Characterization of lower urinary tract symptoms in patients with idiopathic normal pressure hydrocephalus

AIMS: The purpose of this study was to evaluate lower urinary tract symptoms (LUTS) in idiopathic normal pressure hydrocephalus (iNPH). METHODS: Patients with new-onset iNPH were prospectively evaluated for LUTS via detailed history and physical, and administration of questionnaires from the International Consultation on Incontinence to assess incontinence (ICIq-UI), overactive bladder (ICIq-OAB), and quality of life (ICIq-LUTqol), as well as the American Urological Association Symptom Score bother scale. All patients with moderate-to-severe LUTS were offered urodynamic testing. Sub-analysis was performed based on gender, medical comorbidities, and age. RESULTS: Fifty-five consecutive patients with iNPH completed the initial evaluation and surveys. Total urinary incontinence score was mild to moderate (8.710.64: 0-21 scale) with 90.9% experiencing leakage and 74.5% reporting urge incontinence. The most common OAB symptom was nocturia (2.2 +/- 0.14: 0-4 scale) with urge incontinence the most bothersome (3.71 +/- 0.44: 0-10 scale). Quality-of-life impact was moderate (4.47 +/- 0.4: 0-10 scale) and American Urological Association Symptom Score bother scale was 2.89 +/- 0.22 (0-6 scale). Urodynamics testing revealed 100% detrusor overactivity and mean bladder capacity of 200mL. Several differences were identified based on gender, medical comorbidities, and age. CONCLUSIONS: Patients with iNPH present with mild-moderate incontinence of which nocturia is the most common symptom, urge incontinence the most bothersome, with 100% of patients having detrusor overactivity. Younger patients experienced greater bother related to LUTS. To our knowledge, this is the only prospective evaluation of urinary symptoms in patients with new-onset iNPH

Investigating various thresholds as immunohistochemistry cutoffs for observer agreement

Background: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. Materials and Methods: A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa ([kappa]) statistic was used to assess the strength of agreement for each cutoff. Results: The interobserver agreement between all 7 pathologists using the 3 cutoffs was reasonably good, with mean [kappa] scores of 0.64, 0.59, and 0.62, respectively, for 10%, 20%, and +2/+3 cutoffs. A good agreement was observed for experienced pathologists using the 10% cutoff, and their agreement was statistically higher than for junior pathologists (P=0.02). In addition, the mean intraobserver agreement for all 7 pathologists using the 3 cutoffs was reasonably good, with mean [kappa] scores of 0.71, 0.60, and 0.73, respectively, for 10%, 20%, and +2/+3 cutoffs. For all 3 cutoffs, a positive correlation was observed with perceived ease of interpretation (P<0.003). Finally, cytoplasmic-only staining achieved higher agreement using all 3 cutoffs than mixed staining patterns. Conclusions: All 3 cutoffs investigated achieve reasonable strength of agreement, modestly decreasing interobserver and intraobserver variability in IHC interpretation. These cutoffs have previously been used in cancer pathology, and this study provides evidence that these cutoffs can be reproducible between practicing pathologists

Bioinformatic identification of proteins with tissue-specific expression for biomarker discovery

<p>Abstract</p> <p>Background</p> <p>There is an important need for the identification of novel serological biomarkers for the early detection of cancer. Current biomarkers suffer from a lack of tissue specificity, rendering them vulnerable to non-disease-specific increases. The present study details a strategy to rapidly identify tissue-specific proteins using bioinformatics.</p> <p>Methods</p> <p>Previous studies have focused on either gene or protein expression databases for the identification of candidates. We developed a strategy that mines six publicly available gene and protein databases for tissue-specific proteins, selects proteins likely to enter the circulation, and integrates proteomic datasets enriched for the cancer secretome to prioritize candidates for further verification and validation studies.</p> <p>Results</p> <p>Using colon, lung, pancreatic and prostate cancer as case examples, we identified 48 candidate tissue-specific biomarkers, of which 14 have been previously studied as biomarkers of cancer or benign disease. Twenty-six candidate biomarkers for these four cancer types are proposed.</p> <p>Conclusions</p> <p>We present a novel strategy using bioinformatics to identify tissue-specific proteins that are potential cancer serum biomarkers. Investigation of the 26 candidates in disease states of the organs is warranted.</p

Epidemiology of Normal Pressure Hydrocephalus - Prevalence, Risk Factors, Diagnosis and Prognosis

The number of older persons and individuals with cognitive impairment is expected to increase dramatically in most parts of the world. It is therefore important to learn more about disorders that affect cognition. Idiopathic normal pressure hydrocephalus (iNPH) mainly occurs in older persons and symptoms include cognitive impairment, gait disturbance and urinary symptoms. The aim of this thesis was to examine various aspects regarding the epidemiology of iNPH. The sample comprised data from the Gothenburg population studies. Study participants underwent comprehensive clinical and neuropsychiatric examinations between 1986 and 2009. iNPH was diagnosed in concordance with criteria from international consensus guidelines. Study I: The prevalence of iNPH was higher than previously reported. More than one in twenty, among 80-year-olds, had signs and symptoms consistent with probable iNPH. Study II: Vascular risk factors and markers of cerebrovascular disease were associated with iNPH. Hypertension was related to an almost three-fold increased chance of having imaging signs of iNPH. For diabetes, it was more than four-fold. The strongest relation to iNPH was for cerebral white matter lesions, which were associated with a more than six-fold increased chance. Study III: More than one fifth of the sample had ventricular enlargement, defined by current cut-off values for Evans Index. In addition, men aged 80 years or more, had on average, values equal to or higher than what is currently considered pathological. Study IV: Persons who fulfilled criteria for probable iNPH had an almost four-fold increased risk of death. In those with radiological signs of iNPH, the risk of dementia was almost three-fold increased. iNPH is probably more common than previously supposed. Many older persons have clinical and imaging signs consistent with iNPH. These findings are important considering that iNPH is a treatable disorder. Vascular factors are probably involved in the pathophysiology. Current cut- off values for ventricular enlargement, using Evans Index, ought to be reappraised in order to improve diagnostic possibilities. Untreated iNPH is associated with a poor prognosis with a high risk of death or dementia. Radiological signs of iNPH may have a greater prognostic importance than previously presumed

Tissue biomarkers in prostate cancer

Prostate cancer (PC) is the most common male cancer in the western world. Better biomarkers are needed to support diagnosis, prediction of prognosis and treatment decision Radical prostatectomy (RP) specimens are routinely immersed in formalin overnight. Formalin may also be injected into the prostate for improved fixation. We report that formalin injection does not alter tissue volumes compared to conventional fixation. Formalin may affect epitopes for immunohistochemistry (IHC). Immunoreactivity was compared between fixation methods with no significant difference for the majority of 15 antibodies. We investigated the transcription factor pancreatic duodenal homeobox-1 (PDX-1) and heat shock proteins (HSP) 27, 60 and 70 as prognostic markers in PC. A tissue microarray (TMA) of 289 PCs was constructed and immunostained. HSP 27 and 60, but not HSP 70 and PDX-1 correlated with biochemical recurrence. In multivariate analysis including histopathological prognostic factors, only HSP 60 was an independent predictor of prognosis. PDX-1 was overexpressed in cancer vs. benign tissue but also in atrophy and high-grade prostatic intraepithelial neoplasia (PIN) vs. cancer. The role of GAD1 (glutamate decarboxylase 1) as prostate-specific biomarker was investigated. A TMA of benign and malignant tissues from prostate, rectum, lung and bladder was stained for GAD1, prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA, glutamate carboxypeptidase). Presence of GAD1 protein was validated by Western blot and real-Time PCR (RT-PCR). By IHC, the expression of GAD1 and PSA was stronger in prostatic tissues than in controls. PSMA was stronger in prostate cancer than in urothelial and rectal cancer but had lower specificity than GAD1 and PSA. The intra- and interobserver reproducibility of IHC evaluation in TMA were assessed. Intensity and extent of PDX-1 immunostains of 50 PCs were scored twice by 4 independent observers. Mean weighted kappa for intra- and interobserver agreement was 0.85 and 0.80 for intensity and 0.43 and 0.21 for extent with similar results for 2 pathologists and 2 non-pathologists. Thus, subjective assessment of intensity is highly reproducible while estimation of staining extent is less reliable. In conclusion, we find that TMA is a valuable tool for tissue-based biomarker research. We have attempted to optimize the procedures from tissue handling to evaluation. We also present HSP 27 and HSP 60 as potential predictors of prognosis in PC and GAD1 as a new prostate-specific biomarker

Nationwide prevalence of primary dystonia, progressive ataxia and hereditary spastic paraplegia

Objective: To determine the nationwide prevalence of primary dystonia, ataxia and hereditary spastic paraplegia (HSP) in Sweden. Methods: We extracted data on all patients who were registered in The National Patient Register (NPR) in Sweden (population 9.64 million) at least twice during five consecutive years with a diagnosis of primary dystonia, ataxia or HSP. We excluded patients with an additional diagnosis possibly indicating secondary causes, and determined the proportion of wrongly diagnosed patients at our own tertiary center by patient examination or chart review. We analyzed patients’ age and disorder subtypes, geographical distribution of patients within Sweden and the country of birth of all patients. Results: Nationwide, we identified 4239 patients (31.6% male) with a diagnosis of primary dystonia. Of 347 patients with dystonia at our center, 20.2% may have had a different final diagnosis. Extrapolation of this uncertainty rate to the national population resulted in a prevalence for primary dystonia of 35.1/100,000. There were 672 patients (49.6% male) with ataxia in NPR, and the diagnostic uncertainty rate among 81 patients in our center was 13.6% (prevalence 6.0/100,000). HSP was diagnosed in 235 patients nationwide (52.3% male, prevalence 2.4/100,000). Patients were distributed relatively evenly throughout the country. The proportions of patients with these diagnoses who were born outside of Sweden were lower (8.0–12.7%) than the proportion of all Swedish residents born abroad (15.9%). Conclusions: In this large, nationwide study, the prevalence of dystonia was high compared to previous studies, which partly may be explained by the high coverage of NPR