We tested this assumption in simulations using four prototypical

We tested this assumption in simulations using four prototypical drug inhibitory mechanisms (fast or slow-inactivated state preference, with either fast or slow binding kinetics) and a kinetic model for sodium channels. Unexpectedly, we found that efficacy in these protocols (e. g., a shift of the “”steady-state slow inactivation curve”), was not a reliable indicator of slow-inactivated state preference. Slowly associating fast-inactivated state-preferring GW3965 in vitro drugs were indistinguishable from slow-inactivated state-preferring drugs. On the other hand, fast-and slow-inactivated state-preferring drugs tended to preferentially affect onset and recovery,

respectively. The robustness of these observations was verified: i) by performing a Monte Carlo study on the effects of randomly modifying model parameters, ii) by testing the same drugs in a fundamentally different model and iii) by an analysis of the effect of systematically changing www.selleckchem.com/products/SB-525334.html drug-specific parameters. In patch clamp electrophysiology experiments we tested five sodium channel inhibitor drugs

on native sodium channels of cultured hippocampal neurons. For lidocaine, phenytoin and carbamazepine our data indicate a preference for the fast-inactivated state, while the results for fluoxetine and desipramine are inconclusive. We suggest that conclusions based on voltage protocols that are used to detect slow-inactivated state preference are unreliable and should be re-evaluated.”
“We report photocurrent (PC) and its complemented

photoluminescence investigations of carrier escape dynamics in multi-layered InAs/GaAs self-assembled quantum selleck chemical dots (QDs) subjected to vertical electric fields. We found a nonlinear dependence of PC on the laser excitation power. This unusual behavior can be tuned by bias voltage. Very well agreement between PC data and theoretical prediction ensures that the accumulation of holes trapped in QDs is responsible for this nonlinearity. It is expected that this laser controlled electronic transport might open many potential applications in optoelectronic devices. (C) 2011 American Institute of Physics. [doi:10.1063/1.3562192]“
“Background: Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disease leading to sensory and motor polyneuropathies, and functional limitations. Liver transplantation is the only treatment for FAP, requiring medication that negatively affects bone and muscle metabolism. The aim of this study was to compare body composition, levels of specific strength, level of physical disability risk, and functional capacity of transplanted FAP patients (FAPTx) with a group of healthy individuals (CON).

Methods: A group of patients with 48 FAPTx (28 men, 20 women) was compared with 24 CON individuals (14 men, 10 women). Body composition was assessed by dual-energy X-ray absorptiometry, and total skeletal muscle mass (TBSMM) and skeletal muscle index (SMI) were calculated.

While

comorbidities, pneumonia severity, and risk factors

While

comorbidities, pneumonia severity, and risk factors for multidrug-resistant infection may interact to produce even higher mortality compared to CAP, they alone do not explain the observed click here differences. (C) 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.”
“This paper summarizes the application of thin-layer chromatography coupled with biodetection for the search of substances characterized with properties relevant to the treatment of neurodegenerative diseases. The main focus is on the screening of plant extracts for the presence of acetycholinesterase inhibitors as well as direct antioxidants, taking into account the cholinergic hypothesis of Alzheimer’s disease and oxidative stress theory of neurodegeneration. Practical aspects of performing TLC-bioassay

tests are discussed and typical problems are addressed. Some practical hints are also given referring to the variety of compound classes that may be analyzed by means of these methods.”
“Traditionally, the information content of the neural response is quantified using statistics of the responses relative CDK inhibitor to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the

archer fish retinal ganglion cell. We found that stimulus identity, “”what”", can be estimated from the responses of best single ISRIB solubility dmso cells with an accuracy comparable to that of the animal’s psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “”when”", can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy.”
“Disseminated Nocardia veterana infection has rarely been reported. We describe the first reported case of N. veterana bacteremic pneumonia in an HIV-infected patient. The isolate was confirmed by 16S rRNA sequencing analysis. The patient initially responded well to trimethoprim-sulfamethoxazole treatment (minimum inhibitory concentration 0.25 mu g/ml), but died of ventilator-associated pneumonia. (C) 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.”
“A series of vegetal extracts have been chemically altered by ethanolysis.


“We have studied by transmission electron microscopy the m


“We have studied by transmission electron microscopy the microstructural effects induced by pulsed laser annealing in comparison with thermal treatments of RF plasma hydrogenated Si wafers aiming for further application

in the smart-cut procedure. While thermal annealing mainly produces a slight decrease of the density of plasma-induced planar defects and an increase of the size and number of plasma-induced nanocavities in the Si matrix, pulsed laser annealing of RF plasma hydrogenated Si wafers with a 355 nm wavelength radiation results in both the healing of defects adjacent to the wafer surface and the formation of a well defined layer of nanometric cavities this website at a depth of 25-50 nm. In this way, a controlled fracture of single crystal layers of Si thinner than 50 nm is favored. (C) 2011 American Institute of Physics. [doi:10.1063/1.3560538]“
“Arterial stroke is the main cause of poor outcome in childhood tuberculous meningitis. Aspirin has an antithrombotic action at low dose and anti-ischemic and anti-inflammatory properties, which are dose-related. The aim of the study was to explore the possible benefits of aspirin in children with tuberculous meningitis. A total of 146 consecutive

children with a diagnosis of probable tuberculous meningitis were studied. Patients selleck chemicals llc were randomized into 3 groups: (1) placebo group, (2) low-dose aspirin group, and (3) high-dose aspirin group. Twenty-nine additional patients who received aspirin before admission were excluded from the randomized study, but continued on low-dose aspirin. Aspirin, irrespective of dose, did not show any significant benefit regarding morbidity (hemiparesis and developmental outcome) and mortality. Aspirin was well tolerated, but 1 death was probably related to aspirin. The fact that the outcome of the high-dose aspirin group compared favorably with the other treatment groups despite younger age and more severe neurological involvement at baseline needs further investigation.”
“Recent advances in immunomagnetic separation DMH1 and flow cytometry have made the

detection and characterization of circulating tumor cells (CTC) a reality. This technology has already demonstrated prognostic significance in breast and prostate cancer. In the current review, we will review the historical and current data regarding the enumeration and identification of CTC in colorectal cancer. With immunomagnetic separation techniques, CTC can reliably and reproducibly be identified within 1 to 2 cells in a 7.5 mL sample of peripheral blood. Prospective studies have demonstrated a significant adverse impact on survival with the presence of a parts per thousand yen3 CTC per 7.5 mL blood. Approximately one quarter of patients with metastatic disease will be categorized in this poor prognosis group. In addition, change in number of cells on treatment has prognostic significance.

The optimal permanent magnetic properties are obtained at x = 2,

The optimal permanent magnetic properties are obtained at x = 2, and the value of H-ci, M-s, M-r, and (BH)(max) are 6.52 kOe, 150.2 emu/g, 120.9 emu/g, and 22.34 MGOe, respectively. Typical magnetization behaviors of nanocomposite magnets are found in these ribbons. The significant remanence enhancement indicates Tariquidar in vitro that a strong intergrain

exchange coupling exists in all ribbons studied in this work. By Co substitution, the intergrain exchange coupling is enhanced significantly. The study of microstructure shows that the larger grains of Pr-2(Fe,Co)(14)B hard phase are surrounded by the smaller grains of alpha-(Fe,Co) soft phase with size about 10-20 nm in the ribbon with Co substitution. This kind of microstructure is in favor of exchange coupling between magnetically hard and soft phases and results in excellent magnetic properties. (c) 2011 American Institute of Physics. [doi:10.1063/1.3566074]“
“In view of the analogous transmembrane function to cell penetrating peptides, guanidine group was incorporated into chitosan by chemical modification to enhance the transfection performance of chitosan vectors. Guanidinylated chitosan (GCS) was shown to be well soluble

in neutral aqueous solution. The interaction between GCS with plasmid DNA was characterized by agarose retardation experiment and ethidium bromide displacement assay. GCS formed more stable complexes selleck chemical with DNA under physiological pH than chitosan. The transfection efficiency of GCS was evaluated employing COS-7 cell line-GCS polyplexes demonstrated higher transfection efficiency and lower cytotoxicity relative to chitosan. The optimum efficiency of GCS was achieved in the vicinity of the critical complexing ratio. The results of flow cytometry indicated that guanidinylation

www.selleckchem.com/products/Temsirolimus.html promoted an eightfold increase in the cell uptake. The study revealed that guanidinylated chitosan is a promising candidate as an effective nonviral vector for in vivo gene delivery. (C) 2011 Wiley Periodicals, Inc. J Appl PolymSci 121: 3569-3578, 2011″
“Purpose: To classify peripheral pulmonary arterial pseudoaneurysms (PAPs) associated with infectious lung diseases according to angiographic findings and to determine treatment options for PAPs on the basis of angiographic classifications.

Materials and Methods: The institutional review board approved this study. A total of 24 patients with massive hemoptysis had PAPs that were detected at pulmonary computed tomographic (CT) angiography; underlying diseases were pulmonary tuberculosis (n = 16), a fungus ball (n = 5), lung abscess (n = 2), and pneumonia (n = 1). All patients underwent bronchial and nonbronchial systemic collateral arterial angiography and pulmonary and selective pulmonary angiography.

Single-nucleotide polymorphisms, both tagging and functional, fro

Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, alpha, beta, and gamma (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple

common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response buy IWR-1-endo to low-sodium intervention (rs4073930, P = 1.7 x 10(-5); rs4073291, P = 1.1 x 10(-5); rs7404408, P = 1.9 x 10(-5); rs5735, P = 3.0 x 10(-4); rs4299163, P = 0.004; and rs4499238, P = 0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention.

Conclusions-This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response

to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity.”
“Purpose of reviewAcute cardiac allograft rejection surveillance has historically ML323 research buy been based on serial endomyocardial biopsy (EMB). Limitations with this approach have stimulated interest in identifying noninvasive surrogate markers of rejection. This review summarizes the evidence assessing the use of direct cardiac markers B-type natriuretic peptide (BNP) and cardiac troponins in detecting acute allograft rejection.Recent findingsBNP, its amino-terminal fragment NT-proBNP, and cardiac troponins T and I have all been extensively evaluated for this purpose, and so far have demonstrated inadequate diagnostic accuracy to replace EMB. Longitudinal surveillance of BNP and NT-proBNP appears to offer promise for improved accuracy, but has not been adequately evaluated in prospective studies. Preliminary investigations into highly sensitive troponin assays suggest a potential role in rejection surveillance, but prospective validation in larger studies is needed.SummaryEMB remains the gold standard for cardiac allograft rejection surveillance. However, recent data indicate potential clinical utility for serial monitoring of natriuretic peptides. If further

investigation into highly sensitive troponin assays confirms the positive data so far reported, further efforts directed toward a longitudinal-based rejection surveillance algorithm Dinaciclib manufacturer incorporating both troponin and BNP may identify a strategy that could serve as an alternative to EMB.”
“Background-The catecholamine release-inhibitor catestatin and its precursor chromogranin A (CHGA) may constitute “”intermediate phenotypes”" in the analysis of genetic risk for cardiovascular disease such as hypertension. Previously, the vacuolar H+-ATPase subunit gene ATP6V0A1 was found within the confidence interval for linkage with catestatin secretion in a genome-wide study, and its 3′-UTR polymorphism T + 3246C (rs938671) was associated with both catestatin processing from CHGA and population blood pressure.

One patient died of disease progression 2 months after curative o

One patient died of disease progression 2 months after curative operation.

The other patient underwent surgery followed by adjuvant irinotecan-containing chemoradiation, and the effect was at least modest. Hence, we recommend adjuvant chemoradiation in locally advanced FUA. Individualizing cancer care of chemoregimens in accordance with the tumor origins may probably be beneficial in FUAs.”
“Various composites of polypropylene (PP) produced using natural fibers such as pineapple leaf fiber, banana fiber, and bamboo fiber were studied AR-13324 cell line for their degree and rate of aerobic biodegradation. Composites used contained 10, 15, and 50% volume fractions of pineapple leaf fiber, banana fiber, and bamboo fiber, respectively, which are the optimum fiber percentages of the respective composites as reported by these authors in their previous works. Cellulose has been used as positive reference material. All the composites exhibited partial biodegradation in the range of 5-15% depending PD173074 mouse on the fiber

content. Degradation had not taken place in the covalent ester linkages between the natural fiber and the MA-g-PP compatibilizer but in those areas of the fibers which have remained only physically embedded in the resin matrix. Thus, although natural fibers reinforced PP composites are not excellent biodegradable material, they can address to the management of waste plastics by reducing the amount of polymer content used that in turn will reduce the generation of nonbiodegradable polymeric wastes. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci 121: 2226-2232, 2011″
“Purpose: To assess the diagnostic performance of computed tomographic (CT) and radiographic (as seen on CT topograms) signs of cecal volvulus.

Materials and Methods: In this institutional review board-approved, HIPAA-compliant retrospective study, the CT and CT topogram findings in 11 patients (one man, 10 women; age range, 26-100 years) with surgically confirmed cecal volvulus and 12 control patients were reviewed. The control subjects had suspicious radiographs, had undergone CT within 24 hours of radiography, and had received a clinical

diagnosis other than cecal volvulus. Three radiologists independently click here evaluated the CT topograms for cecal distention, the coffee bean sign, cecal apex location, and distal colon decompression. CT images were analyzed for cecal distention, cecal apex location, distal colon decompression, and presence or absence of the whirl, ileocecal twist, transition point(s), the X-marks-the-spot, and the split wall. Sensitivity, specificity, and predictive values were computed. Baseline statistical values for the cecal volvulus and control groups were analyzed by using a two-tailed Z test to compare proportions with a threshold confidence interval of 95%. CT findings of bowel ischemia (free air or fluid, pneumatosis intestinalis, portal venous gas, mesenteric stranding) were correlated with pathology report findings.

S , Young, D , Wiersenna, B , Mitchell, S , Rhodes, A G , 2007 T

S., Young, D., Wiersenna, B., Mitchell, S., Rhodes, A.G., 2007. The National CriminaI Justice Treatment Practices Survey: Multi-level Survey methods and procedures. J. Subst. Abuse Treat. 32, 225-238], and includes both adult criminal and juvenile justice samples. Results indicated that

several state organizational characteristics were either associated with more EBP use or interacted with local organizational characteristics in associations with EBP use, including: (I) systems integration at the state level was associated with greater EBP use; (2) state staffing adequacy and stability accentuated the association between local training and resources for new programs Birinapant supplier and EBP use (i.e., in states with better staffing, the relationship between training/resources and EBP use in local facilities was stronger): and (3) state executives’ attitudes regarding the missions and goals of corrections tended to diminish the extent to which corresponding local adminstrator attitudes were associated with EBP use. The Study has implications for future research focused on EBP diffusion and implementation in correctional environments,

particularly attempts to influence EBP use by working through state agencies. (C) 2008 Elsevier Ireland Ltd. All rights reserved.”
“Chitosan beads (CB) possesses low defluoridation capacity (DC) have been Suitably modified by carboxylation followed PXD101 ic50 by chelation with Ce(III) to enhance its DC. The carboxylated chitosan beads PF-6463922 (CCB), which has a desirable DC of 1385 mgF(-)/kg, has been further chemically modified by incorporating Ce 31 ion into CCB (Ce-CCB) and its DC was found to be 4798 mgF-/kg, whereas raw chitosan beads (CB) possesses 52 mgF-/kg only. The maximum DC of Ce-CCB was observed at pH 7 and showed selectivity toward fluoride in presence of other coanions. The sorbent was characterized using FTIR and SEM with EDAX analysis. The sorption data was fitted with Freundlich and Langmuir isotherms and kinetic models.

The calculated thermodynamic parameters, viz., Delta G degrees, Delta H degrees and Delta S degrees indicate the nature of fluoride sorption. A field trial was carried out with fluoride water collected from a nearby fluoride-endemic village to test the suitability of Ce-CCB at field conditions. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 112: 1114-1121, 2009″
“Despite strong interest in improving collaborations between correctional and substance abuse treatment organizations, there is a lack of empirical data describing the existing practices. The Current Study used a national Survey of correctional administrators to examine organizational factors related to cross-agency collaboration and integration activities between corrections and Substance abuse treatment organization.

In fact, our objective was to increase the amount of water that m

In fact, our objective was to increase the amount of water that may be stored by the polymer. In this article, we investigated not only the effect of temperature and pH on the satured water absorbency of polymers X10 and X5, but also various swelling behaviours of polymer CT99021 inhibitor X10 in different saline solutions. The results show that for temperature ranging from 10 to 90 degrees C, the

effect of temperature on the satured water absorbency is rather limited when the superabsorbent is swelled by distilled water. Further, water absorbency of X10 and X5 is strongly affected by the pH value. The results also indicate that saline solutions can weaken the swelling abilities of the polymer X10. Water absorbency of polymer X10 in aqueous chloride salt solutions has the following order: Na(+) = K(+) = NH(4)(+) > Ca(2+) = Mg(2+) all through the range of investigated concentration. (C) 2009 Wiley Periodicals, Inc. J Appl Polym Sci 115: 2479-2484, 2010″
“With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there Sotrastaurin are more adults with CHD than children. This population has many unique issues and needs. Since the 2001 Canadian Cardiovascular Society Consensus Conference

report on the management of adults with congenital heart disease, there have been significant advances in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. Part I of the guidelines includes recommendations for the care

of patients with atrial septal defects, ventricular septal defects, atrioventricular septal defects and patent ductus arteriosus. Topics addressed include genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy risk, and follow-up requirements. The complete document consists of four manuscripts, which are published online in the present issue of The Canadian Journal of Cardiology. The complete document and references can also be found at www.ccs.ca or www.cachnet.org.”
“The objective of this study was to investigate the possible protective effects of maca (Lepidium meyenii) extract (MLE) by supercritical fluid extraction on PLX4032 research buy dextran sodium sulfate (DSS)-induced colitis. Experimental colitis was induced by giving male BALB/c mice 3% DSS in drinking water, and MLE (30 mg/kg BW), sulfasalazine (100 mg/kg BW) or vehicle were administered orally. DSS challenge caused significant body weight loss, rectal bleeding, diarrhea, shortened colon length, histological changes, and increased myeloperoxidase (MPO) activity in DSS-treated mice. Oral administration of MLE significantly relieved the symptoms of diarrhea and rectal bleeding, and reduced colonic MPO activity (p < 0.05).


“Estimation of the size of a cancer group, either through


“Estimation of the size of a cancer group, either through number of cases or extrapolation of past observed trends, is indispensable to the planning of effective assistance measures. The aim of this study was to analyze the mortality trends of human papillomavirus-related cancers in Brazil by sex, in the period 1996-2010, and make predictions until the year 2025. All deaths registered as being a result of cervical cancer (ICD-10 code: C53), as well as those

caused by vulvar and vaginal (C51 and C52), anal (C21), penile (C60), and oropharyngeal (C02, C09, C10) cancers, were registered. Adjusted rate calculations for each year were used to study the trends through the regression program Joinpoint’. Predictions were made using the Nordpred program, utilizing the age-period-cohort model. When analyzing

separately by location, it was observed that penile and anal cancers Src inhibitor in men presented an increasing trend for the entire period with a statistically significant annual percentage change of 4% for anal cancer and 1.4% for penile cancer. Predictions indicate a reduction in the risk of death due to oropharyngeal cancer in men and cervical, vulvar, and vaginal cancers in women. It was observed that the increase in the number of deaths occurs mainly because BMS-754807 solubility dmso of population changes (size and age structure). In terms of risk, an increase is predicted for anal and penile cancers in men

and consequently Nutlin-3 mw an increase in mortality rates is observed for these types of cancers, unlike what is expected for human papillomavirus-related cancers in women.”
“Diagnosis of herpes simplex encephalitis (HSE) is based on the detection of herpes simplex virus (HSV) DNA in patients’ CSF samples. HSV DNA quantitation has the potential for estimating the effects of antiviral therapy. The aim of this study was to diagnose HSV DNA in HSE suspected patients and the quantitative analysis of its genome using real-time PCR to assess the value of the viral load in the course of antiviral treatment. The CSF samples were collected from 236 consecutive HSE suspected patients from November 2004 to May 2008. Upon DNA extraction, the samples were analyzed by Real-Time PCR assay. A set of primers amplified a common sequence of HSV glycoprotein B gene. The copy numbers of unknown samples were expressed via a standard curve drawn with a known amount of amplified cloned plasmid. Of the 236 samples, 137 (58%) came from males and 99 (42%) from females. The HSV genome was detected in 22 (9.3%) patients by PCR, 13 males/9 females. Serial CSF samples were available from 10 of the 22 patients. The range of the HSV DNA copy numbers in the clinical samples ranged from 2.5 x 10(2) to 1.7 x 10(6) copies/mL of CSF.

Mesenchymal stem cells offer an attractive alternative cell-sourc

Mesenchymal stem cells offer an attractive alternative cell-source for cartilage repair, due to their ease of isolation and amenability to ex vivo expansion while retaining stem cell properties. Preclinical and clinical studies have demonstrated the potential of mesenchymal stem cells to promote articular cartilage repair, but have also highlighted several key challenges.

Most notably, the quality and durability of the repair tissue, its resistance to endochondral ossification, and its effective integration with the surrounding host tissue. In addition, challenges exist related to the heterogeneity of mesenchymal stem cell preparations and their quality-control, as well as optimising the delivery method. Finally, as our knowledge of the cellular and molecular mechanisms underlying articular cartilage repair increases, promising studies are emerging employing bioactive scaffolds or therapeutics that elicit an effective tissue www.selleckchem.com/products/defactinib.html repair response this website through activation and mobilisation of endogenous stem and progenitor cells. (C) 2013

Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.”
“In the present paper, the associations between residential traffic noise exposure from the noise sources – road, rail and aircraft – and self-reported indicators of health and well-being are investigated in a representative sample of the Swiss population. The study is based on record linkage of the Swiss GIS Noise Database (Son Base) and the Swiss Household Panel (SHP), a large panel survey with more than 10,000 respondents all over the country. A range of exposure-effect relationships of noise exposure and parameters of health and well-being such as self-reported health status, satisfaction with health, sleep disturbances, the intensity of the wish to move from the current residence as well as the awareness of “”noise problems”" at the place of living were investigated. Both unadjusted as well as models that Elafibranor chemical structure controlled for age, sex, socioeconomic status, degree of urbanization at the

place of residence, and personal living conditions were developed. A contribution of residential noise exposure as regards subjective estimates of health cannot been ruled out, but must be put into perspective as the effects of exposure measures were of rather small magnitude, especially compared to well-established determinants of health. Against the background of the explanatory power of classic health predictors, the present analyses allow one to gage the contribution of residential noise exposure on subjective health outcomes from a more general, integral point of view. (C) 2011 Elsevier Ltd. All rights reserved.”
“Objective: To examine the efficacy of a multidisciplinary non-pharmacological intervention in patients with hand osteoarthritis (OA).

Method: Parallel group randomized controlled trial was performed in three participating rheumatology outpatient clinics in the Netherlands.