Body size throughout the life-course and incident benign prostatic hyperplasia-related outcomes and nocturia.

BACKGROUND: Existing evidence suggests that there is an association between body size and prevalent Benign Prostatic Hyperplasia (BPH)-related outcomes and nocturia. However, there is limited evidence on the association between body size throughout the life-course and incident BPH-related outcomes. METHODS: Our study population consisted of men without histories of prostate cancer, BPH-related outcomes, or nocturia in the intervention arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (n = 4710). Associations for body size in early- (age 20), mid- (age 50) and late-life (age ≥ 55, mean age 60.7 years) and weight change with incident BPH-related outcomes (including self-reported nocturia and physician diagnosis of BPH, digital rectal examination-estimated prostate volume ≥ 30 cc, and prostate-specific antigen [PSA] concentration > 1.4 ng/mL) were examined using Poisson regression with robust variance estimation. RESULTS: Men who were obese in late-life were 25% more likely to report nocturia (Relative Risk (RR): 1.25, 95% Confidence Interval (CI): 1.11-1.40; p-trendfor continuous BMI < 0.0001) and men who were either overweight or obese in late-life were more likely to report a prostate volume ≥ 30 cc (RRoverweight: 1.13, 95% CI 1.07-1.21; RRobese: 1.10, 95% CI 1.02-1.19; p-trendfor continuous BMI = 0.017) as compared to normal weight men. Obesity at ages 20 and 50 was similarly associated with both nocturia and prostate volume ≥ 30 cc. Considering trajectories of body size, men who were normal weight at age 20 and became overweight or obese by later-life had increased risks of nocturia (RRnormal to overweight: 1.09, 95% CI 0.98-1.22; RRnormal to obese: 1.28, 95% CI 1.10-1.47) and a prostate volume ≥ 30 cc (RRnormal to overweight: 1.12, 95% CI 1.05-1.20). Too few men were obese early in life to examine the independent effect of early-life body size. Later-life body size modified the association between physical activity and nocturia. CONCLUSIONS: We found that later-life body size, independent of early-life body size, was associated with adverse BPH outcomes, suggesting that interventions to reduce body size even late in life can potentially reduce the burden of BPH-related outcomes and nocturia.

Multi-institutional Outcomes and Associations After Excision and Primary Anastomosis for Radiotherapy-associated Bulbomembranous Urethral Stenoses Following Prostate Cancer Treatment.

OBJECTIVE: To evaluate the outcomes of excision and primary anastomosis (EPA) for radiation-associated bulbomembranous stenoses using a multi-institutional analysis. The treatment of radiation-associated urethral stenosis is typically complex owing to the adverse impact of radiation on adjacent tissue. METHODS: An IRB-approved multi-institutional retrospective review was performed on patients who underwent EPA for bulbomembranous urethral stenosis following prostate radiotherapy. Preoperative patient demographics, operative technique, and postoperative outcomes were abstracted from 1/2007-6/2018. Success was defined as voiding per urethra without the need for endoscopic treatment and a minimum follow-up of 12 months. RESULTS: One hundred and thirty-seven patients from 10 centers met study criteria with a mean age of 69.3 years (50-86), stenosis length of 2.3 cm (1-5) and an 86.9% (119/137) success rate at a mean follow-up 32.3 months (12-118). Univariate Cox regression analysis identified increasing patient age (P = .02), stricture length (P <.0001) and combined modality radiotherapy (P = .004) as factors associated with stricture recurrence while body mass index (P = .79), diabetes (P = .93), smoking (P = .62), failed endoscopic treatment (P = .08) and gracilis muscle use (P = .25) were not. On multivariate analysis, increasing patient age (H.R.1.09, 95%CI 1.01-1.16; P = .02) and stenosis length (H.R.2.62, 95%CI 1.49-4.60; P = .001) remained associated with recurrence. Subsequent artificial urinary sphincter was performed in 30 men (21.9%), of which 25 required a transcorporal cuff and 5 developed cuff erosion. CONCLUSIONS: EPA for radiation-associated urethral stenosis effectively provides unobstructed instrumentation-free voiding. However, increasing stenosis length and age are independently associated with surgical failure. Patients should be counseled that further surgery for incontinence may be necessary.

Long-term follow-up of urethral reconstruction for blunt urethral injury at a young age: urinary and sexual quality of life outcomes.

INTRODUCTION: Little is known about long-term patient-reported outcomes following surgical repair for pediatric blunt urethral trauma. OBJECTIVE: The purpose was to evaluate long-term urinary outcomes, sexual function, and quality of life (QOL) of patients who undergo urethroplasty for blunt urethral trauma in childhood. STUDY DESIGN: After IRB approval, we retrospectively reviewed the records of patients who sustained blunt urethral injury at ≤18 years and underwent urethroplasty at our institution between 1978 and 2013. We then used a web-based survey to assess urinary/sexual/ejaculatory function and overall QOL using validated questionnaires. RESULTS: Of 68 eligible patients, 15 were able to be contacted (table). Median age of injury, age at urethroplasty, and age at follow-up were 17 (4-18), 17 (5-20), and 19 (13.5-21.5) years, respectively. The stricture was membranoprostatic in eight and bulbar in seven patients, with median length of 2 (1.6-2.6) cm. Excision/primary anastomosis was performed in all but three patients who required a buccal graft. Overall, 80% were 'very satisfied' and 20% were 'satisfied' with surgery. One patient reported a subsequent urethral intervention. On urethral stricture surgery patient-reported outcome measurement, the median bother (0 least, 24 worst) was 10 (8-12.5). The force of urine stream (1 strongest, 4 weakest) was 2 (1.5-2), with no report of urinary incontinence. The median Sexual Health Inventory for Men score (0 worst, 25 perfect) was 24 (22.5-24). The median ejaculatory function score (0 worst, 15 normal) was 14 (13-14.75). Six patients had fathered children and none reported infertility. Three patients reported <30° penile curvature not interfering with sex. Median QOL (0 worse, 10 best) was 8 (7.5-8). CONCLUSIONS: Urethroplasty after blunt urethral injury in young adult population is associated with a high long-term success rate with a low rate of long-term urinary and sexual consequences in adulthood.

Management of Delayed Onset Postoperative Hemorrhage after Anastomotic Urethroplasty.

Excision with primary anastomosis (EPA) urethroplasty is generally the preferred method for short strictures in the bulbar urethra, given its high success rate and low complication rate compared to other surgical interventions. Bleeding is a presumed risk factor for any surgical procedure but perioperative hemorrhage after an EPA requiring hospitalization and/or reintervention is unreported with no known consensus on the best course for management. Through our experience with three separate cases of significant postoperative urethral hemorrhage after EPA, we developed an algorithm for treatment beginning with conservative management and progressing through endoscopic and open techniques, as well as consideration of embolization by interventional radiology. All the three of these cases were managed successfully though they did require multiple interventions. We theorize that younger patients with more robust corpus spongiosum and more vigorous spontaneous erections, patients that have undergone fewer prior urethral procedures and therefore have more prominent vasculature, and those patients managed with a two-layer closure of the ventral urethra without ligation of the transected bulbar arteries are at a higher risk for this complication.

Associations of desire for change in sexual life amongst female medical students in North America.

We analyzed associations of dissatisfaction with sexual life and desire for change in female medical students. Students enrolled in medical schools in North America between February and July 2008 were invited to participate in an internet-based survey of sexual function. The principle outcome measure was a single item question on sexual life satisfaction and desire for change. Women who reported dissatisfaction and desire for change were classified as 'sexually bothered'. The survey also assessed ethnodemographic factors, student status, sexual history and depressive symptoms. Respondents completed the Female Sexual Function Index (FSFI) and the Index of Sexual Life. Descriptive statistics, analysis of variance and multivariable logistic regression were utilized to analyze responses. There were 661 non-virgin female subjects with data adequate for analysis. Whereas 281 (43%) of these met criteria for high risk of female sexual dysfunction (HRFSD) based on FSFI scoring, just 173 (26%) reported sexual bother. Among women with HRFSD, 126 (45%) reported sexual bother; in women without HRFSD, 362 (95%) were not sexually bothered. Interference in sexual life from tiredness and stress were associated with sexual bother. Progressively better scores on the FSFI desire, orgasm and satisfaction domains were significantly associated with lower odds of sexual bother. Few women in this cohort with FSFI score >26.55 reported sexual bother. Women with FSFI <26.55 had greater odds of sexual bother but this criterion alone was not pathognomonic for sexual concerns. Issues of sexual desire and orgasm appear to have a more important role than lubrication, arousal and sexual pain issues in this population.

Pelvic lymphadenectomy in prostate cancer.

This review analyzes the anatomy of the prostate gland's lymphatic drainage, the optimal anatomic extend of pelvic lymph node dissection (PLND) and which dissection may be superior, who should undergo a PLND during prostatectomy, and its potential therapeutic benefits and complications. The prostate gland's lymphatic drainage can be variable, but frequently metastatic disease is found in the internal iliac chain. We conclude that the extended PLND yields the most lymph nodes and therefore may be superior. Some have demonstrated an unproven survival benefit after performing an extended PLND, possibly from removal of occult disease or from more accurate staging.

Inhibition of Abl tyrosine kinase enhances nerve growth factor-mediated signaling in Bcr-Abl transformed cells via the alteration of signaling complex and the receptor turnover.

Receptor tyrosine kinase-mediated signaling is tightly regulated by a number of cytoplasmic signaling molecules. In this report, we show that Bcr-Abl transformed chronic myelogenous leukemia (CML) cell lines, K562 and Meg-01, express the receptor for nerve growth factor (NGF), TrkA, on the cell surface; however, the NGF-mediated signal is not particularly strong. Treatment with imatinib, a potent inhibitor of Bcr-Abl tyrosine kinase, downmodulates phosphorylation of downstream molecules. Upon stimulation with NGF, Erk and Akt are phosphorylated to a much greater degree in imatinib-treated cells than in untreated cells. Knockdown of expression of Bcr-Abl using small interfering RNA technique also enhanced NGF-mediated Akt phosphorylation, indicating that Bcr-Abl kinase modifies NGF signaling directly. Imatinib treatment also enhanced NGF signaling in rat adrenal pheochromocytoma cell line PC12 that expresses TrkA and c-Abl, suggesting that it is not only restoration of responsiveness to NGF after blocking oncoprotein activity, but also c-Abl tyrosine kinase per se may be a negative regulator of growth factor signaling. Furthermore, inhibition of Abl tyrosine kinase enhanced clearance of surface TrkA after NGF treatment and simultaneously enhanced NGF-mediated signaling, suggesting that as in neuronal cells 'signaling endosomes' are formed in hematopoietic cells. To examine the role of TrkA in CML cells, we studied cell growth or colony formation in the presence or absence of imatinib with or without NGF. We found that NGF treatment induces cell survival in imatinib-treated CML cell lines, as well as colony formation of primary CD34+ CML cells, strongly suggesting that NGF/TrkA signaling contributes to aberrant signaling in CML.

Fluorescence-based functional assay for Wnt/beta-catenin signaling activity.

Aberrant activation of beta-catenin signaling has been implicated in the development of human cancers. As a Wnt signal transducer, beta-catenin forms a complex with the lymphocyte enhancer-binding factor/T cell factor transcription factor and activates downstream targets that promote cell proliferation. Here we developed a Wnt-dependent beta-catenin-mediated heterologous transactivation system, which consisted of a chimeric transcription factor constructed by fusing the GAL4 DNA-binding domain with the full-length beta-catenin, and a GAL4-responsive reporter expressing GFP. The chimeric transcription factor was highly unstable and exerted no detectable transactivating effect on the GAL4-responsive reporter. However, lithium and Wnt1 significantly stabilized this chimeric transactivator, indicating that this transactivation system is regulated by beta-catenin in a Wnt-responsive fashion. Thus, this transactivation system could be used as a functional reporter to identify potential upstream factors that deregulate beta-catenin signaling during tumorigenesis, as well as to screen for potential anti-cancer agents that specifically inhibit beta-catenin signaling in human tumors.

Tetracycline-regulated gene expression mediated by a novel chimeric repressor that recruits histone deacetylases in mammalian cells.

Regulated gene expression will provide important platforms from which gene functions can be investigated and safer means of gene therapy may be developed. Histone deacetylases have recently been shown to play an important role in regulating gene expression. Here we investigated whether a more tightly controlled expression could be achieved by using a novel chimeric repressor that recruits histone deacetylases to a tetracycline-responsive promoter. This chimeric repressor was engineered by fusing the tetracycline repressor (TetR) with an mSin3-interacting domain of human Mad1 and was shown to bind the tetO(2) element with high affinity, and its binding was efficiently abrogated by doxycycline. The chimeric repressor was shown to directly interact with mSin3 of the histone deacetylase complex. This inducible system was further simplified by using a single vector that contained both a chimeric repressor expression cassette and a tetracycline-responsive promoter. When transiently introduced into mammalian cells, the chimeric repressor system exhibited a significantly lower basal level of luciferase activity (up to 25-fold) than that of the TetR control. When stably transfected into HEK 293 cells, the chimeric repressor system was shown to exert a tight control of green fluorescent protein expression in a doxycycline dose- and time-dependent fashion. Therefore, this novel chimeric repressor provides an effective means for more tightly regulated gene expression, and the simplified inducible system may be used for a broad range of basic and clinical studies.

Peroxisome proliferator-activated receptors: roles in tumorigenesis and chemoprevention in human cancer.

Peroxisome proliferator-activated receptors are nuclear receptors that were isolated for their ability to modulate lipid metabolism. Similar to other members of the nuclear receptor family, peroxisome proliferator-activated receptors bind ligand as heterodimers and exert their effects via transcriptional regulation through their DNA binding domains. During the past decade, it has become clear that peroxisome proliferator-activated receptors also contribute to a variety of different biologic processes, including atherosclerosis, insulin resistance, and more recently, cancer. In this review, we discuss the evidence for the different peroxisome proliferator-activated receptors' roles in tumorigenesis and also their potential application for the treatment and prevention of neoplastic diseases.

Adenoviral vector-mediated gene transfer for human gene therapy.

Human gene therapy promises to change the practice of medicine by treating the causes of disease rather than the symptoms. Since the first clinical trial made its debut ten years ago, there are over 400 approved protocols in the United States alone, most of which have failed to show convincing data of clinical efficacy. This setback is largely due to the lack of efficient and adequate gene transfer vehicles. With the recent progress in elucidating the molecular mechanisms of human diseases and the imminent arrival of the post genomic era, there are increasing numbers of therapeutic genes or targets that are available for gene therapy. Therefore, the urgency and need for efficacious gene therapies are greater than ever. Clearly, the current fundamental obstacle is to develop delivery vectors that exhibit high efficacy and specificity of gene transfer. Recombinant adenoviruses have provided a versatile system for gene expression studies and therapeutic applications. Of late, there has been a remarkable increase in adenoviral vector-based clinical trials. Recent endeavors in the development of recombinant adenoviral vectors have focused on modification of virus tropism, accommodation of larger genes, increase in stability and control of transgene expression, and down-modulation of host immune responses. These modifications and continued improvements in adenoviral vectors will provide a great opportunity for human gene therapy to live up to its enormous potential in the second decade.

[Tumoral angiogenesis--hot topic in science again]. / Tumorska angiogeneza--ponovno vruca znanstvena tema.

Angiogenesis is the formation of new capillary blood vessels. It has a very important role not only in physiological conditions but in the process of malignant tumors growth. Weak muscular layer, chaotical branching and irregular shape, are the characteristics of newly formed tumorous vessels. The number and arrangement of blood vessels differ between benign and malignant tumors. Latest data suggesting that drugs inhibiting angiogenesis can stop growth of malignant tumors made the research on tumorous angiogenesis a hot topic recently. Although reliable in differentiating benign from malignant tumors, two-dimensional ultrasound with color and pulsed Doppler, can not make spatial image of vascular architecture. Three-dimensional (3D) ultrasound with color Doppler allows the investigator to have a three-dimensional architectural picture of tumorous vascular network, and according to the findings it is possible to detect malignant tumors even in doubtful cases.

Manual de diagnóstico ultrasónico / Manual of diagnostic ultrasound

This manual provides guidance on the use of ultrasound in the diagnosis of a wide variety of common conditions at thw primary and first-referral levels of health care. It is intended for use by doctors, sonographers, nurses and midwives with basic training in ultrasound techniques, who are working with a general-purpose scanner, and who do not have ready access to expert advice

The introductory chapters explain how ultrasound works, give advice on choosing a scanner, and describe some misleading artefacts that may occur on ultrasound images. These are followed by 17 chapters dealing with specific organs or systems of the body. Each chapter includes guidance on the indications for ultrasound examination, and describes the preparation of the patient and the techniques that are likely to be successful. Numerous ultrasound scans show both normal and abnormal conditions, and almost every scan is accompanied by a corresponding computer-generated image on which the most significant features are highlighted