Lambertus A Kiemeney

Summary

Affiliation: Radboud University Nijmegen Medical Centre
Country: The Netherlands

Publications

  1. pmc Personal hair dye use and the risk of bladder cancer: a case-control study from The Netherlands
    Martine M Ros
    Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, The Netherlands
    Cancer Causes Control 23:1139-48. 2012
  2. pmc Urinary Bladder Cancer Susceptibility Markers. What Do We Know about Functional Mechanisms?
    Aleksandra M Dudek
    Department of Urology, Radboud University Medical Centre, Geert Grooteplein 16, Nijmegen 6525 GA, The Netherlands
    Int J Mol Sci 14:12346-66. 2013
  3. pmc Urologists' and GPs' knowledge of hereditary prostate cancer is suboptimal for prostate cancer counseling: a nation-wide survey in The Netherlands
    Ruben Cremers
    Department of Epidemiology, Biostatistics and HTA 133, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB, Nijmegen, The Netherlands
    Fam Cancer 11:195-200. 2012
  4. pmc Health inequalities in the Netherlands: a cross-sectional study of the role of Type D (distressed) personality
    Marja J H van Bon-Martens
    Academic Collaborative Centre Public Health Brabant, Tranzo, Tilburg School of Social and Behavioral Sciences, University of Tilburg, Tilburg, The Netherlands
    BMC Public Health 12:46. 2012
  5. pmc Body mass index is not a predictor of biochemical recurrence after radical prostatectomy in Dutch men diagnosed with prostate cancer
    Dieuwertje E G Kok
    Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    World J Urol 29:695-701. 2011
  6. pmc Glenohumeral joint injection: a comparative study of ultrasound and fluoroscopically guided techniques before MR arthrography
    Matthieu J C M Rutten
    Department of Radiology, Jeroen Bosch Hospital, s Hertogenbosch, The Netherlands
    Eur Radiol 19:722-30. 2009
  7. ncbi request reprint [The risk of cancer in the Netherlands]
    L A L M Kiemeney
    Universitair Medisch Centrum St Radboud, afd Epidemiologie, Biostatistiek en HTA, Huispost 133 EBH, Postbus 9101, 6500 HB Nijmegen
    Ned Tijdschr Geneeskd 152:2233-41. 2008
  8. ncbi request reprint Genome-wide association studies in bladder cancer: first results and potential relevance
    Lambertus A Kiemeney
    Department of Epidemiology, Biostatistics and HTA, The Netherlands
    Curr Opin Urol 19:540-6. 2009
  9. pmc A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
    Lambertus A Kiemeney
    Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands
    Nat Genet 42:415-9. 2010
  10. doi request reprint Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients
    Joep G H van Roermund
    Department of Urology, University Medical Center Utrecht, Utrecht, The Netherlands
    BJU Int 107:1775-9. 2011

Detail Information

Publications49

  1. pmc Personal hair dye use and the risk of bladder cancer: a case-control study from The Netherlands
    Martine M Ros
    Department of Epidemiology, Biostatistics and HTA, Radboud University Medical Centre, Nijmegen, The Netherlands
    Cancer Causes Control 23:1139-48. 2012
    ..There has also been concern about a possible increased risk of bladder cancer among users of hair dyes. However, the association between personal hair dye use and bladder cancer risk remains inconclusive...
  2. pmc Urinary Bladder Cancer Susceptibility Markers. What Do We Know about Functional Mechanisms?
    Aleksandra M Dudek
    Department of Urology, Radboud University Medical Centre, Geert Grooteplein 16, Nijmegen 6525 GA, The Netherlands
    Int J Mol Sci 14:12346-66. 2013
    ..The insight into UBC heritability gained through GWAS and further functional studies can impact on cancer prevention and screening, as well as on the development of new biomarkers and future personalized therapies...
  3. pmc Urologists' and GPs' knowledge of hereditary prostate cancer is suboptimal for prostate cancer counseling: a nation-wide survey in The Netherlands
    Ruben Cremers
    Department of Epidemiology, Biostatistics and HTA 133, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB, Nijmegen, The Netherlands
    Fam Cancer 11:195-200. 2012
    ..Hence, PCa counseling might not be optimal for men with a positive family history. Multidisciplinary guidelines on this topic should be developed to optimize personalized counseling...
  4. pmc Health inequalities in the Netherlands: a cross-sectional study of the role of Type D (distressed) personality
    Marja J H van Bon-Martens
    Academic Collaborative Centre Public Health Brabant, Tranzo, Tilburg School of Social and Behavioral Sciences, University of Tilburg, Tilburg, The Netherlands
    BMC Public Health 12:46. 2012
    ..From the perspective of the 'indirect selection hypothesis', this study was designed to expand our understanding of the role of Type D personality as an explanation of health inequalities...
  5. pmc Body mass index is not a predictor of biochemical recurrence after radical prostatectomy in Dutch men diagnosed with prostate cancer
    Dieuwertje E G Kok
    Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    World J Urol 29:695-701. 2011
    ..To determine the effect of body mass index (BMI) on clinical and pathological characteristics at time of diagnosis and on risk of biochemical recurrence after radical prostatectomy among Dutch men diagnosed with prostate cancer...
  6. pmc Glenohumeral joint injection: a comparative study of ultrasound and fluoroscopically guided techniques before MR arthrography
    Matthieu J C M Rutten
    Department of Radiology, Jeroen Bosch Hospital, s Hertogenbosch, The Netherlands
    Eur Radiol 19:722-30. 2009
    ..US-guided injections and especially the anterior approach are significantly less time consuming, more successful on the first attempt, cause less patient discomfort and obviate the need for radiation and iodine contrast...
  7. ncbi request reprint [The risk of cancer in the Netherlands]
    L A L M Kiemeney
    Universitair Medisch Centrum St Radboud, afd Epidemiologie, Biostatistiek en HTA, Huispost 133 EBH, Postbus 9101, 6500 HB Nijmegen
    Ned Tijdschr Geneeskd 152:2233-41. 2008
    ..Calculation of valid and detailed risks of cancer from, and up to, specific ages for inhabitants of the Netherlands...
  8. ncbi request reprint Genome-wide association studies in bladder cancer: first results and potential relevance
    Lambertus A Kiemeney
    Department of Epidemiology, Biostatistics and HTA, The Netherlands
    Curr Opin Urol 19:540-6. 2009
    ..All GWASs have been published in high-impact journals and the strengths of the design are acknowledged by all experts, but there is criticism about the relevance of the results. Late 2008, the first GWAS in bladder cancer was published...
  9. pmc A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
    Lambertus A Kiemeney
    Department of Epidemiology, Biostatistics and Health Technology Assessment, Nijmegen, The Netherlands
    Nat Genet 42:415-9. 2010
    ..The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC...
  10. doi request reprint Periprostatic fat correlates with tumour aggressiveness in prostate cancer patients
    Joep G H van Roermund
    Department of Urology, University Medical Center Utrecht, Utrecht, The Netherlands
    BJU Int 107:1775-9. 2011
    ..Prognostic (case series)...
  11. ncbi request reprint Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma
    Iman J Schultz
    Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur Urol 51:416-22; discussion 422-3. 2007
    ..This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods...
  12. doi request reprint Impact of obesity on surgical outcomes following open radical prostatectomy
    Joep G H van Roermund
    Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Urol Int 82:256-61. 2009
    ..It is unknown whether obesity affects the surgical and oncological outcomes following open radical retropubic prostatectomy (RRP). Knowledge concerning this issue is relevant when counselling obese patients with PCa for RRP...
  13. doi request reprint Polymorphisms in the H19 gene and the risk of bladder cancer
    Gerald W Verhaegh
    Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Eur Urol 54:1118-26. 2008
    ..In this study we examined whether sequence variants within the H19 gene are associated with the risk of developing bladder cancer...
  14. doi request reprint Sequence variant on 8q24 confers susceptibility to urinary bladder cancer
    Lambertus A Kiemeney
    Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands
    Nat Genet 40:1307-12. 2008
    ..A weaker signal, but nonetheless of genome-wide significance, was captured by rs710521[A] located near TP63 on chromosome 3q28 (allele-specific OR = 1.19; P = 1. 15 x 10(-7))...
  15. doi request reprint A single institution experience with biochemical recurrence after radical prostatectomy for tumors that on pathology are of small volume or "insignificant"
    I M van Oort
    Department of Urology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Urol Oncol 27:509-13. 2009
    ..5 cc and Gleason scores <7, InsigPC) are considered clinically insignificant by some investigators. The aim of this study is to determine the biochemical recurrence rate (BCR) of svPC and InsigPC in prostatectomy specimens...
  16. ncbi request reprint The prognostic role of the STK15 T91A polymorphism and of STK15 mRNA expression in patients with urothelial cell carcinoma
    Iman J Schultz
    Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Anticancer Res 27:1025-30. 2007
    ..The prognostic role of the STK15 T91A polymorphism and of STK15 mRNA expression was investigated in patients with urothelial cell carcinoma (UCC)...
  17. doi request reprint Is there a relationship between fatigue perception and the serum levels of thyrotropin and free thyroxine in euthyroid subjects?
    Annenienke C van de Ven
    Department of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Thyroid 22:1236-43. 2012
    ..Thyrotoxicosis and hypothyroidism are associated with fatigue. Here we studied euthyroid subjects to determine if there was a relationship between serum thyrotropin (TSH), free thyroxine (FT(4)) and thyroperoxidase antibodies and fatigue...
  18. doi request reprint Body mass index is not a prognostic marker for prostate-specific antigen failure and survival in Dutch men treated with brachytherapy
    Joep G H van Roermund
    Department of Urology, University Medical Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
    BJU Int 105:42-8. 2010
    ....
  19. doi request reprint Clinical epidemiology of nonurothelial bladder cancer: analysis of the Netherlands Cancer Registry
    Martine Ploeg
    Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    J Urol 183:915-20. 2010
    ..Nonurothelial malignancies represent a small fraction of bladder malignancies and are less extensively studied, resulting in sparse empirical data on these tumors. We sought insight into tumor characteristics and survival...
  20. ncbi request reprint Associations between thyroid function and mortality: the influence of age
    Annenienke C van de Ven
    Division of EndocrinologyDepartment of MedicineDepartment for Health EvidenceDepartment of Laboratory MedicineDepartment of UrologyRadboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSection of EndocrinologyDepartment of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
    Eur J Endocrinol 171:183-91. 2014
    ..The aim of this study was to investigate the influence of age on the association between thyroid function and mortality...
  21. pmc Periprostatic fat measured on computed tomography as a marker for prostate cancer aggressiveness
    Joep G H van Roermund
    Department of Urology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands
    World J Urol 28:699-704. 2010
    ....
  22. doi request reprint Body mass index as a prognostic marker for biochemical recurrence in Dutch men treated with radical prostatectomy
    Joep G H van Roermund
    Department of Urology, University Medical Center Utrecht, The Netherlands
    BJU Int 104:321-5. 2009
    ....
  23. ncbi request reprint Screening for prostate cancer in Dutch hereditary prostate cancer families
    Lambertus A Kiemeney
    Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Int J Cancer 122:871-6. 2008
    ..We suggest that the same PSA testing guidelines should apply to HPC families and the general population. A more aggressive screening policy in HPC families does not seem to be justified...
  24. ncbi request reprint Prediction of recurrence in Ta urothelial cell carcinoma by real-time quantitative PCR analysis: a microarray validation study
    Iman J Schultz
    Department of Clinical Chemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Int J Cancer 119:1915-9. 2006
    ..In conclusion, we were not able to confirm the microarray gene expression pattern of the 26 genes shown by Dyrskjøt et al. The discovery of accurate recurrence predictive markers, therefore, remains a challenge...
  25. ncbi request reprint Segregation analysis of urothelial cell carcinoma
    Katja K H Aben
    Dept of Epidemiology and Biostatistics, Radboud University, Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    Eur J Cancer 42:1428-33. 2006
    ..The 'no major gene' (or sporadic) model appeared to be the most parsimonious one to describe the occurrence of UCC in these families...
  26. ncbi request reprint CDC91L1 (PIG-U) mRNA expression in urothelial cell carcinomas
    Iman J Schultz
    Department of Clinical Chemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
    Int J Cancer 116:282-4. 2005
    ..Our results suggest, in contrast to those of Guo et al. (Nat Med 2004;10:374-81), that the oncogene CDC91L1 is not overexpressed at the mRNA level in urothelial cell carcinomas and cannot be used to predict the course of the disease...
  27. ncbi request reprint No evidence for large-scale germline genomic aberrations in hereditary bladder cancer patients with high-resolution array-based comparative genomic hybridization
    Lambertus A Kiemeney
    Department of Urology, Radboud University Nijmegen Medical Centre, P O Box 9101, NL 6500 HB Nijmegen, The Netherlands
    Cancer Epidemiol Biomarkers Prev 15:180-3. 2006
  28. doi request reprint Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer
    Ruben G Cremers
    Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, The Netherlands
    Eur J Cancer 46:3294-9. 2010
    ..A correlation between the two phenotypes may be relevant for identification of men at high risk of PC. We evaluated the association between AA at different ages and PC in a large case-control study...
  29. ncbi request reprint Prognostic relevance of urinary bladder cancer susceptibility loci
    Anne J Grotenhuis
    Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands
    PLoS ONE 9:e89164. 2014
    ..Elucidation of the causal variant(s) could further our understanding of the mechanism of disease, could point to new therapeutic targets, and might aid in improvement of prognostic tools...
  30. ncbi request reprint DD3(PCA3)-based molecular urine analysis for the diagnosis of prostate cancer
    Daphne Hessels
    Department of Experimental Urology, Nijmegen Center for Molecular Life Sciences, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    Eur Urol 44:8-15; discussion 15-6. 2003
    ..DD3(PCA3) is the most prostate cancer-specific gene described to date. To assess the clinical utility of DD3(PCA3) a time-resolved fluorescence-based, quantitative RT-PCR analysis for DD3(PCA3) was developed...
  31. doi request reprint Prognostic factors for survival in patients with recurrence of muscle invasive bladder cancer after treatment with curative intent
    Martine Ploeg
    Department of Urology, Radboud University Nijmegen Medical Centre, The Netherlands
    Clin Genitourin Cancer 9:14-21. 2011
    ..Multivariable survival analyses were performed. Clinicopathological factors that predict survival after recurrence are recurrence location, treatment for recurrence and age at recurrence diagnosis...
  32. ncbi request reprint Polymorphisms in the E-cadherin (CDH1) gene promoter and the risk of bladder cancer
    Lambertus A Kiemeney
    Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB, Nijmegen, The Netherlands
    Eur J Cancer 42:3219-27. 2006
    ..We studied the association between both polymorphisms and the risk of bladder cancer...
  33. ncbi request reprint The efficacy of different follow-up strategies in clinical stage I Non-seminomatous Germ Cell Cancer: a Markov simulation study
    Jesse Roan Spermon
    Department of Urology, Radboud University Nijmegen Medical Center, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    Eur Urol 48:258-67; discussion 267-8. 2005
    ..In this study, we constructed a Markov model to evaluate the impact of different follow-up strategies on disease-specific mortality (DSM) and life expectancy (LE) of patients with CS I NSGCT...
  34. doi request reprint Combining risk markers improves cardiovascular risk prediction in women
    Suzanne Holewijn
    Department of General Internal Medicine, Division of Vascular Medicine, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB, Nijmegen, The Netherlands
    Clin Sci (Lond) 126:139-46. 2014
    ..The additive value of individual and combined non-invasive risk markers in men is limited to men at intermediate risk only, and to a lesser extent than in women...
  35. doi request reprint Trends in therapy and survival of advanced stage epithelial ovarian cancer patients in the Netherlands
    Anne M van Altena
    Department of Obstetrics and Gynecology, Radboud University Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    Gynecol Oncol 125:649-54. 2012
    ..The aim of this study was to describe trends in survival and therapy in advanced stage epithelial ovarian cancer (EOC) in the Netherlands and to determine if changes in therapy affected survival...
  36. ncbi request reprint Survivin mRNA copy number in bladder washings predicts tumor recurrence in patients with superficial urothelial cell carcinomas
    Iman J Schultz
    Department of Clinical Chemistry, University Medical Center Nijmegen, Nijmegen, The Netherlands
    Clin Chem 50:1425-8. 2004
  37. doi request reprint Germline genetic markers for urinary bladder cancer risk, prognosis and treatment response
    Anne J Grotenhuis
    Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Future Oncol 6:1433-60. 2010
    ....
  38. ncbi request reprint Spouse controls in family case-control studies: a methodological consideration
    Bas A J Verhage
    Department of Epidemiology and Biostatistics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
    Fam Cancer 2:101-8. 2003
    ..Using a simulation study it is illustrated that even strong assortative mating on a factor, which is strongly correlated with a true risk factor under study, will have a negligible effect on the observed extent of familial aggregation...
  39. pmc Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD
    Barbara Franke
    Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Neuropsychopharmacology 35:656-64. 2010
    ..However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD...
  40. doi request reprint Fruit and vegetable consumption and risk of aggressive and non-aggressive urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition
    Martine M Ros
    Centre for Nutrition and Health, National Institute for Public Health and the Environment RIVM, Bilthoven, The Netherlands
    Eur J Cancer 48:3267-77. 2012
    ..Therefore, we examined the relation between fruit and vegetable consumption and the risk of aggressive and non-aggressive UCC in the European Prospective Investigation into Cancer and Nutrition (EPIC)...
  41. ncbi request reprint Ultrasound-guided transrectal implantation of gold markers for prostate localization during external beam radiotherapy: complication rate and risk factors
    Johan F Langenhuijsen
    Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    Int J Radiat Oncol Biol Phys 69:671-6. 2007
    ..To report the complication rate and risk factors of transrectally implanted gold markers, used for prostate position verification and correction procedures...
  42. ncbi request reprint DD3(PCA3), a very sensitive and specific marker to detect prostate tumors
    Jacques B de Kok
    Department of Clinical Chemistry, University Medical Centre Nijmegen, 6500 HB Nijmegen, The Netherlands
    Cancer Res 62:2695-8. 2002
    ..Consequently, DD3 measurements may be used for clinical application in prostate needle biopsies or bodily fluids such as blood, ejaculate, urine, or prostate massage fluid...
  43. doi request reprint The effect on pain experienced by male patients of watching their office-based flexible cystoscopy
    Erik B Cornel
    Department of Urology, Ziekenhuis Groep Twente, Hengelo, The Netherlands
    BJU Int 102:1445-6. 2008
    ..To confirm the recently published positive effect on visual analogue pain (VAS) scale levels for men watching their flexible cystoscopy...
  44. pmc The present and future burden of urinary bladder cancer in the world
    Martine Ploeg
    Department of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    World J Urol 27:289-93. 2009
    ..But the burden of UBC will increase in less developed areas of the world. These changes can be attributed to global changes in exposure to risk factors for UBC and growth and aging of the world population...
  45. doi request reprint Underestimation of effect of thyroid function parameters on morbidity and mortality due to intra-individual variation
    Annenienke C van de Ven
    Department of Endocrinology 471, Radboud University Nijmegen Medical Centre, P O Box 9101, 6500 HB Nijmegen, The Netherlands
    J Clin Endocrinol Metab 96:E2014-7. 2011
    ....
  46. ncbi request reprint Phenotypic characteristics of male subfertility and its familial occurrence
    Ron J T van Golde
    Department of Obstetrics and Gynecology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
    J Androl 25:819-23. 2004
    ..Furthermore, examination of the data suggests that subfertile men with a familial occurrence of male subfertility more often have normal levels of FSH and LH and a lower percentage of motile sperm...
  47. ncbi request reprint The prevalence of urinary incontinence in community-dwelling married women: a matter of definition
    Vera Vandoninck
    Department of Urology, University Medical Center, Nijmegen, The Netherlands
    BJU Int 94:1291-5. 2004
    ..To determine the prevalence of female urinary incontinence (UI) and its impact on quality of life...
  48. ncbi request reprint Underestimation of subfertility among relatives when using a family history: taboo bias
    Irene A M van der Avoort
    Department of Obstetrics and Gynaecology, University Medical Centre Nijmegen, Nijmegen, The Netherlands
    J Androl 24:285-8. 2003
    ..Therefore, researchers and clinicians should be aware that an inquiry of family history is likely to lead to underestimation of subfertility among relatives...
  49. ncbi request reprint Baseline prostatic specific antigen does not predict the outcome of high energy transurethral microwave thermotherapy
    M Pilar Laguna
    Department of Urology, University Medical Centre St Radboud, Nijmegen, The Netherlands
    J Urol 167:1727-30. 2002
    ..We assessed the prognostic value of baseline prostate specific antigen (PSA) for outcome after high energy transurethral thermotherapy in patients with lower urinary tract symptoms...