False-positive screening results in the Finnish prostate cancer screening trial.

BACKGROUND: There is evidence that prostate cancer (PC) screening with prostate-specific antigen (PSA) serum test decreases PC mortality, but screening has adverse effects, such as a high false-positive (FP) rate. We investigated the proportion of FPs in a population-based randomised screening trial in Finland. METHODS: Finland is the largest centre in the European Randomized Study of Screening for Prostate Cancer. We have completed three screening rounds with a 4-year screening interval (mean follow-up time 9.2 years) using a PSA cutoff level of 4.0 ng ml(-1); in addition, men with PSA 3.0-3.9 and a positive auxiliary test were referred. An FP result was defined as a positive screening result without cancer in biopsy within 1 year from the screening test. RESULTS: The proportion of FP screening results varied from 3.3 to 12.1% per round. Of the screened men, 12.5% had at least one FP during three rounds. The risk of next-round PC following an FP result was 12.3-19.7 vs 1.4-3.7% following a screen-negative result (depending on the screening round), risk ratio 3.6-9.9. More than half of the men with one FP result had another one at a subsequent screen. Men with an FP result were 1.5 to 2.0 times more likely to not participate in subsequent rounds compared with men with a normal screening result (21.6-29.6 vs 14.0-16.7%). CONCLUSION: An FP result is a common adverse effect of PC screening and affects at least every eighth man screened repeatedly, even when using a relatively high cutoff level. False-positive men constitute a special group that receives unnecessary interventions but may harbour missed cancers. New strategies are needed for risk stratification in PC screening to minimise the proportion of FP men.

Tumor features and survival after radical prostatectomy among antidiabetic drug users.

BACKGROUND: To evaluate the association between use of metformin and other antidiabetic drugs with tumor characteristics and survival in surgically managed prostate cancer (PCa) patients. METHODS: The study population included 1314 men who underwent radical prostatectomy at the Tampere University Hospital during 1995-2009. Causes of deaths were collected from the Finnish Cancer Registry. Individual-level data on medication use during 1995-2009 was obtained from national prescription database. Fasting blood glucose and hemoglobin A1c values during the study period were gathered from hospital district database. Gleason grade and pathological stage were compared by drug use before surgery and separately by metformin usage. Risk of biochemical recurrence, all-cause death and PCa-specific death were calculated using Cox proportional hazard regression with adjustment for age, tumor characteristics, glycemic control and use of other drug groups. RESULTS: High-grade tumors were more common among antidiabetic drug users (P=0.032), including metformin users (P=0.012). Despite this, no difference in PSA levels was observed. Men who had used antidiabetic drugs before surgery had an increased risk of Gleason 7-10 disease (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.04-3.23). The risk of high-grade PCa was higher among metformin users compared with other antidiabetic drug users (OR 3.11, 95% CI 1.16-8.33). During the median follow-up of 8.6 years after surgery, 551 men had biochemical recurrence and 244 died, 32 owing to PCa. Generally, no association with risk of disease recurrence was observed. Risk of death was increased by preoperative use of antidiabetic drugs (hazard ratio 1.81 95% CI 1.03-3.19), but no survival associations for postoperative use of antidiabetic drugs or metformin were observed. CONCLUSION: Diabetic men have more high-grade PCa at lower PSA levels, but that does not have a clear impact on disease-specific survival in the short term even when glycemic control is being considered.

Language functions in incipient cognitive decline in multiple sclerosis.

Although the mechanisms of cognitive impairment in multiple sclerosis (MS) have been extensively studied, evaluation of language functions has been given little attention. In the present study, we evaluated whether impairment of language functions is associated with cognitive decline in MS. We studied naming, reading, and writing performance of two carefully matched patient groups differing only with respect to cognitive status. In language tasks, the patients with incipient cognitive decline not only demonstrated performance slowness but also made more errors than the patients with preserved cognitive capacity and the healthy controls. The comprehensive naming error analysis revealed that the cognitively deteriorated patients produced error types not present in the other two study groups. Contrary to previous suggestions, the present study indicates that impaired language performances in MS are attributable to mild cognitive deterioration rather than to sensory or motor factors. Thus, assessment of language functions should be included in neuropsychological evaluations of MS patients.

On the nature of naming difficulties in aphasia.

An extensive naming battery was administered to ten patients representing classical aphasia syndromes. The battery included traditional performance measures and error scoring, phonological cuing, multiple-choice tasks tapping semantic and phonological knowledge, and word repetition tests. Differences in the patients' performance profiles were interpreted as reflecting lexical-phonological, phoneme assembly or multiple deficits. The results suggest that the hypothesized naming deficits have complex relationships to classical aphasia syndromes.

Candida immunity in patients undergoing surgical treatment for heart valve disease.

The appearance of Candida antigen (Latex agglutination method), Candida antibodies (indirect immunofluorescence) and positive fungal cultures as well as the lymphocyte transformation response to Candida antigen "in vitro" was studied in a series of 37 successive patients before and after heart valve replacement. The Candida antigen test was positive preoperatively in 11/36 (31%) and postoperatively in 14/36 (39%) of the patients and in 2/200 (1%) of the controls (blood donors). The differences in the frequencies of positive tests between the patient group and the control group are significant (p less than 0.001). The lymphocyte response to Oidiomycin (Candida albicans) preoperatively was greater than the mean control value in 6/11 (54.5%) of the patients showing a positive Candida antigen test, but only in 4/25 (16.0%) of the patients who were Candida antigen negative. The total number of lymphocytes and the number of ANAE positive (T) cells as well as the lymphocyte response to Oidiomycin (OID), tuberculoprotein (PPD) and phytohaemagglutinin (PHA) decreased markedly postoperatively. Candida antibody titres were positive (greater than or equal to 1:128) in 3/37 (8%) of the postoperative patients and in 2/84 (2.4%) of the controls. This difference is not significant. Positive Candida antibody titres were found postoperatively in 15/37 (41%) of the patients, which is a significantly higher frequency than that seen preoperatively (p less than 0.005). More positive fungal cultures from throat specimens (p less than 0.005) were found in the patient group before surgery than in the control group (hospital personnel). After surgery the number of positive fungal cultures in these cases decreased (p less than 0.001) due to the use of oral antifungal prophylaxis with nystatin tablets.(ABSTRACT TRUNCATED AT 250 WORDS)

Amenorrhea with low normal thyroid function and thyroxine treatment.

The effect of thyroxine treatment in cases of functional amenorrhea accompanied by low normally thyroid function was studied. During six months of follow-up, regular or single menstrual cycles were restored in ten of the 17 patients with thyroxine treatment and in four of the 11 patients without thyroxine treatment. During thyroxine treatment, thyroxine and free thyroxine index levels were elevated and serum testosterone levels decreased, but no significant changes were observed in serum estradiol, prolactin, follicle-stimulating hormone or luteinizing hormone levels. In the thyroid-releasing hormone/luteinizing-releasing hormone test, the thyroid-stimulating hormone response was markedly suppressed, but there were no changes in follicle-stimulating hormone, luteinizing hormone or prolactin responses. In one patient with primary hypothyroidism, regular menstrual cycles were restored and serum prolactin and thyroid-stimulating hormone levels normalized during thyroxine treatment. Thyroxine treatment seems to have benefits in some amenorrheic patients with low normal thyroid function.

Guidelines on processing and reporting of prostate biopsies: the 2013 update of the pathology committee of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

The histopathological examination of a prostate biopsy is the basis of prostate cancer diagnostics. Prostate cancer grade and extent of cancer in the diagnostic biopsy are important determinants of patient management. Quality of the prostate biopsy and its processing may influence the outcome of the histopathological evaluation. Further, an unambiguous and concise pathology reporting is essential for an appropriate clinical decision process. Since our initial report in 2003, there have been several practice changes, including the increased uptake of follow-up biopsies of patients who are under active surveillance, increasingly taken under guidance of MRI, or who underwent a prostate-sparing therapy. Therefore, we investigated the literature on the current pathology practices and recommendations with regard to prostate biopsy processing and reporting, both at initial diagnosis and in the context of follow-up biopsies in order to update our guidelines on the optimal processing and reporting of prostate biopsies.

Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer.

THE AIM OF THE STUDY: This article presents the incidence of prostate cancer, isolated high grade prostatic intraepithelial neoplasia (PIN) and atypical lesions suspicious for prostate cancer (LSPC) during subsequent screening rounds in the centres of five of the countries participating in the European Randomized Study of Screening for Prostate Cancer (ERSPC). The incidence and predictive value of high grade PIN and LSPC for prostate cancer in subsequent biopsy following these diagnoses were evaluated. PATIENTS AND METHODS: Study group consisted of 56,653 screened men in the ERSPC centres of Finland, Italy, Netherlands, Sweden and Switzerland, who underwent 3-7 screening rounds at 2-4 year interval. Data for prostate cancer were obtained from the ERSPC central database. Data for high grade PIN and LSPC were gathered from each ERSPC centre. Detection rates of subsequent prostate cancer in the first re-biopsy after these diagnoses were determined. RESULTS: The average cancer detection rate was 3.5%, 3.2% and 3.5% for the completed rounds 1, 2 and 3, respectively, in all five centres. Incidence of high grade PIN increased from 1.5% in the first round to 5.0% in the third round, varying among centres in the first round between 0.8% and 7.6%. The cancer detection rate in the first re-biopsy after the diagnosis of high grade PIN was 12.9%. Incidence of LSPC was 2.4%, 2.7%, 2.2% and 2.6% in the first, second, third and fourth round, respectively. The cancer detection rate at the first re-biopsy after the diagnosis of LSPC was in average 33.8%. CONCLUSIONS: Cancer detection rate was stable during the three screening rounds. The wide variation in frequency in particular of high grade PIN among the ERSPC centres suggests a considerable inter-observer variation. The average comparatively low detection rate of isolated high grade PIN in the first screening round may be screening-related, while its consistent increase during three screening rounds could be the consequence of a.o. previous screening and ageing of the population. The observed low risk of prostate cancer after isolated high grade PIN in this screening setting is in line with the current recommendation to abstain from early repeat biopsies after this diagnosis. The association of LSPC with high incidence of prostate cancer in re-biopsies confirms the need for early repeat biopsies and follow-up of these men. The low percentage of LSPC (<3% of biopsies) throughout all rounds is reassuring as it limits the biopsy burden in a screening setting.

Aurothiomalate and hydroxychloroquine inhibit nitric oxide production in chondrocytes and in human osteoarthritic cartilage.

OBJECTIVES: Nitric oxide (NO) is a destructive mediator produced by activated chondrocytes. The aim of the present study was to investigate the effect of disease-modifying anti-rheumatic drugs (DMARDs) on interleukin-1beta (IL-1beta)-induced NO production in chondrocyte cultures, and in human osteoarthritic cartilage. RESULTS: Aurothiomalate, hydroxychloroquine, methotrexate and leflunomide inhibited IL-1beta-induced inducible NO synthase (iNOS) expression and NO production in immortalized H4 chondrocytes, while penicillamine and sulfasalazine had no effect. This can be explained by the fact that the four effective DMARDs also suppressed IL-1beta-induced activation of nuclear factor kappa B (NF-kappaB), which is a crucial transcription factor for iNOS. Aurothiomalate and hydroxychloroquine also inhibited IL-1beta-induced NO production in OA cartilage whereas methotrexate and leflunomide had no effect. CONCLUSION: Aurothiomalate and hydroxychloroquine suppressed IL-1beta-induced NO production in chondrocyte cultures and in OA cartilage. The results suggest an additional anti-inflammatory mechanism for aurothiomalate and hydroxychloroquine and indicates their possible therapeutic value in the treatment of osteoarthritis (OA).

The progress of cognitive decline in multiple sclerosis. A controlled 3-year follow-up.

The purpose of this study was to illustrate how cognitive functioning evolves over time in patients with multiple sclerosis. We followed the evolution of cognitive performances in two clinically and demographically similar multiple sclerosis groups, the 'cognitively preserved' (n = 20) and the 'cognitively mildly deteriorated' (n = 22), and in healthy controls (n = 34). We conducted the follow-up examination using the Mild Deterioration Battery, the Mini-Mental State Examination, and a set of additional neuropsychological measures after an interval of 3 years. The drop-out rate in our study was only 5%. The 'cognitively preserved' multiple sclerosis group showed substantial neuropsychological stability by performing as well as the controls both at baseline and at follow-up. By contrast, the initially 'cognitively mildly deteriorated' group demonstrated progressive cognitive decline on many neuropsychological tests. The intermediate-length screening battery, the Mild Deterioration Battery, was sensitive to this decline, whereas the briefer Mini-Mental State Examination was not. The progressive cognitive decline could not be predicted from other disease variables. The study demonstrated that intact cognitive functioning in multiple sclerosis may remain stable, whereas incipient cognitive decline seems to be widespread and progressive in nature. Thus, progressive cognitive deterioration should be considered as one of the characteristics of multiple sclerosis.

Memory deficits and early cognitive deterioration in MS.

INTRODUCTION: In the present study, the pattern of memory and learning deficits in two cognitively different, but clinically and demographically similar, multiple sclerosis (MS) groups was compared. MATERIAL & METHODS: 23 patients represented the cognitively preserved MS group and 22 patients the MS group with early cognitive decline. A control group of 35 healthy controls was also included. The cognitive status of the subjects was defined using the Mild Deterioration Battery (MDB). Furthermore, all subjects were given a set of memory and learning tests and were instructed to evaluate the frequency of their memory and learning difficulties. The Mini-Mental State Examination (MMSE) was also administered to all subjects. RESULTS: The cognitively deteriorated patients, even those with normal MMSE performance, showed widespread memory and learning deficits, but adequate self-evaluation of their everyday memory and learning difficulties. The preserved group, in turn, performed similarly to the controls. CONCLUSION: Widespread memory and learning deficits are associated with relatively mild cognitive decline in MS. These deficits were observable in the intermediate-length screening battery, the MDB, but not in the MMSE. The present study suggests that the accuracy of patients' own evaluations of their memory and other cognitive problems is superior to the results of very brief screening batteries, like the MMSE. Therefore, brief screening in neuropsychological assessment of MS patients is not recommendable.

Attention related performance in two cognitively different subgroups of patients with multiple sclerosis.

To evaluate the underlying mechanisms of cognitive decline in multiple sclerosis, two clinically and demographically matched multiple sclerosis groups differing in cognitive status were assessed with attention related tasks. In addition to the attention tests recommended by the Cognitive Function Study Group of the American National Multiple Sclerosis Society, a test of sustained attention was used to evaluate the role of possible fatigue on cognitive performance. The cognitively mildly deteriorated group was slower than the cognitively preserved group and the controls on all tests of attention. The mildly deteriorated group did not, however, consistently differ from the other groups in the error scores of the attention tests. The preserved group exhibited slowness at the end of the visual vigilance test, but no deficits were found on the other attention related tests in this group. It is suggested that dissociable kinds of processing slowness are the origin of the deficits found on the attention tests in the two multiple sclerosis groups. Our preserved group exhibited signs of motor and fatigue related slowness, whereas the mildly deteriorated group also had extensive cognitive slowness. As sensitive indicators of cognitive slowness, attentional tests should be included in evaluation of the cognitive status of patients with multiple sclerosis.

Alphavirus replicase protein NSP1 induces filopodia and rearrangement of actin filaments.

Expression of the NSP1 protein of Semliki Forest virus and Sindbis virus in cultured cells induced filopodia-like extensions containing NSP1 but not F actin. The actin stress fibers disappeared, whereas vimentin, keratin, and tubulin networks remained intact. The effects of NSP1 were dependent on its palmitoylation but not on its enzymatic activities and were also observed in virus-infected cells.

Airborne transmission of tularemia in farmers.

In a tularemia epidemic during 1982 in northern Finland, 53 patients showed no peripheral portal of entry for infection or associated lymphadenopathy. Respiratory symptoms were observed in 72% of the patients. 26/38 cases had abnormal chest films. Hilar adenopathy was the most common finding (36%). Four patients did not receive antibiotics; 43 received tetracyclines, 5 streptomycin and 1 cefuroxime and amoxycillin. All patients recovered. 50 patients acquired the infection during common farming activities, such as making fresh hay with a hay-cutter, handling dry hay, threshing, etc. Thus, airborne transmission may be an important source of infection in normal farming activities in endemic areas of tularemia.