing to N-terminal modification by myristoylation and/or S-acylation. The ZmPti1a:GFP fusion protein was not evenly distributed at the pollen plasma membrane but accumulated as an annulus-like structure which co-localized with callose (1,3-β-glucan) deposition. In addition, co-localization of ZmPti1a and callose was observed during stages of pollen mitosis I and pollen tube germination. Maize plants in which ZmPti1a expression was silenced by RNA interference (RNAi) produced pollen with decreased competitive ability. Hence, our data provide evidence that ZmPti1a plays an important part in a signalling pathway that accelerates pollen performance and male fitness.

Conclusion

ZmPti1a from maize is involved in pollen-specific processes during the progamic phase of reproduction, probably in crucial signalling processes associated with regions of callose deposition. Pollen-sporophyte interactions and pathogen induced HR show certain similarities. For example, HR has been shown to be associated with cell wall reinforcement through callose deposition. Hence, it is hypothesized that Pti1 kinases from maize act as general components in evolutionary conserved signalling processes associated with callose, however during different developmental programs and in different tissue types.
Highly active antiretroviral therapy and hospital readmission: comparison of a matched cohort
Authors: Nosyk Bohdan , Sun Huiying , Li Xin , Palepu Anita , Anis Aslam H
Published: October 2006

Background

Despite the known efficacy of highly active antiretroviral therapy (HAART), a large proportion of potentially-eligible HIV-infected patients do not access, and may stand to benefit from this treatment. In order to quantify these benefits in terms of reductions in hospitalizations and hospitalization costs, we sought to determine the impact of HAART on hospital readmission among HIV-infected patients hospitalized at St. Paul's Hospital (SPH) in Vancouver, BC, Canada.

Methods

All patients admitted to a specialized HIV/AIDS ward at SPH (Apr. 1997 – Oct. 2002) were selected and classified as being on HAART or not on HAART based upon their initial admission. Patients were then matched by their propensity scores, which were calculated based on patients' sociodemographics such as age, gender, injection drug use (IDU) status, and AIDS indication, and followed up for one year. Multivariate logistic regression was used to estimate the difference in the odds of hospital readmission between patients on and not on HAART.

Results

Out of a total 1084 patients admitted to the HIV/AIDS ward between 1997 and 2002, 662 were matched according to their propensity score; 331 patients each on and not on HAART. Multivariate logistic regression revealed that patients on HAART had lower odds of AIDS hospital readmission (OR, 0.61; 95% CI, 0.42 – 0.89) compared to patients not on HAART. Odds of readmission among patients on HAART were also significantly lower for non-IDU related readmission (OR, 0.73; 95% CI, 0.53 – 0.99) and overall readmission (OR, 0.72; 95% CI, 0.53 – 0.98).

Conclusion

Propensity score matching allowed us to reliably estimate the association between exposure (on or not on HAART) and outcome (readmitted to hospital). We found that HIV-infected patients who were potentially eligible for, but not on HAART had higher odds of being readmitted to hospital compared to those on HAART. Given the low level of uptake (31%) of HAART observed in our pre-matched hospitalized cohort, a large potential to achieve clinical benefits, reduce hospitalization costs and possibly slow disease progression from improved HAART uptake still exists.
A super-spreading ewe infects hundreds with Q fever at a farmers' market in Germany
Authors: Porten Klaudia , Rissland Jürgen , Tigges Almira , Broll Susanne , Hopp Wilfried , Lunemann Mechthild , van Treeck Ulrich , Kimmig Peter , Brockmann Stefan O , Wagner-Wiening Christiane , Hellenbrand Wiebke , Buchholz Udo
Published: October 2006

Background

In May 2003 the Soest County Health Department was informed of an unusually large number of patients hospitalized with atypical pneumonia.

Methods

In exploratory interviews patients mentioned having visited a farmers' market where a sheep had lambed. Serologic testing confirmed the diagnosis of Q fever. We asked local health departments in Germany to identiy notified Q fever patients who had visited the farmers market. To investigate risk factors for infection we conducted a case control study (cases were Q fever patients, controls were randomly selected Soest citizens) and a cohort study among vendors at the market. The sheep exhibited at the market, the herd from which it originated as well as sheep from herds held in the vicinity of Soest were tested for Coxiella burnetii (C. burnetii).

Results

A total of 299 reported Q fever cases was linked to this outbreak. The mean incubation period was 21 days, with an interquartile range of 16–24 days. The case control study identified close proximity to and stopping for at least a few seconds at the sheep's pen as significant risk factors. Vendors within approximately 6 meters of the sheep's pen were at increased risk for disease compared to those located farther away. Wind played no significant role. The clinical attack rate of adults and children was estimated as 20% and 3%, respectively, 25% of cases were hospitalized. The ewe that had lambed as well as 25% of its herd tested positive for C. burnetii antibodies.

Conclusion

Due to its size and point source nature this outbreak permitted assessment of fundamental, but seldom studied epidemiological parameters. As a consequence of this outbreak, it was recommended that pregnant sheep not be displayed in public during the 3rd trimester and to test animals in petting zoos regularly for C. burnetii.
Relevance of cyclin D1b expression and CCND1polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma
Authors: Krieger Sophie , Gauduchon Juliette , Roussel Mikel , Troussard Xavier , Sola Brigitte
Published: October 2006

Background

The CCND1 gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of a common A/G polymorphism. Cyclin D1a and b proteins differ in their C-terminus, a region involved in protein degradation and sub-cellular localization. Recent data have suggested that cyclin D1b could be a nuclear oncogene. The presence of cyclin D1b mRNA and protein has been studied in two hemopathies in which cyclin D1 could be present: multiple myeloma (MM) and mantle cell lymphoma (MCL). The A/G polymorphism of CCND1 has also been verified in a series of patients.

Methods

The expression of cyclin D1 mRNA isoforms has been studied by real-time quantitative PCR; protein isoforms expression, localization and degradation by western blotting. The CCND1 polymorphism was analyzed after sequencing genomic DNA.

Results

Cyclin D1 mRNA isoforms a and b were expressed in mantle cell lymphoma (MCL) and multiple myeloma (MM). Cyclin D1b proteins were present in MCL, rarely in MM. Importantly, both protein isoforms localized the nuclear and cytoplasmic compartments. They displayed the same short half-life. Thus, the two properties of cyclin D1b recognized as necessary for its transforming activity are missing in MCL. Moreover, CCND1 polymorphism at the exon/intron boundary had no influence on splicing regulation in MCL cells.

Conclusion

Our results support the notion that cyclin D1b is not crucial for the pathogenesis of MCL and MM.
Priority setting in developing countries health care institutions: the case of a Ugandan hospital
Authors: Kapiriri Lydia , Martin Douglas K
Published: October 2006

Background

Because the demand for health services outstrips the available resources, priority setting is one of the most difficult issues faced by health policy makers, particularly those in developing countries. However, there is lack of literature that describes and evaluates priority setting in these contexts. The objective of this paper is to describe priority setting in a teaching hospital in Uganda and evaluate the description against an ethical framework for fair priority setting processes – Accountability for Reasonableness.

Methods

A case study in a 1,500 bed national referral hospital receiving 1,320 out patients per day and an average budget of US$ 13.5 million per year. We reviewed documents and carried out 70 in-depth interviews (14 health planners, 40 doctors, and 16 nurses working at the hospital). Interviews were recorded and transcribed. Data analysis employed the modified thematic approach to describe priority setting, and the description was evaluated using the four conditions of Accountability for Reasonableness: relevance, publicity, revisions and enforcement.

Results

Senior managers, guided by the hospital strategic plan make the hospital budget allocation decisions. Frontline practitioners expressed lack of knowledge of the process. Relevance: Priority is given according to a cluster of factors including need, emergencies and patient volume. However, surgical departments and departments whose leaders "make a lot of noise" are also prioritized. Publicity: Decisions, but not reasons, are publicized through general meetings and circulars, but this information does not always reach the frontline practitioners. Publicity to the general public was through ad hoc radio programs and to patients who directly ask. Revisions: There were no formal mechanisms for challenging the reasoning. Enforcement: There were no mechanisms to ensure adherence to the four conditions of a fair process.

Conclusion

Priority setting decisions at this hospital do not satisfy the conditions of fairness. To improve, the hospital should: (i) engage frontline practitioners, (ii) publicize the reasons for decisions both within the hospital and to the general public, and (iii) develop formal mechanisms for challenging the reasoning. In addition, capacity strengthening is required for senior managers who must accept responsibility for ensuring that the above three conditions are met.
Interest of major serum protein removal for Surface-Enhanced Laser Desorption/Ionization – Time Of Flight (SELDI-TOF) proteomic blood profiling
Authors: Roche Stéphane , Tiers Laurent , Provansal Monique , Piva Marie-Thérèse , Lehmann Sylvain
Published: October 2006

Background

Surface-Enhanced Laser Desorption/Ionization – Time Of Flight (SELDI-TOF) has been proposed as new approach for blood biomarker discovery. However, results obtained so far have been often disappointing as this technique still has difficulties to detect low-abundant plasma and serum proteins.

Results

We used a serum depletion scheme using chicken antibodies against various abundant proteins to realized a pre-fractionation of serum prior to SELDI-TOF profiling. Depletion of major serum proteins by immunocapture was confirmed by 1D and 2D gel electrophoresis. SELDI-TOF analysis of bound and unbound (depleted) serum fractions revealed that this approach allows the detection of new low abundant protein peaks with satisfactory reproducibility.

Conclusion

The combination of immunocapture and SELDI-TOF analysis opens new avenues into proteomic profiling for the discovery of blood biomarkers.
Differential involvement of RelB in morphine-induced modulation of chemotaxis, NO, and cytokine production in murine macrophages and lymphocytes
Authors: Martucci Cataldo , Franchi Silvia , Lattuada Donatella , Panerai Alberto E , Sacerdote Paola
Published: October 2006

Acute morphine impairs innate and acquired immunity. The mechanisms involved in immunosuppression have not been well defined yet. The transcription factor NF-κB is a central regulator of immunity, and of the NF-κB family, RelB is particularly involved in the expression of genes important in immune responses. We investigated the involvement of RelB in morphine-induced immnosuppression in mice deficient for the RelB factor. RelB−/− mice and wild-type (WT) controls were injected s.c. with morphine 20 mg/Kg, and 1 h later, immune parameters were evaluated. Morphine significantly reduced macrophage production of the proinflammatory cytokines IL-1β, TNF-α, and IL-12 in WT animals, and the drug failed to diminish the production of these cytokines in the RelB−/− mice. In contrast, the anti-inflammatory cytokine IL-10 was similarly affected in the two strains. Macrophage NO production was modulated by morphine in WT animals only, and morphine similarly decreased macrophage chemotaxis in the presence or in the absence of RelB. When Th1 and Th2 cytokines were evaluated, we observed a clear morphine-induced reduction of IL-2 and IFN-γ production by WT splenocytes, whereas no effect of the drug was observed in RelB−/− mice. On the contrary, the production of the Th2 cytokines IL-4 and IL-10 was lessened to the same degree by morphine in WT and RelB−/− mice. In conclusion, our data suggest that RelB is an important target for morphine modulation of proinflammatory and Th1 cytokines. They also indicate that morphine uses multiple intracellular pathways to exert its generalized immunosuppression.
Aspartic protease and caspase 3/7 activation are central for macrophage apoptosis following infection withEscherichia coli
Authors: Albee Lee , Shi Bo , Perlman Harris
Published: October 2006

Macrophages are vital for host defense against microbial infections. We have previously shown that infection of macrophages with a nonpathogenic strain of Escherichia coli induces apoptosis rapidly. Here, we demonstrate that infection of macrophages results in the activation of caspases prior to the induction of the intrinsic apoptosis pathway. Caspases 9 and 3 are activated prior to the release of intermembrane mitochondrial protein cytochrome C into he cytosol in infected macrophages. Treatment with an inhibitor to caspase 9 has no effect on the death of macrophages and does not prevent activation of the downstream effector caspase 3/7. In contrast, an inhibitor to caspase 3/7 reduces cell death in E. coli-infected macrophages. Although caspase 9 is not required, activation of aspartic proteases, of which cathepsin D is one of the central members, is essential for activation of caspase 3/7. Treatment with pepstatin A, an inhibitor of aspartic proteases, markedly diminishes the activation of cathepsin D and caspase 3/7 and reduces death in E. coli-infected macrophages. Collectively, these data suggest that cathepsin D activation of caspase 3/7 may be required for inducing one of the death pathways elicited by E. coli.
Palmitate Induced Mitochondrial Deoxyribonucleic Acid Damage and Apoptosis in L6 Rat Skeletal Muscle Cells
Authors: Rachek L. I. , Musiyenko S. I. , LeDoux S. P. , Wilson G. L.
Published: October 2006

A major characteristic of type 2 diabetes mellitus (T2DM) is insulin resistance in skeletal muscle. A growing body of evidence indicates that oxidative stress that results from increased production of reactive oxygen species and/or reactive nitrogen species leads to insulin resistance, tissue damage, and other complications observed in T2DM. It has been suggested that muscular free fatty acid accumulation might be responsible for the mitochondrial dysfunction and insulin resistance seen in T2DM, although the mechanisms by which increased levels of free fatty acid lead to insulin resistance are not well understood. To help resolve this situation, we report that saturated fatty acid palmitate stimulated the expression of inducible nitric oxide (NO) synthase and the production of reactive oxygen species and NO in L6 myotubes. Additionally, palmitate caused a significant dose-dependent increase in mitochondrial DNA (mtDNA) damage and a subsequent decrease in L6 myotube viability and ATP levels at concentrations as low as 0.5 mm. Furthermore, palmitate induced apoptosis, which was detected by DNA fragmentation, caspase-3 cleavage, and cytochrome c release. N-acetyl cysteine, a precursor compound for glutathione formation, aminoguanidine, an inducible NO synthase inhibitor, and 5,10,15,20-tetrakis(4-sulphonatophenyl) porphyrinato iron (III), a peroxynitrite inhibitor, all prevented palmitate-induced mtDNA damage and diminished palmitate-induced cytotoxicity. We conclude that exposure of L6 myotubes to palmitate induced mtDNA damage and triggered mitochondrial dysfunction, which caused apoptosis. Additionally, our findings indicate that palmitate-induced mtDNA damage and cytotoxicity in skeletal muscle cells were caused by overproduction of peroxynitrite.
Vascular Lipotoxicity: Endothelial Dysfunction via Fatty-Acid-Induced Reactive Oxygen Species Overproduction in Obese Zucker Diabetic Fatty Rats
Authors: Chinen Ichiro , Shimabukuro Michio , Yamakawa Ken , Higa Namio , Matsuzaki Toshihiro , Noguchi Katsuhiko , Ueda Shinichiro , Sakanashi Matao , Takasu Nobuyuki
Published: October 2006

Vascular endothelial dysfunction has been demonstrated in obesity, but the molecular basis for this link has not been clarified. We examined the role of free fatty acids (FFA) on vascular reactivity in the obese fa/fa Zucker diabetic fatty (ZDF) rat. Addition of acetylcholine produced a dose-dependent relaxation in aortic rings of ZDF and lean +/+ rats, but the ED50 value was higher in ZDF (−6.80 ± 0.05 vs. −7.11 ± 0.05 log10 mol/liter, P = 0.033). A 2-wk treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, pitavastatin (3 mg/kg/d) or a reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin (5 mmol/liter in drinking water), improved the response in ZDF (ED50, −7.16 ± 0.03 and −7.14 ± 0.05 log10 mol/liter, P = 0.008 and P = 0.015 vs. vehicle, respectively). Vasodilator response to sodium nitroprusside was identical between ZDF and +/+ rats. Vascular reactive oxygen species (ROS) levels and NADPH oxidase activity in aorta were increased in ZDF rats but were decreased by pitavastatin. In in vitro cell culture, intracellular ROS signal and NADPH oxidase subunit mRNA were increased by palmitate, but this palmitate-induced ROS production was inhibited by NADPH oxidase inhibitor or pitavastatin. In conclusion, FFA-induced NADPH oxidase subunit overexpression and ROS production could be involved in the endothelial dysfunction seen in obese ZDF rats, and this could be protected by pitavastatin or NADPH oxidase inhibitors.
Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Authors: Turgeon Judith L. , Carr Molly C. , Maki Pauline M. , Mendelsohn Michael E. , Wise Phyllis M.
Published: October 2006

Recent publications describing the results of the Women’s Health Initiative (WHI) and other studies reporting the impact of hormone therapy on aging women have spurred reexamination of the broad use of estrogens and progestins during the postmenopausal years. Here, we review the complex pharmacology of these hormones, the diverse and sometimes opposite effects that result from the use of different estrogenic and progestinic compounds, given via different delivery routes in different concentrations and treatment sequence, and to women of different ages and health status. We examine our new and growing appreciation of the role of estrogens in the immune system and the inflammatory response, and we pose the concept that estrogen’s interface with this system may be at the core of some of the effects on multiple physiological systems, such as the adipose/metabolic system, the cardiovascular system, and the central nervous system. We compare and contrast clinical and basic science studies as we focus on the actions of estrogens in these systems because the untoward effects of hormone therapy reported in the WHI were not expected. The broad interpretation and publicity of the results of the WHI have resulted in a general condemnation of all hormone replacement in postmenopausal women. In fact, careful review of the extensive literature suggests that data resulting from the WHI and other recent studies should be interpreted within the narrow context of the study design. We argue that these results should encourage us to perform new studies that take advantage of a dialogue between basic scientists and clinician scientists to ensure appropriate design, incorporation of current knowledge, and proper interpretation of results. Only then will we have a better understanding of what hormonal compounds should be used in which populations of women and at what stages of menopausal/postmenopausal life.
Expanding the Scales: The Multiple Roles of MCH in Regulating Energy Balance and Other Biological Functions
Authors: Pissios Pavlos , Bradley Richard L. , Maratos-Flier Eleftheria
Published: October 2006

Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified as a 17-amino-acid circulating hormone in teleost fish, where it is secreted by the pituitary in response to stress and environmental stimuli. In fish, MCH lightens skin color by stimulating aggregation of melanosomes, pigment-containing granules in melanophores, cells of neuroectodermal origin found in fish scales. Although the peptide structure between fish and mammals is highly conserved, in mammals, MCH has no demonstrable effects on pigmentation; instead, based on a series of pharmacological and genetic experiments, MCH has emerged as a critical hypothalamic regulator of energy homeostasis, having effects on both feeding behavior and energy expenditure.
CNC electrical discharge rough machining of turbine blades
Authors: Ding S , YuanZ R , Li Z , Wang K
Published: October 2006

This paper introduces a method for rough machining of turbine blades with CNC electrical discharge machining (EDM), which is similar to mechanical milling geometrically and is also modelled by intersections between a cylindrical tool and the workpiece. However, special factors such as DC arcing, electrode wear, and discharging gap compensation have to be considered in the process. These special factors are analysed, and a CAM system catering to four-axis CNC EDM rough machining of turbine blades with a cylindrical electrode is introduced. The tool path generation algorithm has been integrated in an industrial CAD/CAM system (Unigraphics). In addition to machining simulations, real cutting experiments are presented.