bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ‘allosteric modulator’ SCH‐202676 disrupts G protein‐coupled receptor function via sulphydryl‐sensitive mechanisms
Authors: Lewandowicz Anna M , Vepsäläinen Jouko , Laitinen Jarmo T 
Published: January 2006

Previous studies suggest that the thiadiazole compound SCH‐202676 (N‐(2,3‐diphenyl‐1,2,4‐thiadiazol‐5‐(2H)‐ylidene)methanamine) acts as an allosteric modulator of a variety of structurally distinct G protein‐coupled receptors (GPCRs). It was postulated that SCH‐202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family. The molecular mechanisms of such a promiscuous action, however, remain obscure.
To clarify the mechanism of SCH‐202676 action, we used the functional approach of [35S]GTPγS autoradiography with rat brain cryostat sections together with classical membrane [35S]GTPγS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi‐family of G proteins.
We found that in the absence of dithiotreitol (DTT), SCH‐202676 (10−7–10−5 M) elicits nonspecific effects in the [35S]GTPγS‐based G protein activation assays, thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor‐mediated G protein activity. Such a nonspecific behaviour was fully reversed upon addition of DTT (1 mM), revealing thiol‐based mechanism of action.
In routine incubations containing DTT, SCH‐202676 had no effect on receptor‐driven G protein activity, as assessed for adenosine A1, α2‐adrenergic, cannabinoid CB1, lysophosphatidic acid LPA1, muscarinic M2/M4, purinergic P2Y12 or sphingosine 1‐phosphate receptors, suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function.
1H NMR analysis indicated that SCH‐202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue.
We conclude that SCH‐202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms.

British Journal of Pharmacology (2006) 147, 422–429. doi:10.1038/sj.bjp.0706624
A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen‐containing bisphosphonates
Authors: Mönkkönen Hannu , Auriola Seppo , Lehenkari Petri , Kellinsalmi Maarit , Hassinen Ilmo E , Vepsäläinen Jouko , Mönkkönen Jukka 
Published: January 2006

Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. On the basis of their molecular mechanism of action, bisphosphonates can be divided into two pharmacological classes; nitrogen‐containing (N‐BPs) and non‐nitrogen‐containing bisphosphonates (non‐N‐BP). Both classes induce apoptosis but they evoke it differently; N‐BPs by inhibiting the intracellular mevalonate pathway and protein isoprenylation, and non‐N‐BPsviacytotoxic ATP analog‐type metabolites. N‐BPs are not metabolized to ATP analogs, but we report here that these bisphosphonates can induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of the mevalonate pathway in cells. We also investigated whether ApppI is involved in the apoptosis induced by N‐BPs.Mass spectrometry and NMR were used to identify ApppI in N‐BP treated osteoclasts, macrophages and glioma cells. The potency of different bisphosphonates to promote ApppI production was tested in J774 macrophages. The effects of ApppI on ADP/ATP translocase in isolated mitochondria and its capability to induce apoptosis in osteoclasts were also studied.ApppI production correlated well with the capacity of N‐BPs to inhibit mevalonate pathway. ApppI inhibited the mitochondrial ADP/ATP translocase and caused apoptosis in osteoclasts.In conclusion, these findings provide the basis for a new mechanism of action for N‐BPs. Some of these very potent bisphosphonates, such as zoledronic acid, represent a third class of bisphosphonates that can act bothviathe inhibition of the mevalonate pathway and by the blockade of mitochondrial ADP/ATP translocase, which is known to be involved in the induction of apoptosis.British Journal of Pharmacology(2006)147, 437–445. doi:10.1038/sj.bjp.0706628
Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro
Authors: Abe Mineo , Kuroda Yoshihiro , Hirose Munetaka , Watanabe Yoshihiko , Nakano Minoru , Handa Tetsurou 
Published: January 2006

Inhibition of uncontrolled epidermal growth factor receptor (EGFR) is one of the approaches for the treatment of breast and lung cancers. We designed oligopeptides consisting of amino‐acid sequences of the major (Y1068, Y1148, and Y1173) and minor (Y992) autophosphorylation sites of EGFR. These peptides may be exogenous substrates or pseudosubstrates that interfere with the autophosphorylation of EGFR. The effects of the peptides on autophosphorylation of EGFR were studied.
Purified EGFR was phosphorylated in vitro with EGF in the presence of various synthetic peptides. The phosphorylation level of EGFR was then evaluated after SDS–PAGE separation, followed by Western blot analysis with antiphosphotyrosine antibody.
Ac‐VPEYINQ‐NH2 (Y1068) and Ac‐DYQQD‐NH2 (Y1148) showed the most potent inhibitory effects, followed by Ac‐ENAEYLR‐NH2 (Y1173). These peptides at 4 mM suppressed phosphorylation to 30–50%.
Combination of the three kinds of peptides much more strongly inhibited autophosphorylation. The 50% inhibitory concentration (IC50) value was 0.5 mM as a mixture and was comparable to that of AG1478 (IC50, 0.3 mM) at 0.2 mM ATP.
Neither Ac‐DIYET‐NH2 or Ac‐KIYEK‐NH2, designed previously based on the amino‐acid sequence of an autophosphorylation site of insulin receptor, nor their related (Ac‐KIFMK‐NH2) or unrelated (Ac‐LPFFD‐NH2) peptides showed an inhibitory effect. These results suggest that the small peptides that originated from the autophosphorylation sites of EGFR interact solely with EGFR.
The peptides containing the sequences surrounding Y1068, Y1148, and Y1173 may be a promising seed for the development of therapeutic agents for breast and lung cancers.

British Journal of Pharmacology (2006) 147, 402–411. doi:10.1038/sj.bjp.0706634
Impact of an Infection Control Program in an Intensive Care Unit in France
Authors: Verdier Régis , Parer Sylvie , Jean-Pierre Hélène , Dujols Pierre , Picot Marie-Christine 
Published: January 2006

Objective.To evaluate the impact of an infection control program in an intensive care unit (ICU).Design.Prospective before-after study. Two 6-month study periods were compared; between these periods, an infection control program based on isolation was implemented.Setting.Polyvalent ICU of Montpellier Teaching Hospital.Patients.Any patient who was hospitalized in the ICU for >48 hours and was discharged during 1 of the 2 periods.Main Outcome Measures.The main patient-related variables were sex, age at admission, type of patient (surgical, medical, or trauma), Simplified Acute Physiology Score II, length of ICU stay, need for intubation, duration of exposure to invasive devices, onset of nosocomial infection and pathogens responsible, and death. We compared the 2 study periods with respect to the incidence of 4 nosocomial infections (pneumonia, urinary tract infection, bacteremia, and catheter-associated infection), the frequency of infection with the main multidrug-resistant pathogens, and patient survival.Results.Patients in periods 1 and 2 were similar with regard to sex, age, physiology score, and exposure to invasive devices. The rates of infection with multidrug-resistant pathogens were significandy lower during period 2 than during period 1 (infection rate: 28.1% of patients in period 1 and 9.6% of patients in period 2 [P = .01]; pneumonia rate: 32.6% of patients in period 1 and 4.2% of patients in period 2 [P = .008]). The mortality rate among patients with nosocomial pneumonia was 38.2% in period 1 and 4.3% in period 2 (P = .009).Conclusions.After implementation of an infection control program, the rate of infection with multidrug-resistant pathogens decreased, as did the mortality rate among patients with nosocomial pneumonia.
A Prospective Trial of a Novel, Silicone-Based, Silver-Coated Foley Catheter for the Prevention of Nosocomial Urinary Tract Infections
Authors: Srinivasan Arjun , Karchmer Tobi , Richards Ann , Song Xiaoyan , Perl Trish M. 
Published: January 2006

Objective.To evaluate the efficacy of silicone-based, silver ion–impregnated urinary catheters in the prevention of nosocomial urinary tract infections (NUTIs).Design.Prospective, crossover study to compare the efficacy of a silicone-based, hydrogel-coated, silver-impregnated Foley catheter with that of a silicone-based, hydrogel-coated catheter in the prevention of NUTIs.Setting.Adult medical and surgical wards of a university teaching hospital.Results.A total of 3,036 patients with catheters were evaluated; 1,165 (38%) of the catheters were silver impregnated, and 1,871 (62%) were not silver impregnated. Study groups were not identical; there were more men, a shorter duration of catheterization, and fewer urine cultures per 1,000 catheter-days in the silver catheter group. The rate of NUTIs per 1,000 Foley-days was 14.29 in the silver catheter group, compared with 16.15 in the nonsilver catheter group (incidence rate ratio, 0.88; 95% confidence interval, 0.70-1.11;P= .29). The median length of catheterization prior to the onset of a urinary tract infection (ie, exposure time) was 4 days for each group. There were no differences in the recovery of gram-positive, gram-negative, or fungal organisms in NUTIs. In a multivariate survival analysis, no factors, including silver catheters, were protective against NUTI.Conclusions.Unlike previous trials of latex-based, silver ion–impregnated Foley catheters, we found that silicone-based, silver-impregnated Foley catheters were not effective in preventing NUTIs; however, this study was affected by differences in the study groups. Prospective trials remain important in assessing the efficacy and cost-effectiveness of new silver-coated products.
Knowledge About HIV Infection and Attitude of Nursing Staff Toward Patients With AIDS in Iran
Authors: Askarian Mehrdad , Hashemi Zohreh , Jaafari Peyman , Assadian Ojan 
Published: January 2006

Background.Although adequate knowledge about HIV infection and effective antitransmission measures, such as taking universal precautions in the handling of blood and other body fluids, are important factors in minimizing the risk of HIV transmission in the healthcare setting, little has been reported on the knowledge of nurses with regard to HIV infection and their attitude toward patients with AIDS in Iran. The aim of the present study was to assess these matters.Methods.A questionnaire-based cross-sectional study was conducted from March to April 2003. Included were 1098 nursing staff (registered nurses, registered midwives, and auxiliary nurses) from 8 university teaching hospitals affiliated with the Shiraz University of Medical Sciences.Results.Registered nurses and midwives had a significantly higher level of knowledge about HIV infection than did auxiliary nurses (χ2 = 16.4; df = 1; P<.001). With regard to the causative agent of AIDS, nurses holding a bachelor of science in nursing or a master of science in nursing (MSN) had a significantly higher level of knowledge than did auxiliary nurses (χ2 = 18.6; df = 1; P<.001). Women more often answered correctly that it is not possible to identify HIV-infected patients by their appearance during the early stages of disease than did men (χ2 = 17.52; df= 1; P<.001). Although 50.7% of respondents had previously cared for patients with AIDS and 54.3% had participated in education programs on AIDS, nearly half stated that they would not want to have to care for patients with AIDS and that, if assigned to care for such a patient, they would ask to be assigned elsewhere.Conclusions.Our finding that those who scored best on the questionnaire were midwives and single female nurses holding an MSN who had previously cared for HIV-infected patients scored best might indicate that use of selective education campaigns is the most suitable education strategy. The effectiveness of targeted education programs on HIV/AIDS should be repeatedly evaluated in the future.
Disinfection of Needleless Catheter Connectors and Access Ports With Alcohol May Not Prevent Microbial Entry: The Promise of a Novel Antiseptic-Barrier Cap
Authors: Menyhay Steve Z. , Maki Dennis G. 
Published: January 2006

Background.Needleless valve connectors for vascular catheters are widely used throughout the United States because they reduce the risk of biohazardous injuries from needlesticks and exposure to bloodborne pathogens, such as human immunodeficiency virus and hepatitis C virus. Patients with long-term central venous catheters are at significant risk of acquiring catheter-related bloodstream infections caused by microbes that gain access through the connection between the administration set and the catheter or an injection port. Most healthcare practitioners wipe the membranous septum of the needleless connector or the injection port with 70% alcohol before accessing it. We report a simulation study of the efficacy of conventional alcohol disinfection before access, compared with that of a novel antiseptic-barrier cap that, when threaded onto a needleless luer-activated valved connector, allows a chlorhexidine-impregnated sponge to come into continuous contact with the membranous surface; after removal of the cap, there is no need to disinfect the surface with alcohol before accessing it.Methods.One hundred five commercial, needleless luer-activated valved connectors, each accessible by a blunt male-connector luer-lock attachment, were purchased from 3 manufacturers and were tested. The membranous septum of each test device was first heavily contaminated with ~105colony-forming units ofEnterococcus faecalisand then was allowed to dry for 24 hours. Fifteen of the contaminated devices were not disinfected (positive controls), 30 were conventionally disinfected with a commercial 70% alcohol pledget, and 60 had the antiseptic cap threaded onto the connector and then removed after 10 minutes. The test connectors were then accessed with a sterile syringe containing nutrient broth media, which was injected, captured on the downstream side of the intraluminal fluid pathway, and cultured quantitatively.Results.All 15 control connectors (100%) showed massive transmission of microorganisms across the membranous septum (4,500-10,000 colony-forming units). Of the 30 connectors accessed after conventional disinfection with 70% alcohol, 20 (67%) showed transmission of microorganisms (442-25,000 colony-forming units). In contrast, of the 60 connectors cultured after application of the novel antiseptic cap, only 1 (1.6%) showed any transmission of microorganisms (P<.001).Conclusions.The findings of this study show that, if the membranous septum of a needleless luer-activated connector is heavily contaminated, conventional disinfection with 70% alcohol does not reliably prevent entry of microorganisms. In contrast, the antiseptic-barrier cap provided a high level of protection, even in the presence of very heavy contamination. This novel technology deserves to be studied in a clinical trial.
Effect of protracted treatment with rosiglitazone, a PPARγ agonist, in patients with Cushing's disease
Authors: Giraldi Francesca Pecori , Scaroni Carla , Arvat Emanuela , De Martin Martina , Giordano Roberta , Albiger Nora , Leao Adriana A. S. , Picu Andreea , Mantero Franco , Cavagnini Francesco 
Published: January 2006

SummaryObjective  Cushing's disease, hypercortisolism due to a pituitary ACTH‐secreting tumour, is a highly morbid illness as yet without effective medical therapy. Recent studies have demonstrated that peroxisome proliferator‐activated receptor gamma (PPARγ) agonists effectively suppress ACTH secretion in a murine tumoral corticotroph cell line, but the few studies conducted so far in patients with ACTH‐secreting pituitary adenomas have yielded variable results.Design  Ten patients with Cushing's disease were treated with 4–16 mg rosiglitazone p.o. daily for 1–8 months (median 3 months) and plasma ACTH and cortisol, urinary free cortisol (UFC), as well as parameters of insulin sensitivity, were recorded. An acute challenge with 8 mg rosiglitazone for 2 days preceded long‐term rosiglitazone administration.Results  The acute challenge with rosiglitazone did not significantly modify plasma ACTH and cortisol levels. During protracted treatment with rosiglitazone, four patients showed a persistent reduction in UFC levels (up to 24% of pretreatment values), achieving normalization in three. In the others, UFC as well as plasma ACTH and cortisol decrements were inscribed within wide, random oscillations indicating that disease activity was substantially unchanged. Insulin sensitivity was ameliorated in most patients, without relation to ACTH or cortisol secretion. Untoward effects, such as weight gain, oedema and worsening of ecchymoses, were reported in several patients.Conclusions  Although effective in a subset of patients, protracted rosiglitazone administration did not consistently restrain ACTH and cortisol secretion in patients with Cushing's disease. Further investigations are needed to fully define the therapeutic potential of PPARγ agonists in this disorder.
Application of a variance decomposition method to compare satellite and aerial inventory data: a tool for evaluating wildlife–habitat relationships
Authors: BROWN G. S. , RETTIE W. J. , MALLORY F. F. 
Published: January 2006

Summary

Researchers frequently rely on forest inventories derived for other purposes when characterizing wildlife–habitat associations. When studied populations are remote and inventory coverage is incomplete for one or more data sets, researchers must often choose between the need for greater detail in habitat information and complete coverage of the land base. Forest inventories are often limited to canopy‐level information; however, different aspects of the overstorey and understorey may be important to wildlife.
We compared the explanatory power of a forest resource inventory (FRI) and Landsat‐derived inventory to account for variation in vegetation communities available to woodland caribou Rangifer tarandus caribou. Forest canopy and understorey data were collected from stands in the Clay Belt region of Ontario, Canada, and cluster analysis and ordination were used to identify discrete community types.
Canonical correspondence analysis revealed strong relationships between forest inventories and vegetation communities derived from field data. The integration of field‐based species and structural data with remote sensing land cover information provided sufficient detail among vegetation communities to identify features of known importance to woodland caribou. Variance decomposition revealed that FRI and Landsat variables had different capacities to explain variation in community composition, and overlap existed in the explanatory power. FRI species factors had greater explanatory power than Landsat habitat classes; however, Landsat structural variables accounted for more variation than FRI structural variables.
Synthesis and applications. The results support the use of forest inventory attributes to infer vegetation characteristics in the overstorey and understorey, thus providing a tool for wildlife–habitat management. The need to account for woodland caribou habitat needs in forest management planning can be facilitated by using readily available vegetation descriptions within the FRI and Landsat data sets. This approach to community classification is of particular benefit for characterizing wildlife habitat in remote areas where collection of detailed vegetation information is impractical. When using habitat inventories derived from different data sources, variance decomposition can aid the researcher in identifying how explanatory power is structured within different data sets, quantifying the independent and confounded components of explained variation.
Assessing river biotic condition at a continental scale: a European approach using functional metrics and fish assemblages
Authors: PONT D. , HUGUENY B. , BEIER U. , GOFFAUX D. , MELCHER A. , NOBLE R. , ROGERS C. , ROSET N. , SCHMUTZ S. 
Published: January 2006

Summary

The need for sensitive biological measures of aquatic ecosystem integrity applicable at large spatial scales has been highlighted by the implementation of the European Water Framework Directive. Using fish communities as indicators of habitat quality in rivers, we developed a multi‐metric index to test our capacity to (i) correctly model a variety of metrics based on assemblage structure and functions, and (ii) discriminate between the effects of natural vs. human‐induced environmental variability at a continental scale.
Information was collected for 5252 sites distributed among 1843 European rivers. Data included variables on fish assemblage structure, local environmental variables, sampling strategy and a river basin classification based on native fish fauna similarities accounting for regional effects on local assemblage structure. Fifty‐eight metrics reflecting different aspects of fish assemblage structure and function were selected from the available literature and tested for their potential to indicate habitat degradation.
To quantify possible deviation from a ‘reference condition’ for any given site, we first established and validated statistical models describing metric responses to natural environmental variability in the absence of any significant human disturbance. We considered that the residual distributions of these models described the response range of each metric, whatever the natural environmental variability. After testing the sensitivity of these residuals to a gradient of human disturbance, we finally selected 10 metrics that were combined to obtain a European fish assemblage index. We demonstrated that (i) when considering only minimally disturbed sites the index remains invariant, regardless of environmental variability, and (ii) the index shows a significant negative linear response to a gradient of human disturbance.
Synthesis and applications. In this reference condition modelling approach, by including a more complete description of environmental variability at both local and regional scales it was possible to develop a novel fish biotic index transferable between catchments at the European scale. The use of functional metrics based on biological attributes of species instead of metrics based on species themselves reduced the index sensitivity to the variability of fish fauna across different biogeographical areas.