Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic.

BACKGROUND: A mutation found in the BRCA1 or BRCA2 gene of a breast tumor could be either germline or somatically acquired. The prevalence of somatic BRCA1/2 mutations and the ratio between somatic and germline BRCA1/2 mutations in unselected breast cancer patients are currently unclear. PATIENTS AND METHODS: Paired normal and tumor DNA was analyzed for BRCA1/2 mutations by massively parallel sequencing in an unselected cohort of 273 breast cancer patients from south Sweden. RESULTS: Deleterious germline mutations in BRCA1 (n = 10) or BRCA2 (n = 10) were detected in 20 patients (7%). Deleterious somatic mutations in BRCA1 (n = 4) or BRCA2 (n = 5) were detected in 9 patients (3%). Accordingly, about 1 in 9 breast carcinomas (11%) in our cohort harbor a BRCA1/2 mutation. For each gene, the tumor phenotypes were very similar regardless of the mutation being germline or somatically acquired, whereas the tumor phenotypes differed significantly between wild-type and mutated cases. For age at diagnosis, the patients with somatic BRCA1/2 mutations resembled the wild-type patients (median age at diagnosis, germline BRCA1: 41.5 years; germline BRCA2: 49.5 years; somatic BRCA1/2: 65 years; wild-type BRCA1/2: 62.5 years). CONCLUSIONS: In a population without strong germline founder mutations, the likelihood of a BRCA1/2 mutation found in a breast carcinoma being somatic was ∼1/3 and germline 2/3. This may have implications for treatment and genetic counseling.

Outcomes of medical and surgical treatment for lower urinary tract symptoms (benign prostatic obstruction)--a population-based cohort study.

OBJECTIVE: To compare outcome of lower urinary tract symptoms (LUTS) between men with medical and surgical treatment. MATERIALS AND METHODS: A questionnaire was mailed to men aged 55, 65 and 75 years living in Tampere region, Finland in 1999 and the survey was repeated in 2004. LUTS were evaluated using DAN-PSS-1 questionnaire. A total of 1679 men (68% of the eligible) responded to both questionnaires. Of them, 114 men reported LUTS at baseline and medical treatment in the repeat survey and 47 men with LUTS had received surgical treatment. Seventy-two men with prostate cancer were excluded. Men with no medical treatment or surgery for LUTS in either questionnaire were included to no-treatment group. RESULTS: The men after surgical treatment showed a reduction in all LUTS symptom groups. However, among the medically treated and untreated men, all the symptoms worsened during the follow up. The proportion of symptomatic men after surgery was lower than among the medically treated men. In men with medical treatment, the prevalence of all 12 LUTS increased. Dysuria and postmicturition dribble were the only symptoms that had slightly better results in medical than in surgical treatment group. CONCLUSIONS: In this population-based study, operative treatment seemed to relieve LUTS, whereas medical treatment only slowed down their progression. These findings suggest that men with surgical treatment experience a more favourable outcome in LUTS than those receiving medical treatment.

Cardiovascular drug use and the incidence of erectile dysfunction.

It is unclear whether high blood pressure per se or antihypertensive drug use causes erectile dysfunction (ED). The aim of this study was to investigate the effect of cardiovascular diseases and their concomitant medications use on the incidence of ED. The target population consisted of men aged 55, 65 or 75 years old residing in the study area in Finland in 1999. Questionnaires were mailed to 2837 men in 1999 and to 2510 of them 5 years later. The follow-up sample consisted of 1665 men (66% of those eligible) who responded to both baseline and follow-up questionnaires. Men free of moderate or severe ED at baseline (N=1000) were included in the study. ED was assessed by two questions on subject ability to achieve or maintain an erection sufficient for intercourse. Poisson regression model was used in the multivariable analyses. The risk of ED was higher in men suffering from treated hypertension or heart disease than in those with the untreated condition. The risk of ED was higher in men using calcium channel inhibitor (adjusted relative risk (RR)=1.6, 95% confidence interval (CI) 1.0-2.4), angiotensin II antagonist (RR=2.2, 95% CI 1.0-4.7), non-selective beta-blocker (RR=1.7, 95% CI 0.9-3.2) or diuretic (RR=1.3, CI 0.7-2.4) compared with non-users. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective beta-blockers and serum lipid-lowering agents. In summary, calcium channel inhibitors, angiotensin II antagonists, non-selective beta-blockers and diuretics may increase the risk of ED.

Erectile dysfunction influences the subsequent incidence of lower urinary tract symptoms and bother.

It is unclear whether lower urinary tract symptoms (LUTS) cause erectile dysfunction (ED) independently or through common underlying pathophysiology and shared risk factors. The aim of this study was to investigate the effect of ED on the incidence of frequency and bother of LUTS. Target population consisted of men aged 50, 60 or 70 years residing in the study area in Finland in 1994. Questionnaires were mailed to 3143 men in 1994 and to 2837 of them 5 years later. The follow-up sample comprised 1683 men who responded to both baseline and follow-up surveys. ED was assessed by two questions on subject's ability to achieve or maintain an erection sufficient for intercourse and LUTS by the Danish Prostatic Symptom Score questionnaire. A dose-response relation was found between the severity of ED at baseline and the incidence of LUTS or bother during follow-up. After adjustment for the confounders, the incidence rate ratio (RR) of LUTS was higher in men with moderate (RR 1.5, 95% confidence interval (CI) 1.0-2.3) or severe ED (RR 2.3, 95% CI 1.4-3.8) than in those free of ED at entry. Compared with men free of ED at baseline, the RRs of urinary bother were 1.6 (95% CI 1.1-2.4), 1.9 (95% CI 1.1-3.2) and 2.2 (95% CI 1.1-4.3) for minimal, moderate or severe ED, respectively. In summary, ED is associated with an increased incidence of LUTS and bother. ED and LUTS may have a common underlying pathophysiology or shared risk factors.

Relationship between smoking and erectile dysfunction.

We estimated the effects of smoking on the risk and prognosis of erectile dysfunction (ED), and of ED on smoking behavior. The follow-up sample consisted of the 1442 men aged 50-75 y, who responded to both baseline and follow-up questionnaires. We estimated the effect of smoking on the incidence of ED among the 1130 men free from ED, ED on risk to start smoking in the 502 nonsmokers, smoking on the prognosis of ED among the 312 with ED and ED on quitting smoking among the 292 current smokers at baseline. Risk of ED increased nonsignificantly with smoking (odds ratio (OR)=1.4), while ED recovery reduced (OR=0.6). Therefore, there was the ratio of 2.3 (1.4/0.6) describing the total effect of smoking on the risk of ED. Both quitting (OR=1.7) and starting (OR=1.9) smoking were rare and nonsignificantly higher in men with ED. Most of the OR estimates on smoking-ED relationships were not statistically significant, probably due to small numbers. There are two bidirectional relations between ED and smoking. Those who smoked had a higher risk of ED than nonsmokers. The men with ED were more likely to start smoking than those free from ED. The estimates of effects were not statistically significant, but they were consistent with each other and with the hypothesis that smoking causes ED and ED causes smoking. The recovery from ED was less in smokers than among nonsmokers, and current smokers with ED were more likely to stop smoking than men free from ED. Numbers were few and estimates of effects were not significant, but consistent with the hypothesis of smoking preventing recovery from ED and ED improving the success of smoking cessation. Such transitions in four directions explain indirectly the known positive association between the prevalence of smoking and the prevalence of ED.

Are questions on both achieving and maintaining an erection needed to define erectile dysfunction?

Our aim was to ascertain if the assessment of erectile dysfunction (ED) should include questions on difficulty in both achieving and maintaining erection. A population-based study of 3143 men in Tampere region in Finland was conducted by mailed questionnaire. The 1983 men who responded questions on erectile function were included in the analysis. Different levels in the severity of ED were used to examine the agreement between the two questions. Consistency was measured by kappa coefficient. Consistency was fairly high (kappa=0.71) when the severity of ED was examined in four groups. In those cases where alternative responses were categorized into three groups, consistency was best (kappa=0.86) when the alternatives 'never' and 'sometimes' were combined. Consistency was almost perfect (kappa=0.97) when ED dichotomized into two groups and the cutoff was set between the alternatives 'quite often' and 'intercourse does succeed'. The kappa index was 0.86 with the cutoff level between 'sometimes' and 'quite often' and 0.67 with the cutoff between 'never' and 'sometimes'. When ED was examined in different age groups, the consistency was the highest among the oldest respondents. Responses on both symptoms are needed to distinguish between normal erectile function and minimal ED, and also between minimal and moderate ED, especially in young men. When the aim is to distinguish between complete ED and a milder form, the information from one question is the same as that from two questions.

Measurement of organ blood flow with coloured microspheres in the rat.

OBJECTIVE: The aim was to establish a method for measuring organ blood flow in rats using commercially available, coloured, dye extraction microspheres. METHODS: A mixture of radiolabelled and dye extraction microspheres was infused into rats at rest (basal) and during intravenous administration of either angiotensin II (0.5 microgram.kg-1.min-1) or isoprenaline [12.5 ng.(g0.74)-1.min-1]. Tissues were removed and placed in test tubes, counted for radioactivity, then digested with 2N sodium hydroxide. Within the same tube, microspheres were isolated using centrifugation and the dye was extracted with dimethylformamide. The dye was quantified by spectrophotometry. RESULTS: Recovery of microspheres averaged greater than 95% for all tissues studied; larger reagent volumes were required to achieve this level of recovery from white adipose tissue. Statistical analyses showed excellent correlations between blood flow values obtained by the dye extraction and radiolabelled microsphere techniques. Blood flow values obtained with the radioactive technique tended to be slightly higher. There were no differences in the results obtained with the two techniques when they were simultaneously used to measure changes in organ blood flow induced by angiotensin II or isoprenaline. CONCLUSIONS: The coloured, dye extraction microsphere technique accurately measured organ blood flow in rats. This technique is potentially useful for estimating blood flow in any animal, even if tissue sample size is limited.

A Potts Neuron Approach to Communication Routing.

A feedback neural network approach to communication routing problems is developed, with emphasis on multiple shortest path problems, with several requests for transmissions between distinct start and end nodes. The basic ingredients are a set of Potts neurons for each request, with interactions designed to minimize path lengths and prevent overloading of network arcs. The topological nature of the problem is conveniently handled using a propagator matrix approach. Although the constraints are global, the algorithmic steps are based entirely on local information, facilitating distributed implementations. In the polynomially solvable single-request case, the approach reduces to a fuzzy version of the Bellman-Ford algorithm. The method is evaluated for synthetic problems of varying sizes and load levels, by comparing to exact solutions from a branch-and-bound method, or to approximate solutions from a simple heuristic. With very few exceptions, the Potts approach gives high-quality legal solutions. The computational demand scales merely as the product of the numbers of requests, nodes, and arcs.

Is high-dose yohimbine hydrochloride effective in the treatment of mixed-type impotence? A prospective, randomized, controlled double-blind crossover study.

OBJECTIVES: To determine the effectiveness and safety of high-dose yohimbine for the treatment of mixed-type impotence. METHODS: Twenty-nine patients who had mixed-type impotence diagnosed on the basis of a sexual history, results of a physical examination, laboratory analysis, assessment of the sensory pain threshold of the dorsal nerve of the penis, and dynamic color Doppler sonography of the cavernosal arteries were entered into a randomized, double-blind, placebo-controlled, crossover comparison of a placebo with high-dose yohimbine hydrochloride (36 mg per day orally). The treatment consisted of two 25-day courses; after a 14-day washout period, the patients who initially received the placebo for 25 days were switched to yohimbine hydrochloride for 25 days. Erectile function, ejaculation, interest in sex, physical examination findings, blood pressure, pulse rate, weight, and audiovisual sexual stimulation test were investigated before treatment and at the end of each drug period. The Mann-Whitney test was used for the statistical analysis. RESULTS: Twenty-seven patients (93%) completed the whole treatment schedule. Positive clinical results (complete and partial responses) were obtained in 12 cases (44%) at the end of the yohimbine phase and in 13 (48%) after the placebo period. No statistical difference was indicated. Drug-related adverse effects occurred in 2 patients in the yohimbine group (7%). CONCLUSIONS: Yohimbine is no better than placebo as a first-line treatment for mixed-type impotence.

Effect of life-style factors on incidence of erectile dysfunction.

We estimated the incidence of erectile dysfunction (ED) in a population-based sample during 5-y follow-up and determined how the rate was affected by sociodemographic and life-style factors. The target population comprised all men aged 50, 60 or 70 y residing in the city of Tampere or 11 surrounding municipalities in Finland at the start of follow-up. A questionnaire was mailed to 3143 men in 1994 and to 2864 in 1999. The follow-up sample consisted of 1442 men who responded to both baseline and follow-up questionnaires. We estimated the effect of sociodemographic and life-style factors on the incidence of ED among the 1130 men free of ED at baseline. We found no differences in the incidence of ED by the level of education, marital status, urban/rural place of residence, amount of alcohol and coffee consumption. Obesity (rate ratio (RR)=1.7, 95% confidence interval (CI): 1.1-2.5) and current smoking (RR=1.5, 95% CI: 0.9-2.2) increased the incidence of ED. Current smokers free of comorbidity were also at higher risk of ED (RR=1.3, 95% CI: 0.8-2.1), but no effect was observed among past smokers. Our results indicate that sociodemographic and life-style factors, except age and obesity, have little influence on ED.

Neon colour spreading in three-dimensional illusory objects in humans.

We studied whether neon spreading can be induced within three-dimensional illusory triangles. Kanizsa triangles were induced by black pacman disks consisting of red sectors with curved sides. Viewing our stimuli monocularly produced two-dimensional illusory contours and surfaces as well as neon spreading in each figure. Triangles appeared concave or convex under stereoscopical viewing. Neon colour spreading was induced within illusory figures bending in three-dimensional space, suggesting that neural contour completion and surface filling-in interact across depth. Surprisingly, neon spreading was induced above the intervening surface even when the inducers were below the surface. Neon colour and illusory configuration were preserved behind the intervening surface only when it appeared transparent.

Depth asymmetry in da Vinci stereopsis.

We investigated processes that determine the depth localization of monocular points which have no unambiguous depth. It is known that horizontally adjacent binocular objects are used in depth localization and for a distance of 25-40 min arc monocular points localize to the leading edge of a depth constraint zone, which is an area defined by the visibility lines between which the points in the real world must be. We demonstrate that this rule is not valid in complex depth scenes. Adding other disparate objects to the scene changes the localization of the monocular point in a way that cannot be explained by the da Vinci explanation of monocular-binocular integration. The effect of additional disparate objects is asymmetric in depth: a crossed object does not affect the da Vinci effect but an uncrossed object biases the depth localization of monocular objects to uncrossed direction. We conclude that a horizontally adjacent binocular plane does not completely determine the depth localization of a monocular point and that depth spreading from other binocular elements biases the localization process.

Phantom surface captures stereopsis.

A phantom surface is a stereoscopic illusory area that can be seen in depth although there is no conventional stereoscopic cues [Liu, L., Stevenson, S.B., & Schor, C.M. (1994). Quantitative stereoscopic depth without binocular correspondence. Nature, 367, 66-69; Gillam, B. & Nakayama, K. (1999). Quantitative depth for a phantom surface can be based on cyclopean occlusion cues alone. Vision Research, 39, 109-112]. The phenomenon has been explained as an example of half-occlusion processing in which the visual system uses information about cyclopean occlusion structure of the visual world. We created stereo capture stereograms in which phantom surfaces changed the perceived depth of conventionally defined binocular textures. Because conventional stereoscopic matching is strongly affected by half-occlusion processing, we suggest that half-occlusion processing is an integral part of the early stereoscopic processing and solving of the correspondence problem.

Three-dimensionally slanted illusory contours capture stereopsis.

In stereo capture a stereogram of a crossed illusory figure pulls a texture bounded by the illusory contours to the same depth plane with the illusory figure. We investigated whether three-dimensionally curved and slanted illusory figures could capture a repeating background texture. According to results, stereoscopic capture was perceived when a disparate illusory contour was slanted provided that the period of the background texture was consistent with the three-dimensional geometry of the illusory surface. We suggest that stereo capture is actually induced by disparate rows of points defined by vertical cut-out sectors and the induced disparity spread is constrained by illusory contours and possible discrete matches of the background texture.

The effects of solar UV-B radiation on embryonic mortality and development in three boreal anurans (Rana temporaria, Rana arvalis and Bufo bufo).

Many species of amphibians have experienced population and range reductions. It has been hypothesized that sensitivity to UV-B may contribute to the population declines of some amphibian species. We performed field experiments to measure the effects of solar UV-B on the hatching success of three Finnish anuran species, the common frog (Rana temporaria), moor frog (Rana arvalis) and common toad (Bufo bufo). Further, the effects of natural UV-B radiation on survival of the tadpoles of the same three species of anurans were tested. A significant percentage of R. temporaria and B. bufo embryos survived when exposed to and protected from solar UV-B and hatching success was not affected by solar radiation. Elimination of solar UV-B significantly increased the hatching success of R. arvalis, but embryonic mortality was high in both treatments. The data indicates that under natural conditions, solar UV-B radiation influences embryo survival in R. arvalis, but has no effect on R. temporaria and B. bufo. Solar UV-B radiation had no effect on R. temporaria and R. arvalis tadpoles, but elimination of UV-B significantly increased survival of B. bufo tadpoles. It seems that ambient UV-radiation levels have no effect on R. temporaria but may affect R. arvalis and B. bufo at different developmental stages.

Effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction.

PURPOSE: We estimated the effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction. MATERIALS AND METHODS: The target population consisted of men 50, 60 or 70 years old residing in the study area in Finland in 1994. Questionnaires were mailed to 3,143 men in 1994 and to 2,864 men 5 years later. The followup sample consisted of 1,683 men who responded to baseline and followup questionnaires. We estimated the effect of NSAIDs on the incidence of ED in men free from moderate or complete ED at baseline (in 1,126). ED was assessed by 2 questions on subject ability to achieve or maintain an erection sufficient for intercourse. Confounding was assessed by stratification and by adjustment in multivariate Poisson regression model. RESULTS: The incidence of ED was 93 cases per 1,000 person-years in men who used and 35 in those who did not use NSAIDs. Among men with arthritis, the most common indication for NSAID use, ED incidence was 97 cases per 1,000 in those using and 52 in men who did not use NSAIDs. Compared with men who did not use NSAIDs and were free from arthritis, the relative risk of ED after controlling for the effects of age, smoking, and other medical conditions and medications was higher in men who used NSAIDs but were free of arthritis (IDR 2.0, 95% CI 1.2-3.5) and in those who used NSAIDs and had arthritis (IDR 1.9, 95% CI 1.2-3.1). The relative risk was only somewhat higher in men who had arthritis but did not use NSAIDs (IDR 1.3, 95% CI 0.9-1.8). CONCLUSIONS: The use of nonsteroidal anti-inflammatory drugs increases the risk of ED and the effect is independent of indication.

Temporal properties of colour and shape priming: evidence of multiple components of attention.

It has been shown in several studies that the selection of letters or numerals from an array can occur efficiently if criteria such as location, colour, shape, or size are used. It is also known that there are at least two components of spatial attention, the transient exogenous and the sustained endogenous. An interesting question is whether it is possible to elicit similar components when colour or shape information is used as a selection criterion. Experiments are reported the aim of which was to try to produce colour or shape precue effects on location and colour/shape discrimination accuracy, and to determine the minimum latency of these effects by sampling numerous cue lead times from 0 ms to 1000 ms. The results showed that, although accuracy did not increase monotonically with increased cue lead time, there were two transient peaks of performance at cue lead times of 0-200 ms, culminating at 30-50 ms and at 160-200 ms. It is suggested that the first component reflects nonspecific exogenous activation, triggered by the onset of a cue; the second component, in turn, may reflect feature-specific endogenous activation related to selection by colour or shape.

Occlusion constraints and stereoscopic slant.

In binocular vision horizontal magnification of one retinal image leads to a percept of three-dimensional slant around a vertical axis. It is demonstrated that the perception of slant is diminished when an occlusion interpretation is possible. A frontoparallel plane located in the immediate vicinity of a slanted surface in a location which allows a perception of occlusion reduces the magnitude of perceived slant significantly. When the same plane is placed on the other side, the slant perception is normal because there is no alternative occlusion interpretation. The results indicate that a common border between the occluder and a slanted surface is not a necessary condition for the reduction effect. If the edges are displaced and the edge of the slanted surface is placed in a location in which it could be occluded, the effect still appears.

Studies on the mechanism of ethanol-induced gastric damage in rats.

Concentrated ethanol causes gastric lesions by a mechanism that is poorly understood. We have investigated this mechanism in the rat stomach via gross morphologic, videomicroscopic, histochemical, and pharmacologic approaches. Within 1 min of contact, ethanol caused diffuse mucosal hyperemia. By 5 min, hyperemia greatly intensified at some mucosal sites. Beneath sites where mucosal hyperemia developed, intramural venules strongly constricted at 3-13 s postethanol, whereas submucosal arterioles dilated more than two times in diameter by 25 s. Submucosal venular constriction began sooner than arteriolar dilation (9 vs. 16 s, p less than 0.05). One-third of the gastric mucosal mast cells degranulated by 15 s postethanol; 50% discharged by 30 s. Ethanol-induced hyperemia was markedly reduced by lipoxygenase-selective inhibitors BW755C or nordihydroguaiaretic acid, or by the H1-antihistamine pyrilamine, but not by indomethacin, cimetidine, phentolamine, or methysergide. Based on these results, a model for the pathogenesis of ethanol-induced gastric lesions is proposed.

Sexual functions in patients with benign prostatic hyperplasia before and after transurethral resection of the prostate.

The purpose of this prospective study was to evaluate the sexual function of patients with benign prostatic hyperplasia (BPH) before and after transurethral resection of the prostate (TURP). The sexual functions of 155 patients with BPH were evaluated before TURP and 6 and 12 months afterwards. The mean age of the patients was 69 years (range 49-86 years). The only significant change in sexual function after TURP was improvement in early morning erections (P < 0.01). Sixty-eight per cent of the patients were satisfied with their sex life before TURP, 69% after 6 months and 67% after 12 months. The corresponding percentages of patients satisfied with their libido were 60%, 59% and 54%. Only 26% of the patients had completely satisfactory erections before TURP, while 22% had them 6 months later and 24% 12 months later. The proportion of fully impotent patients was 11% before the procedure, 13% after 6 months and 16% after 12 months. In 84% of the patients ejaculation was retrograde 6 months and 12 months after TURP. We conclude that TURP does not affect the sexual function of patients with BPH, with the exception of retrograde ejaculation.