bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune Response in Malnutrition. Effect of Protein Deficiency on the DNA Synthetic Response to Alloantigens
Authors: Malavé Inés , Németh Andrea , Blanca Isaac
Published: July 2009

To evaluate the DNA synthetic response to alloantigens by lymphocytes from mice fed diets with normal (27%) and low (8%) protein content, we quantitated the uptake of 125IUDR in spleens of lethally irradiated adult F1 hybrids injected with cells from parental C57BL/6 donors kept on either diet. Thymocytes, spleen and lymph node cells from protein-restricted parental mice synthesized higher amounts of DNA than those from normally fed controls. Added thymocytes from either malnourished or normal F1 hybrids had similar inhibitory effects on the response of an active parental inoculum. The results indicate that cells from mice kept on a moderately protein-deficient diet for 3–5 weeks after weaning, have increased capacity to proliferate in response to alloantigens, suggesting a high proportion of reactive cells and/or changes in the ratio of the interacting cell populations in their lymphoid organs.
Suppression of Reaginic Antibodies with Modified Allergens
Authors: Lee Weng Y. , Sehon Alec H.
Published: July 2009

The conjugates of ovalbumin (OA) and of the nondialysable constituents of the aqueous extract of ragweed pollen (RAG) with polyethylene glycols of molecular weights of 6,000 or 20,000 (PEG6 or PEG20) were shown to be nonantigenic, nonallergenic and nonimmunogenic. Thus, the i.v. administration of OA-PEG and RAG-PEG conjugates into mice did not elicit antibodies to OA and RAG, respectively, and these conjugates were shown to suppress in an immunologically specific manner the capacity of these animals to mount primary as well as secondary IgE responses to sensitizing doses of dinitrophenylated OA or of RAG. Moreover, the PEG-modified antigens did not combine either in vitro or in vivo with IgE antibodies directed against the natural antigens. Hence, OA-PEG and RAG-PEG conjugates were incapable of triggering allergic reactions in animals possessing IgE antibodies to the unmodified antigens. These PEG-modified antigens were also shown to be tolerogenic.
Immunological Relationships of Human and Subhuman Primate Pregnancy-Associated Plasma Proteins
Authors: Lin Tsue-Ming , Halbert Seymour P.
Published: July 2009

(1) Four pregnancy-associated plasma proteins cross-reactive with antibodies to the human pregnancy proteins were detected in several species of pregnant subhuman primates. In the case of the two apes studied (chimpanzee and orangutan), these appeared to be immunologically identical to the human PAPPs (PAPP-A, -B, -C, and HCS). In the old world monkeys analyzed, equivalent partially cross-reactive PAPPs were found; while in the new world squirrel monkey, only faint traces of cross-reactive PAPP-C and HCS were observed with the most sensitive methods used. (2) As in the human, these proteins appeared to be specific for pregnancy, not being detectable in nonpregnant animals, female or male. (3) The pregnant chimpanzee possessed significantly higher concentrations of PAPP-A and PAPP-C than did women at an equivalent stage of pregnancy, while the HCS and PAPP-B levels appeared to be approximately the same. (4) The primate PAPP-C analogues were more complex than human PAPP-C, often revealing multiple gel diffusion patterns with subfractions of differing electrophoretic mobilities. (5) Based on the changes of electrophoretic mobility upon exposure to neuraminidase, the subhuman primate as well as human PAPP-A and PAPP-C appeared to be glycoproteins containing sialic acid. (6) In the chimpanzee and rhesus monkey, as in the human, the levels of PAPP-A, PAPP-C, and HCS were appreciably higher during the third trimester of pregnancy than they were during the second trimester.
Cell-Mediated Immunity in Pregnancy Evaluated Using Lymphocyte Transformation Tests and Rosette Tests for T and B Lymphocytes
Authors: Birkeland S.A. , Kristoffersen K.
Published: July 2009

In vitro tests of cellular immune response using lymphocyte transformation tests and rosette tests for T and B lymphocytes were studied in a cross-section analysis of a total of 55 patients in six groups (non-pregnant, 2–3 month pregnant, 4–5 month pregnant, 6–7 month pregnant, at parturition and 3 months after parturition). No pregnancy-related changes were found in the numbers of T, B or nil cells, nor changes in PHA, PWM or MLC responses. However, a significant reversible depression of the PPD response was found in the second half of pregnancy.
Experimental Autoimmune Orchitis in T-Cell-Deficient Mice
Authors: Bernard Claude C.A. , Mitchell Graham F. , Leydon Jennifer , Bargerbos Alex
Published: July 2009

Experimental autoimmune orchitis (EAO) was induced in inbred strains of mice by injection of mouse testis homogenate (MTH) in Freund’s complete adjuvant with pertussis vaccine. Although all mice injected with MTH and adjuvants developed signs of EAO, there were marked strain variations in susceptibility to EAO suggesting that genetic factors may be involved in the response to antigen or to adjuvants. Studies in hypothymic BALB/c. nu/nu mice indicated that a source of T cell was required for induction of EAO. Thus BALB/c. nu/nu mice were not able to develop EAO, despite adequate orchitogenic challenge; reconstitution of nu/nu mice with syngeneic thymocytes completely restored the capacity of such mice to develop orchitis. Transfer of EAO was effected in nu/nu mice with lymphoid cells from appropriately immunized donors but not with immune serum. However, both T cells and antibodies may be necessary in the effector stages of the disease since the capacity of lymphoid cells to transfer EAO was only partially inhibited by anti-Thy-1.2 treatment.
Contributions to the Regulatory Role of Insulin in Inflammation and Anaphylaxis
Authors: Ottlecz Anna , Koltai M. , Blazsó G. , Minker E.
Published: July 2009

Insulin, in doses which did not influence the blood sugar level, potentiated the anaphylactic shock in ovalbumin-sensitized CFLP mice and moderatedly inhibited the carrageenan-induced paw edema. Higher doses were found to produce a dose-dependent inhibition of the inflammatory process at the 2nd hour, and caused less suppression at the 4th hour of the swelling. These results suggest that insulin may play a complex regulatory role in hypersensitivity and inflammatory reactions, and its effect is not necessarily related to hypoglycemia.
The Diagnostic Application of Specific Antiprocollagen Sera
Authors: Wick G. , Brunner H. , Penner E. , Timpl R.
Published: July 2009

Frozen, unfixed sections of human liver biopsies from patients with acute, subchronic, and chronic hepatitis or fibrotic liver disease were studied in indirect immuno-fluorescence with specific antisera to type I and type III procollagen. In early stages of both hepatitis and fibrotic liver disease, intraiobular type III collagen synthesis is increased. Maximum values are reached years after the onset of disease. Intraiobular procollagen I content is not increased in the acute stage, but rises only later. An increase of procollagen I seems to herald irreversible liver changes. This approach allows for exact localization and semiquantitative analysis of the synthesis of type I and type III collagen, and adds a new parameter to the diagnostic approaches in liver diseases.
Effect of a Low Protein Diet on the Capacity of Mice to Express a Type I Hypersensitivity Response
Authors: Rose Alison H. , Turner Keven J.
Published: July 2009

The capacity of Balb/c mice maintained since weaning on a 4% protein diet to express in vivo immediate (type 1) hypersensitivity reactions was compared to that of age-matched animals maintained on a normal (18%) protein diet. The deprived mice had a lower total cellular population and lower mast cell numbers in their peritoneal cavity. However, the mean cellular histamine content was comparable between the two groups. The skin responses of malnourished mice to the histamine liberator 48/80 were depressed but both groups reacted equally to passive cutaneous anaphylaxis when sensitized with serum from immunized mice. These studies indicate that protein deprivation has not inhibited the capacity to synthesize physiologically active amines or to impair the biochemical pathway of amine release from mast cells.
Regulating Influence of Transferred Immune Spleen Cells on the Primary Response of Mice to Sheep Red Blood Cells
Authors: Benner Robbert , Rozing Jan
Published: July 2009

The regulating influence of transferred immune spleen cells on the primary response of mice to sheep red blood cells (SRBC) was investigated. When splenic memory cells were intravenously inoculated, the greater part of these cells disappeared from the peripheral blood between 30 min and 6 h after injection. Transfer of immune spleen cells 2 days before immunization with 4 × 108 SRBC intravenously caused decreased numbers of PFC in the recipient spleen and up to 10 times as many PFC in the bone marrow. Apparently, the regulating influence of immune spleen cells upon antibody formation during the primary response can differ in different organs.
Studies of the Paw Test and Tumor-Associated Immunosuppression in Mice
Authors: Wells James H. , Pollack Vincent A. , Cox Charles P. , Cain William A.
Published: July 2009

Specific paw test reactivity to tumor cells was transferred to normal mice using lymphoid cells or serum from mice with a growing or surgically excised methyl-cholanthrene-induced transplantable sarcoma. When the donors had been sensitized to PPD and to tumor, normal recipients of lymphoid cells became reactive by specific paw test to tumor cells and PPD. Normal recipients of serum from the same donors also became reactive to tumor cells. Normal recipients of serum from tumor-bearing mice developed depressed PHA paw tests. Adoptive transfer with cells or serum of paw test reactivity to tumor and PPD was unsuccessful when recipients had large tumors. This was the case when the recipients had either tumor of the same line or that of a separate line that did not cross-react antigenically.
Eosinophil Chemotactic Factor (ECF)
Authors: Czarnetzki Beate M. , König Wolfgang , Lichtenstein Lawrence M.
Published: July 2009

A low molecular weight eosinophil chemotactic factor (ECF) can be released from human peripheral polymorphonuclear leukocytes by phagocytosis, by reverse anaphylaxis or by the calcium ionophore A 23187. During later phases of ECF-release, a leukocyte-derived ECF inhibitor (LDI) is concomitantly released. Inhibitory activity is also present in sonicates of unstimulated cells, suggesting that the factor is preformed. On chromatographic analysis of neutrophil (PMN) sonicates, two peaks of inhibitory activity at >200,000 and at about 80,000 daltons each are eluted. With preparations containing lymphocytes, monocytes and basophils (L/M/B), only peak ( >200,000 daltons) is apparent. The LDI is heat stabile (56°C, 1 h), affects only the ECF and not the migrating eosinophils, and does not inactive bacterial factor or deactivate neutrophils. Evidence is presented suggesting that the mode of action is by binding of ECF rather than by enzymatic destruction.
Inhibition of Allergic Reactions by Cromoglycate and by a New Anti-Allergy Drug U-42,585E
Authors: Johnson Herbert G. , VanHout Christine A. , Wright John B.
Published: July 2009

A new inhibitor of IgE-mediated allergic reactions has been studied in rats. This new inhibitor is chemically different from cromoglycate and shows qualitative and quantitative advantages over it. It is 2,500 times more active in rats than disodium cromoglycate and shows oral activity. This new inhibitor possesses no bronchodilator or end-organ antagonism activity and does not raise intracellular cAMP levels but as cromoglycate acts by inhibition of mediator release. Multiple high (25 mg/kg) doses in rats lead to tachyphylaxis. This effect is reversed both by decreasing the first dose and increasing the time between doses. Over a 5- to 10-fold concentration range, this inhibitor in mast cells can be stimulatory or inhibitory to 45Ca++ flux into cells. This ability to inhibit ionophore-induced 45Ca++ flux correlates well with inhibition of histamine release.
Studies on the Role of Histamine and 5-Hydroxytryptamine in Immunity Against the Nematode Trichostrongylus colubriformis
Authors: Rothwell T.L.W. , Love R.J. , Evans D.P.
Published: July 2009

Significant numbers of fourth larval stage Trichostrongylus colubriformis from sheep donors are expelled from the small intestine of T. colubriformis-immune guinea pigs within 8 h of transplantation into this organ. This model system for the immune expulsion of gastrointestinal nematode parasites was used in the current experiments to examine the effect of drugs recently shown to modify the release of histamine. The experiments showed that worm expulsion was inhibited by the β-adrenergic agonists salbutamol and isoprenaline, the phosphodiesterase inhibitors aminophylline and ICI 63,197, the antiallergic drug ICI 74,917 and the antihistamine mepyramine. The β-blocker propranolol prevented inhibition of worm expulsion following salbutamol treatment and there was some evidence of synergistic action between salbutamol and ICI 63,197. The results support previous findings suggesting an important role for histamine release in the effector mechanism of the immune response of guinea pigs against the parasitic nematode T. colubriformis.
IgE-Induced Changes in Human Basophil Cyclic AMP Levels
Authors: Lichtenstein Lawrence M. , Sobotka Anne K. , Malveaux Floyd J. , Gillespie Elizabeth
Published: July 2009

We studied a unique patient with 77% basophils, not different from normal by a number of criteria, in order to measure the changes in cyclic AMP level associated with IgE-mediated histamine release. In accordance with previous hypothesis and circumstantial evidence, anti-IgE challenge led to a significant fall in the cyclic AMP level which preceded histamine release.
Inhibition of Allergic Reactions by Cromoglycate and by a New Antiallergy Drug U-42,585E
Authors: Johnson Herbert G. , VanHout Christine A. , Wright John B.
Published: July 2009

Immediate type hypersensitivity to Ascaris antigen in Rhesus reactor monkeys was used to assess the pharmacologic profile of cromolyn Na (DSCG) and a new inhibitor of IgE-mediated lung function changes (U-42,585E). Two parameters used to measure lung function, respiratory rate increase and tidal volume decrease, were significantly altered in a dose-related fashion by U-42,585E when the latter was administered either by the intravenous, intrabronchial, or the oral route. Oral activity of U-42,585E was demonstrated with doses as low as 5 mg/kg in Ascaris reactor primates.
Peritoneal Anaphylaxis in the Rat after Sensitisation with Mouse Antiserum
Authors: Spicer Barbara A. , Ross Janet W. , Sharpe T.J. , Smith H.
Published: July 2009

Passive peritoneal anaphylaxis in rats, sensitised with mouse antiserum, had characteristics of an IgE-mediated reaction, in that the serum was heat-labile and pretreatment of the rats with disodium cromoglycate (DSCG), or sodium nivimedone, inhibited the release of both histamine and slow-reacting substance of anaphylaxis (SRS-A). Sodium nivimedone was more potent than DSCG as an inhibitor of histamine release. Peak concentrations of histamine and SRS-A in the peritoneal fluids of the rats, were reached within 2 min of antigen challenge and fell to control levels after 20–30 min.
Activation of Complement by Radiographic Contrast Media: Generation of Chemotactic and Anaphylatoxin Activities
Authors: Till Gerd , Rother Ursula , Gemsa Diethard
Published: July 2009

lodinated radiographic contrast media such as methylglucamine diatrizoate and sodium ioglycamate activate serum complement in vitro. This was shown by a dose-, time-, and temperature-dependent decrease of total hemolytic complement activity in normal human serum, consumption of C4 and C6 activity, conversion of C3 to C3b, and generation of C5-derived chemotactic and smooth muscle contracting activity. Complement activation was achieved even in sera depleted of immunoglobulin and properdin, which may indicate that contrast media induce complement activation by mechanisms different from the classical or alternative pathway.
C3 Activator in Agammaglobulinemia
Authors: Nakajima S. , Nihei K. , Hyodo Y.
Published: July 2009

C3 activator in sera of patients with agammaglobulinemia shows higher levels compared with age-matched healthy controls. This fact may be due to a compensatory function of the alternative pathway of the complement system to make up for the defect of production of antibody in these patients.
Shortage of Cardiothoracic Surgeons Is Likely by 2020
Authors: Grover Atul , Gorman Karyn , Dall Timothy M. , Jonas Richard , Lytle Bruce , Shemin Richard , Wood Douglas , Kron Irving
Published: July 2009

Background—

Even as the burden of cardiovascular disease in the United States is increasing as the population grows and ages, the number of active cardiothoracic surgeons has fallen for the first time in 20 years. Meanwhile, the treatment of patients with coronary artery disease continues to evolve amid uncertain changes in technology. This study evaluates current and future requirements for cardiothoracic surgeons in light of decreasing rates of coronary artery bypass grafting procedures.

Methods and Results—

Projections of supply and demand for cardiothoracic surgeons are based on analysis of population, physician office, hospital, and physician data sets to estimate current patterns of healthcare use and delivery. Using a simulation model, we project the future supply of cardiothoracic surgeons under alternative assumptions about the number of new fellows trained each year. Future demand is modeled, taking into account patient demographics, under current and alternative use rates that include the elimination of open revascularization. By 2025, the demand for cardiothoracic surgeons could increase by 46% on the basis of population growth and aging if current healthcare use and service delivery patterns continue. Even with complete elimination of coronary artery bypass grafting, there is a projected shortfall of cardiothoracic surgeons because the active supply is projected to decrease 21% over the same time period as a result of retirement and declining entrants.

Conclusion—

The United States is facing a shortage of cardiothoracic surgeons within the next 10 years, which could diminish quality of care if non–board-certified physicians expand their role in cardiothoracic surgery or if patients must delay appropriate care because of a shortage of well-trained surgeons.
Termination of Atrial Fibrillation Using Pulsed Low-Energy Far-Field Stimulation
Authors: Fenton Flavio H. , Luther Stefan , Cherry Elizabeth M. , Otani Niels F. , Krinsky Valentin , Pumir Alain , Bodenschatz Eberhard , Gilmour Robert F.
Published: July 2009

Background—

Electrically based therapies for terminating atrial fibrillation (AF) currently fall into 2 categories: antitachycardia pacing and cardioversion. Antitachycardia pacing uses low-intensity pacing stimuli delivered via a single electrode and is effective for terminating slower tachycardias but is less effective for treating AF. In contrast, cardioversion uses a single high-voltage shock to terminate AF reliably, but the voltages required produce undesirable side effects, including tissue damage and pain. We propose a new method to terminate AF called
far-field antifibrillation pacing
, which delivers a short train of low-intensity electric pulses at the frequency of antitachycardia pacing but from field electrodes. Prior theoretical work has suggested that this approach can create a large number of activation sites (“virtual” electrodes) that emit propagating waves within the tissue without implanting physical electrodes and thereby may be more effective than point-source stimulation.

Methods and Results—

Using optical mapping in isolated perfused canine atrial preparations, we show that a series of pulses at low field strength (0.9 to 1.4 V/cm) is sufficient to entrain and subsequently extinguish AF with a success rate of 93% (69 of 74 trials in 8 preparations). We further demonstrate that the mechanism behind far-field antifibrillation pacing success is the generation of wave emission sites within the tissue by the applied electric field, which entrains the tissue as the field is pulsed.

Conclusions—

AF in our model can be terminated by far-field antifibrillation pacing with only 13% of the energy required for cardioversion. Further studies are needed to determine whether this marked reduction in energy can increase the effectiveness and safety of terminating atrial tachyarrhythmias clinically.
Circulating Transforming Growth Factor-β in Marfan Syndrome
Authors: Matt Peter , Schoenhoff Florian , Habashi Jennifer , Holm Tammy , Van Erp Christel , Loch David , Carlson Olga D. , Griswold Benjamin F. , Fu Qin , De Backer Julie , Loeys Bart , Huso David L. , McDonnell Nazli B. , Van Eyk Jennifer E. , Dietz Harry C. ,   the GenTAC Consortium
Published: July 2009

Background—

Marfan syndrome (MFS) is caused by mutations in the fibrillin-1 gene and dysregulation of transforming growth factor-β (TGF-β). Recent evidence suggests that losartan, an angiotensin II type 1 blocker that blunts TGF-β activation, may be an effective treatment for MFS. We hypothesized that dysregulation of TGF-β might be mirrored in circulating TGF-β concentrations.

Methods and Results—

Serum obtained from MFS mutant mice (
Fbn1

C1039G
/+

) treated with losartan was analyzed for circulating TGF-β1 concentrations and compared with those from placebo-treated and wild-type mice. Aortic root size was measured by echocardiography. Data were validated in patients with MFS and healthy individuals. In mice, circulating total TGF-β1 concentrations increased with age and were elevated in older untreated
Fbn1

C1039G
/+

mice compared with wild-type mice (
P
=0.01; n=16; mean±SEM, 115±8 ng/mL versus n=17; mean±SEM, 92±4 ng/mL). Losartan-treated
Fbn1

C1039G
/+

mice had lower total TGF-β1 concentrations compared with age-matched
Fbn1

C1039G
/+

mice treated with placebo (
P
=0.01; n=18; 90±5 ng/mL), and circulating total TGF-β1 levels were indistinguishable from those of age-matched wild-type mice (
P
=0.8). Correlation was observed between circulating TGF-β1 levels and aortic root diameters in
Fbn1

C1039G
/+

and wild-type mice (
P
=0.002). In humans, circulating total TGF-β1 concentrations were elevated in patients with MFS compared with control individuals (
P
<0.0001; n=53; 15±1.7 ng/mL versus n=74; 2.5±0.4 ng/mL). MFS patients treated with losartan (n=55) or β-blocker (n=80) showed significantly lower total TGF-β1 concentrations compared with untreated MFS patients (
P
≤0.05).

Conclusions—

Circulating TGF-β1 concentrations are elevated in MFS and decrease after administration of losartan, β-blocker therapy, or both and therefore might serve as a prognostic and therapeutic marker in MFS.
Deletion of Mineralocorticoid Receptors From Macrophages Protects Against Deoxycorticosterone/Salt-Induced Cardiac Fibrosis and Increased Blood Pressure
Authors: Rickard Amanda J. , Morgan James , Tesch Greg , Funder John W. , Fuller Peter J. , Young Morag J.
Published: July 2009

Increased mineralocorticoid levels plus high salt promote vascular inflammation and cardiac tissue remodeling. Mineralocorticoid receptors are expressed in many cell types of the cardiovascular system, including monocytes/macrophages and other inflammatory cell types. Although mineralocorticoid receptors are expressed in monocytes/macrophages, their role in regulating macrophage function to date has not been investigated. We, thus, used the Cre/LoxP-recombination system to selectively delete mineralocorticoid receptors from monocytes/macrophages with the lysozyme M promoter used to drive Cre expression (MR
flox/flox
/LysM
Cre/−
mice). Male mice from each genotype (MR
flox/flox
or wild-type and MR
flox/flox
/LysM
Cre/−
mice) were uninephrectomized, given 0.9% NaCl solution to drink, and treated for 8 days or 8 weeks with either vehicle (n=10) or deoxycorticosterone (n=10). Equivalent tissue macrophage numbers were seen for deoxycorticosterone treatment of each genotype at 8 days; in contrast, plasminogen activator inhibitor type 1 and NAD(P)H oxidase subunit 2 levels were increased in wild-type but not in MR
flox/flox
/LysM
Cre/−
mice given deoxycorticosterone. Baseline expression of other inflammatory genes was reduced in MR
flox/flox
/LysM
Cre/−
mice compared with wild-type mice. At 8 weeks, deoxycorticosterone-induced macrophage recruitment and connective tissue growth factor and plasminogen activator inhibitor type 1 mRNA levels were similar for each genotype; in contrast, MR
flox/flox
/LysM
Cre/−
mice showed no increase in cardiac fibrosis or blood pressure, as was seen in wild-type mice at 8 weeks. These data demonstrate the following points: (1) mineralocorticoid receptor signaling regulates basal monocyte/macrophage function; (2) macrophage recruitment is not altered by loss of mineralocorticoid receptor signaling in these cells; and (3) a novel and significant role is seen for macrophage signaling in the regulation of cardiac remodeling and systolic blood pressure in the deoxycorticosterone/salt model.
Klotho Gene Delivery Prevents the Progression of Spontaneous Hypertension and Renal Damage
Authors: Wang Yuhong , Sun Zhongjie
Published: July 2009

Klotho is a recently discovered antiaging gene. The objective of this study was to test the hypothesis that klotho gene delivery attenuates the progression of spontaneous hypertension and renal damage in spontaneous hypertensive rats (SHRs). An adeno-associated virus (AAV) carrying mouse klotho full-length cDNA (AAV.mKL) was constructed for in vivo expression of klotho. Four groups of male SHRs and 1 group of sex- and age-matched Wistar-Kyoto rats (5 rats per group) were used. Blood pressure was measured twice in all of the animals before gene delivery. Four groups of SHRs received an IV injection of AAV.mKL, AAV.LacZ, AAV.GFP, and PBS, respectively. The Wistar-Kyoto group received PBS and served as a control. AAV.mKL stopped the further increase in blood pressure in SHRs, whereas blood pressures continued to increase in other SHR groups. One single dose of AAV.mKL prevented the progression of spontaneous hypertension for at least 12 weeks (length of the study). Klotho expression and production were suppressed in SHRs, which were reverted by AAV.mKL. AAV.mKL increased plasma interleukin 10 levels but decreased Nox2 expression, NADPH oxidase activity, and superoxide production in kidneys and aortas in SHRs. AAV.mKL abolished renal tubular atrophy and dilation, tubular deposition of proteinaceous material, glomerular collapse, and collagen deposition seen in SHRs, indicating that klotho gene delivery attenuated renal damage. Therefore, the suppressed klotho expression may play a role in the progression of spontaneous hypertension and renal damage in SHRs. AAV delivery of klotho may offer a new approach for the long-term control of hypertension and for renoprotection.
Cognitive Deficit in Amyloid-β–Injected Mice Was Improved by Pretreatment With a Low Dose of Telmisartan Partly Because of Peroxisome Proliferator-Activated Receptor-γ Activation
Authors: Tsukuda Kana , Mogi Masaki , Iwanami Jun , Min Li-Juan , Sakata Akiko , Jing Fei , Iwai Masaru , Horiuchi Masatsugu
Published: July 2009

The pathological hallmark of Alzheimer disease is deposition of amyloid-β protein (Aβ) in the brain. Telmisartan is a unique angiotensin II receptor blocker with peroxisome proliferator-activated receptor-γ (PPAR-γ)–stimulating activity. Activation of PPAR-γ is expected to prevent inflammation and Aβ accumulation in the brain. We investigated the possible preventive effect of telmisartan on cognitive decline in an Alzheimer disease mouse model via PPAR-γ activation. Here, male ddY mice underwent ICV injection of Aβ 1-40. Cognitive function was evaluated by the Morris water maze test. A low dose of telmisartan (0.35 mg/kg per day) was administered in drinking water with or without GW9662, a PPAR-γ antagonist. Cerebral blood flow was evaluated by laser speckle flowmetry. Inflammatory cytokine levels were measured by quantitative RT-PCR. Aβ 1-40 ICV injection significantly impaired cognitive function. Pretreatment with telmisartan improved this cognitive decline to a similar level to that in control mice. Cotreatment with GW9662, a PPAR-γ antagonist, attenuated this telmisartan-mediated improvement of cognition. Treatment with telmisartan enhanced cerebral blood flow and attenuated the Aβ-induced increase in expression of cytokines, such as tumor necrosis factor-α and inducible NO synthase in the brain. Interestingly, coadministration of GW9662 cancelled these beneficial effects of telmisartan. Aβ 1-40 concentration in the brain was significantly decreased by treatment with telmisartan, whereas administration of GW9662 attenuated the decrease in telmisartan-mediated Aβ 1-40 concentration. Taken together, our findings suggest that even a low dose of telmisartan had a preventive effect on cognitive decline in an Alzheimer disease mouse model, partly because of PPAR-γ activation.
Mind over body: Physical and psychotherapeutic discourses and the regulation of the older worker
Authors: Ainsworth Susan , Hardy Cynthia
Published: July 2009

We examine how physical and psychotherapeutic discourses regulate the identity work of older workers. We show that they have separate effects: physical discourse inferred that the loss of work for older workers would be permanent whereas psychotherapeutic discourse suggested that the solution to unemployment lay in the mind of older workers themselves. They also have combined effects through the notion of grief: older workers are expected to progress through the normative stages of grief to arrive at acceptance of job loss and continued exclusion from the labour market. Despite moments of resistance in the identity work of older workers, these individuals were subjected to these regulatory effects through three key processes: participation by individual older workers in these discourses through their own identity work; collaboration from a range of diverse actors in contributing to this identity work; and translation of the meaning as initial narratives are retold by other actors.
Archaeology and the Construction of Identities in Medieval North India
Authors: Varma Supriya , Menon Jaya
Published: July 2009

Archaeologists have at times perceived the early medieval to medieval period as marked by a break at the end of the twelfth century, thus separating the period 700–1200 CE—often described as the ‘Rajput’ period—from the period 1200–1500 CE—commonly designated as the ‘Sultanate’ period. It is frequently believed that this break is manifested in the entire range of archaeological materials with clear changes perceived between the two periods. Moreover, there has been a tendency to ascribe particular religious identities to the artefacts of the ‘Rajput’ and ‘Sultanate’ periods. Implicit in such a reading of the material culture are certain assumptions that have been made by archaeologists. One is that a change in political elites will bring about a change in daily practices and, concomitantly, in the artefacts. Another assumption is that certain artefacts indicate a specific religious/ethnic identity and that their use can be attributed only to a particular period. However, while excavating the cuttings at Indor Khera, which we dated from the tenth/eleventh to thirteenth/fourteenth centuries CE, we realized that not only was such a neat demarcation not evident in the material culture, but that the problem was far more complex and had not quite received the attention it deserved from archaeologists. This article discusses the issue of ascribing religious and ethnic identities to artefacts.
‘Rights over Wastelands’ and New Narratives of the Paraiyan Past (1860–1900)
Authors: Basu Raj Sekhar
Published: July 2009

The rural world of nineteenth-century Tamil Nadu was highly diversified in terms of land control and ownership. Academic efforts have largely focused on the various claims to ‘privileged’ land-ownership. This overemphasis on the authority, rights, claims and protests of the ‘privileged’ too often negated the prospects of a serious introspection into the twin issues of agrestic servitude and landlessness. The present article is concerned with one group of rural labourers, who in nineteenth-century Tamil Nadu were essentially regarded as ‘agrestic serfs’. The Paraiyans were mostly landless labourers and depended for their livelihood on the dominant rural groups. Their existence as a depressed social category, denied of all privileges including landownership, provokes a serious investigation into the operation and mechanism of the institution of mirasi in the Tamil country. The definition of ‘waste’ was mired in terms of complexities emanating from the classification of lands, which were essentially referred to as anadu karambu or gramanattams. These complexities in course of the nineteenth century had fashioned differing sets of opinions within the conservative and reformist sections of the colonial bureaucracy. Such contradictions alongside discussions on the hidden ‘Paraiyan history’ have been explored to understand the broader issues centring around the ‘Sedentary Paraiyan’ as well as the ‘Slave Paraiyan’.
Scale appropriate modelling of diffuse microbial pollution from agriculture
Authors: Oliver David M. , Heathwaite A. Louise , Fish Rob D. , Chadwick Dave R. , Hodgson Chris J. , Winter Michael , Butler Allan J.
Published: July 2009

The prediction of microbial concentrations and loads in receiving waters is a key requirement for informing policy decisions in order to safeguard human health. However, modelling the fate and transfer dynamics of faecally derived microorganisms at different spatial scales poses a considerable challenge to the research and policy community. The objective of this paper is to critically evaluate the complexities and associated uncertainties attributed to the development of models for assessing agriculturally derived microbial pollution of watercourses. A series of key issues with respect to scale appropriate modelling of diffuse microbial pollution from agriculture is presented, and these include: (1) appreciating inadequacies in baseline sampling to underpin model development; (2) uncertainty in the magnitudes of microbial pollutants attributed to different faecal sources; (3) continued development of the empirical evidence base in line with other agricultural pollutants; (4) acknowledging the value of interdisciplinary working; and (5) beginning to account for economics in model development. It is argued that uncertainty in model predictions produces a space for meaningful scrutiny of the nature of evidence and assumptions underpinning model applications around which pathways towards more effective model development may ultimately emerge.
Turning Adolescents Into Analysts of Their Own Discourse: Raising Reflexive Awareness of Everyday Talk to Develop Peer-Based Health Activities
Authors: Lamerichs Joyce , Koelen Maria , te Molder Hedwig
Published: July 2009

Adopting principles applied in discursive psychology and translated to suit the practice of participatory health education, we describe in this article the five steps of the discursive action method (DAM). With this method, adolescents are stimulated to explore their own everyday conversations to become consciously aware of how they talk about health issues with their peers. Using detailed accounts of adolescents' experiences with the method, we present some first indications of the kinds of results this method can achieve. We show that the strength of the method specifically lies in two closely related domains: (a) stimulating adolescents' attentiveness to interactional problems and strategies as they occur in their own everyday talk, and (b) operating as a catalyst for developing participatory health activities aimed at peers.
The Changing Nature of the Academic Deanship
Authors: de Boer Harry , Goedegebuure Leo
Published: July 2009

The university as an organization is changing, incorporating elements of private sector management in an academic setting. In these transforming universities middle management has changed as well. In this contribution changes in the role and position of the academic deanship are analysed in more detail. On the basis of a literature review, a description of the deanship is provided, including the main challenges this position entails. It is argued that the deanship has become more demanding, more senior, more strategic, more complex and more managerial in nature, though within the overall context of academe. We illustrate both the complexity and changing nature of the deanship by drawing on two empirical studies. Since research on middle management in universities is still rather thin, more research is welcome. Therefore we conclude with some suggestions for further research to enhance our understanding of what we see as a key management position within today's universities.
Neutrophils express CD52 and exhibit complement-mediated lysis in the presence of alemtuzumab
Authors: Ambrose Lyn R. , Morel Anne-Sophie , Warrens Anthony N.
Published: July 2009

Neutropenia is a recognized adverse event in patients treated with the humanized anti-CD52 monoclonal antibody alemtuzumab. However, as it is widely believed that neutrophils do not express CD52, the etiology of alemtuzumab-associated neutropenia is unclear. We have found that neutrophils express both mRNA coding for CD52 and the protein itself on the cell surface. We confirmed cell-surface expression using 3 different anti-CD52 antibodies, and note that neutrophils express lower levels of CD52 than lymphocytes and eosinophils. Further, incubation of alemtuzumab with neutrophils results in dose-dependent, complement-mediated lysis in the presence of both heterologous and autologous complement. These data offer an explanation for the etiology of alemtuzumab-associated neutropenia. In a climate of increased use of alemtuzumab in leukemia and other disease states, as well as in transplantation, these data highlight the need for increased vigilance of emerging neutropenia in patients treated with alemtuzumab.
Regulation of mitotic spindle formation by the RhoA guanine nucleotide exchange factor ARHGEF10
Authors: Aoki Takuji , Ueda Shuji , Kataoka Tohru , Satoh Takaya
Published: July 2009

Background

The Dbl family guanine nucleotide exchange factor ARHGEF10 was originally identified as the product of the gene associated with slowed nerve-conduction velocities of peripheral nerves. However, the function of ARHGEF10 in mammalian cells is totally unknown at a molecular level. ARHGEF10 contains no distinctive functional domains except for tandem Dbl homology-pleckstrin homology and putative transmembrane domains.

Results

Here we show that RhoA is a substrate for ARHGEF10. In both G1/S and M phases, ARHGEF10 was localized in the centrosome in adenocarcinoma HeLa cells. Furthermore, RNA interference-based knockdown of ARHGEF10 resulted in multipolar spindle formation in M phase. Each spindle pole seems to contain a centrosome consisting of two centrioles and the pericentriolar material. Downregulation of RhoA elicited similar phenotypes, and aberrant mitotic spindle formation following ARHGEF10 knockdown was rescued by ectopic expression of constitutively activated RhoA. Multinucleated cells were not increased upon ARHGEF10 knockdown in contrast to treatment with Y-27632, a specific pharmacological inhibitor for the RhoA effector kinase ROCK, which induced not only multipolar spindle formation, but also multinucleation. Therefore, unregulated centrosome duplication rather than aberration in cytokinesis may be responsible for ARHGEF10 knockdown-dependent multipolar spindle formation. We further isolated the kinesin-like motor protein KIF3B as a binding partner of ARHGEF10. Knockdown of KIF3B again caused multipolar spindle phenotypes. The supernumerary centrosome phenotype was also observed in S phase-arrested osteosarcoma U2OS cells when the expression of ARHGEF10, RhoA or KIF3B was abrogated by RNA interference.

Conclusion

Collectively, our results suggest that a novel RhoA-dependent signaling pathway under the control of ARHGEF10 has a pivotal role in the regulation of the cell division cycle. This pathway is not involved in the regulation of cytokinesis, but instead may regulate centrosome duplication. The kinesin-like motor protein KIF3B may modulate the ARHGEF10-RhoA pathway through the binding to ARHGEF10.
Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10
Authors: Somayajulu-Niţu Mallika , Sandhu Jagdeep K , Cohen Jerome , Sikorska Marianna , Sridhar TS , Matei Anca , Borowy-Borowski Henryk , Pandey Siyaram
Published: July 2009

Background

Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance.

Results

Here we report that prophylactic application of water-soluble formulation of coenzyme Q10 could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the substantia nigra region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q10 in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats.

Conclusion

Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q10 formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.
Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery
Authors: Sam Wai Johnn , Hammer Gregory B , Drover David R
Published: July 2009

Background

The aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Methods

We studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance.

Results

The pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively.

Conclusion

Remifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 μg remifentanil followed by an infusion of 3.7 μg/min before, during and post-CPB, supplemented with a bolus dose of 25 μg given at the start of CPB.
Streptococcal peritonitis in Australian peritoneal dialysis patients: predictors, treatment and outcomes in 287 cases
Authors: O'Shea Stacey , Hawley Carmel M , McDonald Stephen P , Brown Fiona G , Rosman Johan B , Wiggins Kathryn J , Bannister Kym M , Johnson David W
Published: July 2009

Background

There has not been a comprehensive, multi-centre study of streptococcal peritonitis in patients on peritoneal dialysis (PD) to date.

Methods

The predictors, treatment and clinical outcomes of streptococcal peritonitis were examined by binary logistic regression and multilevel, multivariate poisson regression in all Australian PD patients involving 66 centres between 2003 and 2006.

Results

Two hundred and eighty-seven episodes of streptococcal peritonitis (4.6% of all peritonitis episodes) occurred in 256 individuals. Its occurrence was independently predicted by Aboriginal or Torres Strait Islander racial origin. Compared with other organisms, streptococcal peritonitis was associated with significantly lower risks of relapse (3% vs 15%), catheter removal (10% vs 23%) and permanent haemodialysis transfer (9% vs 18%), as well as a shorter duration of hospitalisation (5 vs 6 days). Overall, 249 (87%) patients were successfully treated with antibiotics without experiencing relapse, catheter removal or death. The majority of streptococcal peritonitis episodes were treated with either intraperitoneal vancomycin (most common) or first-generation cephalosporins for a median period of 13 days (interquartile range 8–18 days). Initial empiric antibiotic choice did not influence outcomes.

Conclusion

Streptococcal peritonitis is a not infrequent complication of PD, which is more common in indigenous patients. When treated with either first-generation cephalosporins or vancomycin for a period of 2 weeks, streptococcal peritonitis is associated with lower risks of relapse, catheter removal and permanent haemodialysis transfer than other forms of PD-associated peritonitis.
Description of familial keloids in five pedigrees: evidence for autosomal dominant inheritance and phenotypic heterogeneity
Authors: Clark Jason A , Turner Maria L , Howard Lillian , Stanescu Horia , Kleta Robert , Kopp Jeffrey B
Published: July 2009

Background

Familial keloids have been reported, having either autosomal dominant or autosomal recessive inheritance. We wished to determine the inheritance pattern and phenotype of keloids among multigenerational families, as a prelude to a positional mapping strategy to identify candidate genes.

Methods

We studied three African American families, one Afro-Caribbean family and one Asian-American family. Phenotyping including assessing all patients for the presence, distribution, and appearance of keloids, together with the timing of keloid onset and provocative factors. The clinical trial was registered at clinicaltrials.gov (NCT 00005802).

Results

Age of keloid onset varied considerably within families, but commonly occurred by the second decade. The fraction of affected individuals was 38%, 45%, 62%, 67% and 73% among the five families respectively. Keloid severity and morphology differed within and between families. A novel finding is that certain families manifest keloids in distinct locations, with one family showing an excess of extremity keloids and two families showing an excess of axilla-groin keloids.

Conclusion

Familial keloids appear to most commonly manifest autosomal dominant or semidominant inheritance, and there may be familial patterns of keloid distribution.