HB Nijmegen Research Articles

Healthy decisions: towards uncertainty tolerance in healthcare policy.

The pace of innovation in healthcare is accelerating, and society demands innovative healthcare programmes to become available as soon as possible. Therefore, decisions regarding the use and reimbursement of new programmes need to be made when scientific evidence is by definition still scarce and effectiveness and cost effectiveness are (highly) uncertain. Dealing with uncertainty in healthcare decision making is challenging. First, since not all uncertainties are easily incorporated, generally only some uncertainty is explicitly characterised and presented in assessments [1]. As a consequence, researchers focus on quantifiable uncertainties such as measurement error. The logic of quantification, or ‘‘mathematics of certainty’’ [2], may result in ignoring important uncertainties which are hard or impossible to quantify (such as degree of generalisability of effectiveness to different populations and long-term consequences), causing pseudo-certainty of the results generated. Second, decision makers traditionally resort to science for certainty. Being transparent about uncertainty conflicts with this notion of scientific certainty and is perceived by decision makers as complicating decision making. At the same time, the steep rise in healthcare expenses, combined with the ongoing economic crises, necessitates painful and far-reaching decisions on the allocation of healthcare resources. These decisions are often based on model-based assessments of the comparative (cost)effectiveness of the innovative programme [3]. To account for timely and optimal decisions in the long run, it is crucial that all relevant uncertainties are incorporated in the assessments [4]. These uncertainties need to be identified as soon as possible, before the assessment is performed. This allows for transparent decision-making processes leading to defensible decisions and maintaining or increasing public trust in research results as well as policymaking bodies [5]. Moreover, allowing relevant uncertainties to be neglected in the assessments may stimulate companies to not collect evidence, in order to increase the chances of reimbursement for their product [6]. What is— and, hence, also what is not—assessed sets the agenda and frames the debate [4]. In this commentary, we argue that knowledge and concepts on dealing with uncertainty from other scientific disciplines, such as environmental science and risk governance, can improve the handling of uncertainty in J. P. C. Grutters (&) Department for Health Evidence (HEV 133), Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: janneke.grutters@radboudumc.nl

Erratum: Corrigendum: Rho-directed forces in collective migration

Nat. Cell Biol. 16, 208–210 (2014); published online 28 February 2014; corrected after print 14 March 2014 In the version of this News and Views article originally published, the author affiliations were incorrect. The correct affiliations are as follows: Peter Friedl, Katarina Wolf and Mirjam M. Zegers are in the Department of Cell Biology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

Mevalonate kinase deficiency nomenclature

In the letter of Celsi et al. [1], the authors suggest dropping the names of hyper-IgD syndrome (HIDS) and mevalonate kinase deficiency (MKD) for this hereditary syndrome. They base their conclusion upon the fact that there is no correlation between serum IgD concentration and disease severity, that not all HIDS patients show elevated IgD, and that they do not believe in a causative association with mevalonate kinase. Through the years, several new names for this disease have been used or suggested. It was first called HIDS because of the observation of elevated IgD serum concentrations in patients [2]. It has also been referred to as Dutch-type periodic fever syndrome [3], MKD, and even mevalonate-associated periodic syndrome (MAPS), in analogy with cryopyrin-associated periodic syndrome (CAPS) and TNF receptor-associated periodic syndrome (TRAPS) [4]. We agree that indeed the name HIDS may cause confusion for physicians not familiar with this disease. Although a strongly increased IgD concentration gives a good clue for diagnosis if present, it cannot be used as a diagnostic tool. The name ‘‘MKD’’ also has its drawbacks. Deficiencies in mevalonate kinase lead to a continuum of disease phenotypes, with HIDS at the mild end and the more severe mevalonic aciduria at the other end [5, 6]. Recently, the phenotype associated with deficiency in mevalonate kinase was broadened by discovery of cases of disseminated superficial porokeratosis (DSAP) [7], as well as isolated retinitis pigmentosa [8] associated with mevalonate kinase gene mutations. Sometimes, changing the name of a disease may seem a logical step from the pathophysiological point of view. Accordingly, it is now consensus among specialists to use MKD as the overall name, instead of HIDS, although still specifying the type of disease with the designations HIDS (for the phenotype of fever episodes) or mevalonic aciduria (for the more severely affected patients). However, changing a name causes confusion throughout literature, and as such information to clinicians, researchers, as well as for patients becomes complicated and confusing. This is already very much the case for the field of hereditary autoinflammatory syndromes, making it rather inscrutable for newcomers. This of course is not the purpose of nomenclature. Name changes should be implemented with care, and only when there are solid grounds to do so. We feel that the arguments of the authors of this letter [1] to stop using the name ‘‘MKD’’ are not solid. They mainly base this on in silico SNP data and the suggestion that other novel, previously overlooked genes and mechanisms may play a role in modifying the clinical phenotype. These are merely indications that the pathophysiology of MKD could be more complicated than previously described. This is at present not supported by clinical evidence, and we feel this is not enough reason to reconsider an established concept at this moment. It will actually cause more confusion than anticipated and does not improve understanding at all. These diseases are very rare and not M. Stoffels J. W. M. van der Meer A. Simon (&) Department of Medicine, 463 Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: a.simon@aig.umcn.nl

Tracheal surgery for benign tracheal stenosis: Our experience in sixty three patients

Clinical OtolaryngologyVolume 38, Issue 4 p. 343-347 Correspondence: Our Experience Tracheal surgery for benign tracheal stenosis: Our experience in sixty three patients I.J. Kleiss, I.J. Kleiss Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorA.F.T.M. Verhagen, A.F.T.M. Verhagen Department of Cardio-Thoracic Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorJ. Honings, Corresponding Author J. Honings Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Correspondence: J. Honings, Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel.: +31-24-3540251; Fax: +31-24-3540251; e-mail: [email protected]Search for more papers by this authorO.C.J. Schuurbiers, O.C.J. Schuurbiers Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorH.F.M. van der Heijden, H.F.M. van der Heijden Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorH.A.M. Marres, H.A.M. Marres Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this author I.J. Kleiss, I.J. Kleiss Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorA.F.T.M. Verhagen, A.F.T.M. Verhagen Department of Cardio-Thoracic Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorJ. Honings, Corresponding Author J. Honings Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands Correspondence: J. Honings, Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands. Tel.: +31-24-3540251; Fax: +31-24-3540251; e-mail: [email protected]Search for more papers by this authorO.C.J. Schuurbiers, O.C.J. Schuurbiers Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorH.F.M. van der Heijden, H.F.M. van der Heijden Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this authorH.A.M. Marres, H.A.M. Marres Department of Oto-Rhino-Laryngology and Head & Neck Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsSearch for more papers by this author First published: 28 May 2013 https://doi.org/10.1111/coa.12131Citations: 7Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume38, Issue4August 2013Pages 343-347 RelatedInformation

A “complicated” fracture: a Philadelphia chromosome-positive myeloid sarcoma of the bone

Dear Editor, In April 2009, a 19-year-old male presented with progressive pain on his left upper arm. A MRI scan of the arm showed a large tumor of the distal left humerus (Fig. 1a). Because an osteosarcoma was suspected, a biopsy was performed. After the biopsy, the patient presented with a fracture of his arm as a result of minor trauma. This fracture was managed conservatively with an upper arm cast. The biopsy revealed necrotic bone fragments with an infiltration of myeloblasts admixed with immature eosinophils; hence, the diagnosis of a myeloid sarcoma (MS) was established. Besides the pain in his arm, the patient had no complaints, especially no fever, night sweats, weight loss, hemorrhage, or anemia. On physical examination, neither lymphadenopathy and hepatosplenomegaly nor neurological signs were noticed. His peripheral blood counts were normal. A PET scan did not show any other bone lesion. On histological examination, the MS consisted of myelo/monoblasts with expression of lysozyme, partly weak myeloid peroxidase (MPO), and focally CD34 and CD117. A bone marrow aspirate was performed to exclude acute myeloid leukemia (AML). Morphology of the bone marrow did not support a diagnosis of AML or chronic myeloid leukemia (CML), although with flow cytometric immunophenotyping (IPT), a small population (2 %) of aberrant myeloblasts expressing CD15, CD34, and CD117 were found. Intriguingly, cytogenetic analysis of the bone marrow aspirate showed a Philadelphia chromosome (t(9;22)(q34;q11.2)) in 2 of 13 analyzed cells. Subsequent fluorescence in situ hybridization on the tumor biopsy showed that the blasts harbored the BCR-ABL fusion gene (Fig. 1b). PCR performed on peripheral blood and bone marrow showed BCR-ABL levels of 3.3×10 and 1.5×10 copies/ml, respectively. Because of the bad prognosis, the patient was treated with intensive chemotherapy followed by allogeneic stem cell transplantation (SCT) with peripheral blood stem cells from a matched unrelated donor. The therapy was complemented with local radiotherapy of his left arm. During his treatment, the left arm recovered swiftly, and at the time of SCT, he was no longer depending on the cast. Now 2 years after SCT, he is still in remission with an undetectable BCR-ABL level. MS is a rare disease that is reported in 2.5–9.0 % of patients with AML. It can occur concomitantly, following or, rarely, antedating the onset of systemic AML [1]. MS can also occur in the presence of other hematological diseases such as myelodysplastic syndrome and myeloproliferative neoplasia, including CML [2]. Certain known cytogenetic abnormalities, in particular t(8;21), have been associated with a higher incidence of MS [1, 2]. However, the presence of a Philadelphia chromosome t(9;22) is extremely rare and virtually no reports exist on cases in AML with the remainder almost exclusively occurring during CML blast crisis [2]. The phenotype of MS is mostly monoblastic or myelomonocytic, often expressing CD34, CD68, CD99, CD117, MPO, and TdT [2]. In our patient, the MS had this common L. F. J. van Groningen (*) :W. J. F. M. van der Velden Department of Hematology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands e-mail: l.vangroningen@aig.umcn.nl

What can gut bacteria tell us about colorectal cancer?

*Department of Laboratory Medicine (830), Nijmegen Institute for Infection, Inflammation & Immunity (N4i) and Radboud University Centre for Oncology (RUCO), Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Tel.: +31 24 3618947; Fax: +31 24 3541743; h.tjalsma@labgk.umcn.nl One of the salient features of colonic malignancies is their continuous physical interaction with a dense bacterial population that consists of more than 10 different species [1,2]. In this respect, it may not sound so surprising that both clinical studies and experimental models have directly or indirectly linked the intestinal microbiota, or specific members thereof, to the development of colorectal cancer (CRC) [3]. Several types of evidence provide important information on the impact of host–microbiota interactions during disease development. First, the high bacterial density in the large intestine (~10 cells/ml) compared with the small intestine (~10 cells/ml), is paralleled by an approximate 12-fold increase in cancer incidence in the human colon [4]. Second, inflammatory bowel disease (IBD) patients with a reduced intestinal barrier function, who are thus associated with increased intestinal exposure to microbes, have an approximate fivefold increased risk for CRC [5]. Third, clinical studies have shown that the use of NSAIDs can reduce human CRC by as much as 75% [6]. Fourth, mice that are genetically susceptible to CRC develop significantly less tumors under germ-free conditions [7]. Fifth, it has been shown that toxins from specific gut bacteria can induce DNA damage and increase inflammation, cell proliferation and cancer progression [8,9]. Sixth, bacterial metabolism can generate oxygen radicals that induce DNA damage and chromosomal instability [10]. Seventh, bacterial metabolism of dietary factors was shown to result in the formation of genotoxins and carcinogens [3,11]. Finally, certain infections with opportunistic gut pathogens are s pecifically associated with human CRC [12].

Predictors of Placebo Response in Adults With Attention-Deficit/Hyperactivity Disorder

To find potential correlates of placebo response in adults with attention-deficit/hyperactivity disorder (ADHD) and gain insights into why placebo response may be high in clinical trials. Post hoc analysis of placebo data from 2 randomized controlled trials of osmotic-release oral system (OROS) methylphenidate in adults with ADHD defined according to the Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition: the Long-Acting Methylphenidate in Adults with ADHD (LAMDA-I) study (2005-2006, 5 weeks, n = 95) and the LAMDA-II study (2008-2009, 13 weeks, n = 97). The primary efficacy measure was the Conners' Adult ADHD Rating Scale-observer rated, short version (CAARS:O-SV). Predictors of CAARS:O-SV change were assessed using a random-intercepts model with demographic and disease-related parameters as independent variables. Sensitivity analyses were conducted using the CAARS self-report (CAARS:S-S) and a categorical response criterion (improvement of > 30% in CAARS:O-SV), and in subjects who completed the study. In LAMDA-I, mean ± SD change in CAARS:O-SV was -7.6 ± 9.9 with placebo and -11.9 ± 10.6 with OROS methylphenidate. Higher baseline CAARS score (P = .007) and lower educational achievement (P = .014) were significantly associated with greater improvement in placebo-treated subjects. In LAMDA-II, mean ± SD change in CAARS:O-SV was -10.4 ± 11.0 and -14.1 ± 10.7 in subjects receiving placebo and OROS methylphenidate, respectively. Variables significantly associated with greater placebo response were higher baseline CAARS:O-SV (P = .019), shorter time since ADHD diagnosis (P < .045), and younger age (P = .014). None of the sensitivity analyses challenged the outcomes. Possible predictors of placebo response in adults with ADHD include higher severity of ADHD symptoms, younger age, shorter time since diagnosis, and lower educational level.

Patients with persistent pain after breast cancer surgery show both delayed and enhanced cortical stimulus processing

BackgroundWomen who undergo breast cancer surgery have a high risk of developing persistent pain. We investigated brain processing of painful stimuli using electroencephalograms (EEG) to identify event-related potentials (ERPs) in patients with persistent pain after breast cancer treatment.MethodsNineteen patients (eight women with persistent pain, eleven without persistent pain), who were surgically treated more than 1 year previously for breast cancer (mastectomy, lumpectomy, and axillary lymph node dissection) and/or had chemoradiotherapy, were recruited and compared with eleven healthy female volunteers. A block of 20 painful electrical stimuli was applied to the calf, somatopically remote from the initially injured or painful area. Simultaneously an EEG was recorded, and a visual analog scale (VAS) pain rating obtained.ResultsIn comparison with healthy volunteers, breast cancer treatment without persistent pain is associated with accelerated stimulus processing (reduced P260 latency) and shows a tendency to be less intense (lower P260 amplitude). In comparison to patients without persistent pain, persistent pain after breast cancer treatment is associated with stimulus processing that is both delayed (ie, increased latency of the ERP positivity between 250–310 ms [P260]), and enhanced (ie, enhanced P260 amplitude).ConclusionThese results show that treatment and persistent pain have opposite effects on cortical responsiveness.

Current perspectives to overcome a positive crossmatch in living donor renal transplantation*

Transplantation of a living donor kidney is in general the best treatment option for patients with end-stage renal disease. Two major advantages as compared to transplantation with a deceased donor kidney are the avoidance of waiting time and the superior results in terms of renal function and graft survival. In some patients who are lucky enough to have a person in their neighborhood who are willing to donate a kidney, the transplantation cannot be performed directly because there is ABO blood type incompatibility between donor and recipient, or because of a positive lymphocyte crossmatch, based on the presence of donor-specific antibodies. During recent years, several strategies have been developed to enable transplantation in these cases. A first approach is to use a living donor kidney exchange program, which can result in successful matches in more than half of the crossmatch-positive couples [1]. With the incorporation of kidneys from nondirected, anonymous donors in such an exchange program, domino-paired chains of transplantations can be set up, which end with the transplantation of a living donor kidney to a recipient from the waiting list [2]. However, for a substantial number of recipients, these exchange programs do not result in a successful donor–recipient match. In these cases, desensitization strategies to reduce the titer of ABO blood group antibodies or anti-HLA antibodies can be employed. Desensitization techniques are based on the extracorporeal removal of antibodies, treatment with intravenous immunoglobulins, and on immunosuppressive therapy. Since these procedures carry additional risks for the transplant recipient, desensitization treatment should ideally be reserved for recipients who cannot be served with a donor kidney after several rounds of matching in a (multicenter) exchange program. Unfortunately, kidney exchange programs are not allowed by legislation in every country. In this issue of Transplant International, Morath et al. present the results of living donor kidney transplantation in nine crossmatch-positive patients with peritransplant immunoadsorption (IA) and induction therapy with the anti-CD20 antibody rituximab [3]. Three patients also underwent pretransplant plasmapheresis. In one additional patient with a negative crossmatch but high titers Correspondence L. B. Hilbrands, Department of Nephrology, Radboud University Nijmegen, PO Box 9101, 6500, HB Nijmegen, The Netherlands. E-mail: l.hilbrands@nier.umcn.nl

Endoscopic Endonasal Transsphenoidal Surgery Of Pituitary Tumors

Dr. van Lindert is Neurosurgeon, and Dr. Grotenhuis is Neurosurgeon, Department of Neurosurgery, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands; E-mail: [email protected]. All faculty and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any commercial organizations pertaining to this educational activity. Lippincott Continuing Medical Education Institute, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Lippincott Continuing Medical Education Institute, Inc. designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME article and complete the quiz and evaluation on the enclosed form, answering at least 70% of the quiz questions correctly. This activity expires on January 14, 2012. Category: Tumor

Conceptual analysis and empirical research in medical philosophy and medical ethics

One cannot think of medical practice and medical science without being aware of the phenomena of health and disease (or illness). Since time immemorial health and disease are essential concepts in the philosophy of medicine and health care. It is a long ongoing debate. The concepts of health and disease have been studied and analyzed for decades without reaching any consensus on their content. In the literature, it is argued that the concept of disease is complex, vague, slippery, indefinable, or even dead. In the first paper in this issue, Bjorn Hofmann argues that the arguments for the vagueness, complexity and indefinability of the concept of disease are not overly convincing and that the claim that the concept of disease can be abandoned altogether needs better arguments. His conclusion is that it appears at least as hard to show that disease is indefinable as it is to define it. Marianne Boenink also embarks on the philosophy of disease, especially on the relationship between the emergence of new technologies such as molecular medicine and concepts of disease. It is widely acknowledged that new technologies often not only produce new ‘ontologies’, but also new roles and new ethical responsibilities. The technological constitution of disease raises extensive philosophical debates, but ethical analyses of new biomedical technologies only rarely include conceptual clarification of disease concepts implied by these new technologies. The author argues that it is useful to start with an analysis of concepts of disease which are implied in new emerging technologies, when anticipating ethical issues of biomedical technologies. Thus, a conceptual analysis should precede the ethical debate. The third article in this issue also deals with a conceptual problem. The policy responses to suicide and schizophrenia in the UK—and in many other countries—are predicated on notions of global irrationality as a justification for paternalistic interventions. Jeanette Hewitt argues that it is theoretically possible that suicide may not be an irrational response to the suffering experienced by people with a severe and enduring mental illness and that suicide is not necessarily a consequence of their mental illness per se. What has been conceptualized as ‘‘psychopathological’’ by psychiatric perspectives may be a normal reaction of hopelessness to a realistic appraisal of the course and consequences of living with schizophrenia. However, this point of view does not preclude intervention of any kind to prevent suicide. Also the fourth article in this issue is analytic and argumentative in nature. Dan Egonsson comes up with a new interpretation of the Substituted Judgement Standard (SJS). SJS is commonly understood in a counterfactual and purely hypothetical way culminating in the question what decision the patient here and now would have made, had he or she been competent. Egonsson believes there is another reading in which the emphasis is more on the past, in so far that it bears on the present situation, than on the now. He proposes an alternative, factual, interpretation of the SJS in which the surrogate is required to infer what the patient in the past actually thought about a particular treatment that is being considered. A few decades ago, medical ethics moved from a predominantly theoretical discipline to a discipline that not only explicitly reflects on empirical findings, but also considers empirical research as an important part of its endeavour. The next two articles are in line with this empirical turn in bioethics. Yvonne Denier et al. report about the findings of an empirical, qualitative study based on in-depth interviews with 18 nurses from Flanders W. Dekkers (&) B. Gordijn UMC St Radboud Nijmegen, 114 IQ Healthcare, Section Ethics, PO Box 9101, 6500 HB Nijmegen, The Netherlands e-mail: v.hulsman@iq.umcn.nl

A survey of dynamical complexity in a mean-field nonlinear model of human EEG

Address: 1Brain Sciences Institute (BSI), Swinburne University of Technology, P.O. Box 218, Victoria 3122, Australia, 2Department of Mathematics and Statistics, Faculty of Arts and Sciences, Concordia University, 1455 de Maisonneuve Blvd. W., H3G 1M8 Montreal, Quebec, Canada and 3Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen (Medical Centre), P.O. Box 9101/ /126, 6500 HB Nijmegen, The Netherlands

Emergent phenomena in human EEG: a bifurcation theory approach

Address: 1Brain Sciences Institute (BSI), Swinburne University of Technology, P.O. Box 218, Victoria 3122, Australia, 2Department of Mathematics and Statistics, Faculty of Arts and Sciences, Concordia University, 1455 de Maisonneuve Blvd. W., H3G 1M8 Montreal, Quebec, Canada and 3Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen (Medical Centre), P.O. Box 9101/ /126, 6500 HB Nijmegen, The Netherlands

The Effect of Spreader Grafts on Nasal Dorsal Width in Patients With Nasal Valve Insufficiency

The Effect of Spreader Grafts on Nasal Dorsal Width in Patients With Nasal Valve Insufficiency

Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies directed against various nuclear autoantigens, particularly against components of chromatin, such as doublestranded DNA (dsDNA), histones, nucleosomes, and ribonucleoproteins. Lupus nephritis, a severe clinical manifestation of SLE, is generally associated with high titers of antinuclear antibodies, especially antibodies against chromatin, and with immunoglobulin and complement deposits in the glomerulus. Historically, the formation of antibodies against dsDNA has been considered the serologic hallmark of SLE (1), and anti-dsDNA antibodies are found in the majority of SLE patients (2). In recent years, it has become clear that the nucleosome is the driving autoantigen in SLE (3), and some investigators claim that the presence of antinucleosome antibodies could serve as a better marker for SLE than anti-dsDNA antibodies, since the former are present in up to 90% of lupus patients (4,5). In SLE patients and in lupus-prone mice, nucleosomes can be found in the circulation; they are released from apoptotic cells and are present as a result of either disturbed apoptosis or a defective mechanism for clearing of apoptotic cells (3). Chromatin is basically defined as the entire complex of compacted DNA and associated proteins. The nucleosome is the fundamental unit of chromatin. The core nucleosome particle consists of 146 bp of dsDNA, wrapped twice around a histone octamer (2 copies of each of the core histones H2A, H2B, H3, and H4) (6). Antibodies against epitopes on the nucleosome, called nucleosome-specific antibodies, have no or very low reactivity against individual histones or naked dsDNA. The formation of nucleosome-specific antibodies precedes the appearance of anti-dsDNA and antihistone antibodies as a result of epitope spreading. Anti-dsDNA and antihistone antibodies bind to dsDNA and histones, respectively, but also to nucleosomes (7). A serious topic of debate for several decades involves the pathogenicity, and especially the nephritogenicity, of anti-dsDNA antibodies. DNA itself is not immunogenic, and immunization of mice with naked dsDNA leads to rapid removal, mainly through the liver. Nevertheless, anti-dsDNA antibody levels often show a high correlation with disease activity, especially in lupus nephritis, and elucidating their pathogenic properties is thus of great interest. Therefore, the targets of antidsDNA antibodies have been intensively studied to gain clues to mechanisms that could explain the pathogenicity of anti-dsDNA antibodies in SLE. With regard to their role in the development of lupus nephritis, many investigators postulate that antidsDNA antibodies localize in the glomerular basement membrane (GBM) due to direct cross-reactive binding to intrinsic glomerular antigens (mechanism 1), whereas, in our opinion, glomerular localization of anti-dsDNA antibodies is mediated via nucleosomes, which bind to heparan sulfate (HS) in the GBM (mechanism 2). These two hypotheses may not be mutually exclusive, and until recently, there was no unequivocal proof for either of the two proposed mechanisms. In this review, we will discuss the pros and cons of each of these mechanisms, taking into account recent pertinent observations by Supported by the Dutch Kidney Foundation (grant C05.2119), the PhD student program of the Radboud University Nijmegen Medical Centre, the Health and Rehabilitation Organization, Norway (grant 2001/2/0235), and Oslo Sanitetsforening and Skibsreder Tom Wilhelmsens Stiftelse. Casandra C. van Bavel, MSc, Johan van der Vlag, PhD, Jo H. Berden, MD, PhD: Nijmegen Centre for Molecular Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Kristin A. Fenton, PhD: University of Tromso, Tromso, Norway; Ole P. Rekvig, MD, PhD: University of Tromso, and University Hospital of North Norway, Tromso, Norway. Address correspondence and reprint requests to Jo H. Berden, MD, PhD, Division of Nephrology (464), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: J.Berden@nier.umcn.nl. Submitted for publication November 8, 2007; accepted in revised form April 14, 2008.

Ehlers–Danlos syndrome due to tenascin‐X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies

American Journal of Medical Genetics Part AVolume 143A, Issue 18 p. 2215-2219 Correspondence Ehlers–Danlos syndrome due to tenascin-X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies† N.C. Voermans, Corresponding Author N.C. Voermans n.voermans@neuro.umcn.nl Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsNeuromuscular Centre Nijmegen, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.Search for more papers by this authorG.J. Jenniskens, G.J. Jenniskens Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorB.C. Hamel, B.C. Hamel Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorJ. Schalkwijk, J. Schalkwijk Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorP. Guicheney, P. Guicheney Inserm, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Université Pierre et Marie Curie-Paris 6, UMR S582, IFR14 Paris, FranceSearch for more papers by this authorB.G. van Engelen, B.G. van Engelen Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this author N.C. Voermans, Corresponding Author N.C. Voermans n.voermans@neuro.umcn.nl Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsNeuromuscular Centre Nijmegen, Department of Neurology, 935, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.Search for more papers by this authorG.J. Jenniskens, G.J. Jenniskens Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorB.C. Hamel, B.C. Hamel Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorJ. Schalkwijk, J. Schalkwijk Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this authorP. Guicheney, P. Guicheney Inserm, U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Université Pierre et Marie Curie-Paris 6, UMR S582, IFR14 Paris, FranceSearch for more papers by this authorB.G. van Engelen, B.G. van Engelen Neuromuscular Centre Nijmegen, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The NetherlandsSearch for more papers by this author First published: 17 August 2007 https://doi.org/10.1002/ajmg.a.31899Citations: 36 † How to cite this article: Voermans NC, Jenniskens GJ, Hamel BC, Schalkwijk J, Guicheney P, van Engelen BG. 2007. Ehlers–Danlos syndrome due to tenascin-X deficiency: Muscle weakness and contractures support overlap with collagen VI myopathies. Am J Med Genet Part A 143A:2215–2219. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume143A, Issue1815 September 2007Pages 2215-2219 RelatedInformation

AL amyloidosis enhances development of amyloid A amyloidosis

British Journal of DermatologyVolume 156, Issue 4 p. 748-749 AL amyloidosis enhances development of amyloid A amyloidosis J.C.H. Van Der Hilst, J.C.H. Van Der Hilst Departments of General Internal Medicine (463)Search for more papers by this authorJ.W.M. Van Der Meer, J.W.M. Van Der Meer Departments of General Internal Medicine (463)Search for more papers by this authorJ.P.H. Drenth, J.P.H. Drenth Gastroenterology and Hepatology, Radboud University Medical Centre St Radboud, Geert Grooteplein 8, PO Box 9101, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorA. Simon, A. Simon Departments of General Internal Medicine (463) National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, U.S.A. E-mail: j.vanderhilst@aig.umcn.nlSearch for more papers by this author J.C.H. Van Der Hilst, J.C.H. Van Der Hilst Departments of General Internal Medicine (463)Search for more papers by this authorJ.W.M. Van Der Meer, J.W.M. Van Der Meer Departments of General Internal Medicine (463)Search for more papers by this authorJ.P.H. Drenth, J.P.H. Drenth Gastroenterology and Hepatology, Radboud University Medical Centre St Radboud, Geert Grooteplein 8, PO Box 9101, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorA. Simon, A. Simon Departments of General Internal Medicine (463) National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, U.S.A. E-mail: j.vanderhilst@aig.umcn.nlSearch for more papers by this author First published: 30 January 2007 https://doi.org/10.1111/j.1365-2133.2006.07709.xCitations: 7 Conflicts of interest: none declared. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume156, Issue4April 2007Pages 748-749 RelatedInformation

Cleavage and proteasome-mediated degradation of the basal transcription factor TFIIA.

The transcription factor TFIIA is encoded by two genes, TFIIAalphabeta and TFIIAgamma. In higher eukaryotes, the TFIIAalphabeta is translated as a precursor and undergoes proteolytic cleavage; the regulation and biological implications of the cleavage have remained elusive. We determined by Edman degradation that the TFIIAbeta subunit starts at Asp 278. We found that a cleavage recognition site (CRS), a string of amino acids QVDG at positions -6 to -3 from Asp 278, is essential for cleavage. Mutations in the CRS that prevent cleavage significantly prolong the half-life of TFIIA. Consistently, the cleaved TFIIA is a substrate for the ubiquitin pathway and proteasome-mediated degradation. We show that mutations in the putative phosphorylation sites of TFIIAbeta greatly affect degradation of the beta-subunit. We propose that cleavage and subsequent degradation fine-tune the amount of TFIIA in the cell and consequently the level of transcription.

Human Reproduction and Rights of Action and of Recipience

s should be submitted before 1 December 2004 For more information: Dr. Bert Gordijn, Secretary of the ESPMH, Dept. of Ethics, Philosophy and History of Medicine, University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands, E-mail: b.gordijn@efg.umcn.nl

The role of Lys791 and Asn792 in gastric H,K-ATPase.

Annals of the New York Academy of SciencesVolume 986, Issue 1 p. 308-309 The Role of Lys791 and Asn792 in Gastric H,K-ATPase HERMAN G. P. SWARTS, Corresponding Author HERMAN G. P. SWARTS Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsAddress for correspondence: Herman G.P. Swarts, Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands. Voice: +31-24-3614258; fax: +31-24-3616413. [email protected]Search for more papers by this authorPETER H. G. M. WILLEMS, PETER H. G. M. WILLEMS Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorJAN B. KOENDERINK, JAN B. KOENDERINK Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorJAN JOEP H. H. M. DE PONT, JAN JOEP H. H. M. DE PONT Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this author HERMAN G. P. SWARTS, Corresponding Author HERMAN G. P. SWARTS Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsAddress for correspondence: Herman G.P. Swarts, Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the Netherlands. Voice: +31-24-3614258; fax: +31-24-3616413. [email protected]Search for more papers by this authorPETER H. G. M. WILLEMS, PETER H. G. M. WILLEMS Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorJAN B. KOENDERINK, JAN B. KOENDERINK Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this authorJAN JOEP H. H. M. DE PONT, JAN JOEP H. H. M. DE PONT Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, 6500 HB Nijmegen, the NetherlandsSearch for more papers by this author First published: 24 January 2006 https://doi.org/10.1111/j.1749-6632.2003.tb07196.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article.Citing Literature Volume986, Issue1Na,K‐ATPase AND RELATED CATION PUMPS: Structure, Function, and Regulatory MechanismsApril 2003Pages 308-309 RelatedInformation