Risk factors and potential preventive measures for nephropatia epidemica in Sweden 2011-2012: a case-control study.

INTRODUCTION: Nephropatia epidemica (NE), a relatively mild form of hemorrhagic fever with renal syndrome caused by the Puumala virus (PUUV), is endemic in northern Sweden. We aim to study the risk factors associated with NE in this region. METHODS: We conducted a matched case-control study between June 2011 and July 2012. We compared confirmed NE cases with randomly selected controls, matched by age, sex, and place of infection or residence. We analyzed the association between NE and several occupational, environmental, and behavioral exposures using conditional logistic regression. RESULTS: We included in the final analysis 114 cases and 300 controls, forming 246 case-control pairs. Living in a house with an open space beneath, making house repairs, living less than 50 m from the forest, seeing rodents, and smoking were significantly associated with NE. CONCLUSION: Our results could orient public health policies targeting these risk factors and subsequently reduce the NE burden in the region.

Multiple HIV-1 introductions into the Swedish intravenous drug user population.

In 2001, an increase of HIV-1 diagnoses among intravenous drug users (IVDU) was reported in Sweden. In nearby countries, Finland, Russia and the Baltic states, recent outbreaks had been described. Since there was a concern that these outbreaks would carry over to Sweden a study was initiated to determine the factors leading to the Swedish increase of HIV-1 diagnosed IVDUs. HIV-1 env V3 sequences were obtained from 97 patients enrolled in ongoing epidemiological studies encompassing the years 1987--2004 with a focus on 2001--2002. The sequences were used for maximum likelihood and Bayesian inference of the molecular epidemiology. Among the virus spreading in 2001--2002, we found that four different subtypes/CRFs were present in the Swedish IVDU population (A, B, CRF01_AE and CRF06_cpx). Subtype B constituted 85% of the infections, established by 12 independent introductions into the IVDU population. The worrisome increase in 2001 was mainly not a result of import of the outbreaks in nearby countries, but rather a higher detection rate of secondary cases due to efficient epidemiological tracing of the generally slow spread of established forms of subtype B in the IVDU community. However, a few of the non-subtype B cases were linked to the outbreaks in Finland, Estonia and Latvia. Because HIV-1 outbreaks can easily be exported from one country to another amongst IVDUs, this prompts continued surveillance in the Baltic Sea Region.

Urinary cytology and nuclear matrix protein 22 in the detection of bladder cancer recurrence other than transitional cell carcinoma.

OBJECTIVE: To assess the value of nuclear matrix protein-22 (NMP22), compared with urinary cytology, in predicting the recurrence of bladder cancer that is not transitional cell carcinoma (non-TCC). PATIENTS AND METHODS: We tested the sensitivity, specificity and the predictive accuracy of NMP22 in the context of non-TCC bladder cancer recurrence, and compared it to the performance of urinary cytology. The study group comprised 2687 patients with history of non-muscle-invasive bladder cancer from 10 centres across four continents. RESULTS: The mean patient age was 64.8 years and 75.4% were men; of all patients, 513 (19.1%) had positive urinary cytology, 906 (33.7%) had a positive NMP22 test (>or=10 units/mL) and 80 (3.0%) had non-TCC recurrence. Most of these, i.e. 60 (75%), were stage >or=T2. The sensitivity and specificity of urinary cytology were, respectively, 20.0% and 94.8%, vs 77.5% and 81.8% for NMP22 of >or=10 units/mL. The predictive accuracy of urinary cytology was 57.5%, vs 87.1% for NMP22 >or= 10 units/mL. A combined model that included dichotomized NMP22 and urinary cytology was 85.3% accurate. CONCLUSION: The ability of a NMP22 level of >or=10 units/mL to predict non-TCC recurrence was better than that of urinary cytology, suggesting that NMP22 might have a role in the surveillance of patients at risk of non-TCC recurrence.

A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences.

PURPOSE: We studied whether a single instillation of epirubicin after transurethral bladder tumor resection would influence the interval to and size of the first recurrence. MATERIALS AND METHODS: A total of 404 patients from 13 hospitals were randomized to 1 instillation of 50 mg epirubicin or placebo within 6 hours after transurethral resection of bladder tumors. RESULTS: Of 155 evaluable patients in the epirubicin group 79 (51.0%) had recurrence compared to 95 of 152 (62.5%) in the placebo group (p = 0.04). Of the recurrences 63.3% were small (1 to 5 mm). Tumor size was unknown in 5 patients. Of 79 patients with recurrence in the epirubicin arm 33 (42.9%) vs 29 (31.5%) of 95 in the placebo arm had larger (more than 5 mm) first recurrences (p = 0.12). Approximately half of the patients with first recurrences were treated as outpatients and the other half spent a total of 145 days in the hospital with no difference between the groups. CONCLUSIONS: We confirmed the results of previous studies showing that 8.5 patients must be treated with a single instillation to prevent 1 recurrence. Furthermore, our data may indicate that only small recurrences are prevented, which could easily be fulgurated using local anesthesia at followup cystoscopy. The benefit of single instillations can be questioned if this finding is confirmed by others.

Relationships between lower urinary tract symptoms, the bother they induce and erectile dysfunction.

OBJECTIVE: To study the relationships between lower urinary tract symptoms (LUTS), LUTS-induced bother, age and erectile dysfunction. MATERIAL AND METHODS: A survey consisting of two questionnaires, the International Prostate Symptom Score (IPSS) (reflecting LUTS) and the International Index of Erectile Function (IIEF)-5 (reflecting erectile function), together with instructions on how to perform timed micturition, was sent to 2000 randomly selected men (age range 60-70 years) living in the five counties surrounding our hospital. The IPSS questionnaire included a question concerning the degree of bother induced by LUTS. RESULTS: The survey was answered by 1096 men; after the exclusion of incomplete answers, 924 surveys were evaluated. Of these 924 men, 725 (78%) were sexually active and included in the analyses. The prevalence of moderate-to-severe LUTS (IPSS>or=8) was 45%. The prevalence of erectile dysfunction (ED), defined as an IIEF-5 score of

Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer.

PURPOSE: We assessed variability in the diagnostic performance of NMP22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS transitional cell carcinoma of the bladder in a large international cohort. MATERIALS AND METHODS: NMP22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1 and/or CIS transitional cell carcinoma at 12 participating institutions. RESULTS: Patient characteristics varied considerably among institutions. Overall 1,045 patients (36.4%) had recurrent transitional cell carcinoma (range across institutions 13.6% to 54.3%). Median NMP22 was 5.5 U/ml (range across institutions 2.5 to 18.8). Of the patients 33.5% had grade III tumors (range across institutions 20.6% to 54.0%) and 22.4% had muscle invasive tumors (range across institutions 3.2% to 38.2%). Area under the ROC curve for bladder TCC detection was 0.735 (95% CI 0.715 to 0.755, range across institutions 0.676 to 0.889). The manufacturer recommended cutoff of 10 U/ml detected 57% of cases with a 19% false-positive rate. AUC for grade III and stage T2 or greater disease was 0.806 (95% CI 0.780 to 831) and 0.864 (95% CI 0.839 to 0.890), respectively. For each NMP22 cutoff NMP22 had higher sensitivity for detecting grade III and stage T2 or greater bladder transitional cell carcinoma than for detecting any cancer. No optimal cutoffs for detecting any or aggressive bladder transitional cell carcinoma could be derived based on NMP22 values. CONCLUSIONS: There is a substantial degree of heterogeneity in the diagnostic performance of NMP22 applied to populations from different institutions. There is no clearly defined NMP22 cutoff but there is a continuum of risk for recurrence and progression.

Institutional variability in the accuracy of urinary cytology for predicting recurrence of transitional cell carcinoma of the bladder.

OBJECTIVE: To assess the contemporary inter-institutional accuracy of urinary cytology in predicting the recurrence of transitional cell carcinoma (TCC) of the bladder, in a large multi-institutional cohort from four continents, as cystoscopy and urinary cytology represent the 'gold standards' for surveillance of TCC recurrences, but the ability of cytology to predict recurrence varies. PATIENTS AND METHODS: Ten institutions contributed 2542 patients with a history of superficial TCC, of whom 898 had TCC recurrence. Age- and gender-adjusted logistic regression models were used to evaluate the association between urine cytology and TCC recurrence. The predictive accuracy derived from the logistic regression model was tested using the area under the receiver operating characteristic curve. The resulting predictive accuracy estimates were internally validated with 200 bootstrap re-samples. RESULTS: The mean (range across institutions) age of the patients was 65 (48-69) years and 75 (67-87)% were men. Cytology was positive in 19 (10-38)% of patients; recurrence was identified in 35 (27-54)% of patients. The sensitivity was 38-65% across institutions. Urinary cytology varied significantly in its ability to predict recurrence of bladder cancer. Institution-specific predictive accuracy adjusted for gender and age was 0.627-0.893. Stratifying by grade and stage only partly attenuated the discrepancies between centres. CONCLUSIONS: The variability of urinary cytology results was very appreciable among the 10 centres and ranged from poor (63%) to excellent (89%).

Screening for bladder tumours in men aged 60-70 years with a bladder tumour marker (UBC) and dipstick-detected haematuria using both white-light and fluorescence cystoscopy.

OBJECTIVE: To investigate the relevance of bladder tumour screening using haematuria dipsticks and a bladder tumour marker in a random selection of men, age 60-70 years, from a well-defined geographical area using both fluorescence and white-light cystoscopy. MATERIAL AND METHODS: A total of 2000 randomly selected men, age 60-70 years, were invited by mail to participate in a screening for bladder tumours by having their urine tested with a dipstick for haematuria and a bladder tumour marker (UBC). Men with 5-10 red blood cells (RBC)/microl and an International Prostate Symptom Score (IPSS) of >10 and all men with =25 RBC/microl and/or elevated UBC levels underwent both white-light and fluorescence cystoscopy. RESULTS: A total of 1096 men (55%) responded and were included in the study. The incidence of 5-10 RBC/microl was high: 14%. A tumour was detected in one of the 62 men with 5-10 RBC/microl and an IPSS of >10. Among the 10% of men (n=112) with =25 RBC/microl, four bladder tumours were detected. Another two tumours were detected in men without haematuria (positive UBC test). No tumours were observed using only fluorescence cystoscopy. CONCLUSIONS: Fluorescence cystoscopy and the UBC test were of no use in this screening situation. The incidence of haematuria (=5-10 RBC/microl) was so high (1:4) that this borderline for bladder tumour screening appears unrealistic. The incidence of =25 RBC/microl was 1:10 and one of 28 cystoscopies revealed a bladder tumour. All seven tumours were detected in men who were or had been smokers. A haematuria-based screening among older male smokers with =25 RBC/microl on dipstick testing is thus an option that should be considered.

[One man of five aged 50 years and over referred to a urologist is diagnosed with cancer. PSA analysis is important for correct prioritization of the referrals]. / Var femte man över 50 år som remitteras till urolog har cancer. PSA viktigt för att remisserna ska kunna prioriteras rätt.

In 20% of the men 50 years of age and older referred to a urological specialist clinic, a cancer, mostly a prostate cancer, was diagnosed. No symptom mentioned in the referral form was correlated to the diagnosis of a cancer. S-PSA density did not have a better predictive value than S-PSA alone. S-PSA 3.0 microg/L as a borderline for prostate biopsy or not had a 99.5% negative predictive value and only a slightly lower specificity then 4.0 microg/L. In clinical practice, for patients where curative treatment is feasible, S-PSA 3.0 microg/L appears to be a more appropriate borderline for prostate biopsy than 4 microg/L.

Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder.

PURPOSE: We developed and validated nomograms that accurately predict disease recurrence and progression in patients with Ta, T1, or CIS transitional cell carcinoma (TCC) of the bladder using a large international cohort. METHODS: Univariate and multivariate logistic regression models targeted histologically confirmed disease recurrence, and focused on 2,542 patients with bladder TCC from 10 participating centers. Variables consisted of pre-cystoscopy voided urine Nuclear Matrix Protein 22 (NMP22) assay, urine cytology, age and gender. Resulting nomograms were internally validated with bootstrapping. Nomogram performance was explored graphically with Loess smoothing plots. RESULTS: Overall 957 patients had recurrent TCC. Tumor grade and stage was available for 898 patients, including 24% grade I, 43% grade II, and 33% grade III; 45% stage Ta, 32% T1 and/or CIS, and 23% T2 or greater. Bootstrap corrected predictive accuracy for any TCC recurrence was 0.842; grade III Ta/T1 or CIS was 0.869; and T2 or higher stage TCC of any grade was 0.858. Virtually perfect performance characteristics were observed for the nomograms predicting any TCC recurrence or grade III Ta/T1 or CIS. The nomogram predicting T2 or higher stage TCC overestimated the observed probability for predicted values greater than 45%. CONCLUSIONS: We developed and internally validated nomograms that incorporate urinary NMP22, cytology, age and gender to predict with high accuracy the probability of disease recurrence and progression in patients with Ta, T1, and/or CIS bladder TCC. These nomograms could provide a means for individualizing followup in patients with Ta, T1, CIS bladder TCC.

[Testicular torsion--a diagnostic dilemma. Diagnosis confirmed by exploration in only 9 per cent of cases, color ultrasound more accurate]. / Testistorsion--ett diagnostiskt dilemma. Exploration bekräftar diagnos hos 9 procent, färgdopplerultraljud säkrare.

The diagnosis was confirmed in only 9% of 170 patients surgically explored for suspected testicular torsion over a period of 2 years at four Swedish hospitals. In only every second case of testicular torsion was it considered meaningful to leave the testicle in situ. The high number of explorations, where the preoperative suspicion could not be verified, suggests that the preoperative diagnostic work-up should be improved. The use of power or colour ultrasound is suggested as a way of achieving this.

Deficiency of antibacterial peptides in patients with morbus Kostmann: an observation study.

BACKGROUND: Antibacterial peptides, such as defensins and LL-37, are natural bactericidal components similar in potency to classic antibiotics. These peptides are produced at mucosal linings in the body and the skin, and by leucocytes such as neutrophils and natural killer cells. Patients with morbus Kostmann-a severe congenital neutropenia-are treated by recombinant granulocyte-colony stimulating factor, which restores their levels of neutrophils. Despite this treatment, patients still have recurrent infections and periodontal disease. Our aim was to investigate if defensins and LL-37 are deficient in patients with morbus Kostmann. METHODS: We studied samples of neutrophils, plasma, and saliva from six patients with congenital neutropenia and 22 healthy controls for presence of antibacterial peptides. Neutrophils were analysed by high-performance liquid chromatography and mass spectrometry for alpha-defensins. All samples were analysed by western blot for cathelin-LL-37 (precursor of LL-37) and LL-37. Neutrophils were also tested for lactoferrin and ability to produce oxidative burst. FINDINGS: Neutrophils from patients with morbus Kostmann were deficient in cathelin-LL-37 and had reduced concentrations of a-defensins HNP1-3. No cathelin-LL-37 could be detected in plasma and saliva from patients. One patient with morbus Kostmann who had had bone-marrow transplantation had almost normal concentrations of LL-37. Lactoferrin concentrations and oxidative burst were normal in all patients. All patients with morbus Kostmann had severe periodontal disease, apart from the individual who had had a bone-marrow transplant, whose dental status was normal. INTERPRETATION: Antibacterial peptides are a vital part of the first line of antibacterial immune defence. Deficiency in saliva LL-37 accords with occurrence of periodontal disease in patients with morbus Kostmann.

Newly diagnosed bladder cancer: the relationship of initial symptoms, degree of microhematuria and tumor marker status.

PURPOSE: We recorded initial symptoms and evaluated the frequency and intensity of hematuria in patients with newly diagnosed bladder cancer. We also evaluated and compared the sensitivity of bladder wash cytology, NMP22 (Matritech, Newton, Massachusetts), BTA Stat (Bion Diagnostic Sciences, Redmond, Washington) and UBC antigen (IDL Biotech, Sollentona, Sweden) with hematuria dipsticks and flow cytometry for determining the size of erythrocytes in urine. MATERIALS AND METHODS: Urine samples were collected from 92 patients with newly diagnosed bladder cancer, 64 with idiopathic microhematuria and 42 with nephritis. Urine was analyzed for NMP22, BTA Stat, UBC and erythrocytes size using flow cytometry. Bladder wash cytology was done at cystoscopy. Urine was analyzed for microhematuria with hematuria dipsticks at home for 7 consecutive days immediately before the operation and in the hospital on the day of surgery. RESULTS: Sensitivity was 75% for NMP22, 78% for BTA Stat, 64% for UBC and 61% for flow cytometry at 73% specificity. Cytology had 42% sensitivity at 97% specificity. Tumor size, grade and stage had a statistically significant influence on NMP22, BTA Stat, UBC and cytology. Of the patients 75% had microhematuria on the day of the operation and 75% had hematuria at least 1 of 7 days when tested at home the last week before transurethral bladder resection. The 70% of all patients with macroscopic hematuria as the initial symptom did not seem to differ from those without the condition in tumor size, grade, stage or tumor marker levels. CONCLUSIONS: Flow cytometry was not well enough able to distinguish patients with bladder cancer from controls. The sensitivity of all tested markers, including hematuria dipsticks, was high for large and high grade, high stage tumors. Further studies are needed to evaluate whether a marker could be used to determine priority among patients referred due to microhematuria.

High mobility group box chromosomal protein 1 (HMGB1) is an antibacterial factor produced by the human adenoid.

Antibacterial factors were purified from human adenoid glands by tissue extraction and consecutive steps of reversed-phase chromatography and assayed for bactericidal activity against the airway pathogen Moraxella catarrhalis and also Escherichia coli and Bacillus megaterium. One of the most active components isolated from adenoids was identified by N-terminal sequence analysis and mass spectrometry as high mobility group box chromosomal protein 1 (HMGB1). This novel finding was further substantiated by Western blot analysis, demonstrating a protein of expected size reactive with HMGB1 antiserum. Local synthesis was confirmed by reverse-transcriptase PCR and in situ hybridization. Adenoid-derived HMGB1 and recombinant HMGB1 revealed comparable antibacterial activity at high rate. More than 95% of bacteria were eradicated within 5 min by HMGB1 in the cultures. Secretion from the adenoid gland surface was also demonstrated to contain antibacterial activity, mainly mediated by alpha-defensins, but not by HMGB1. We conclude that HMGB1, produced and stored intracellularly in the adenoid gland, contributes to the local antibacterial barrier defense system in the upper respiratory tract.