Role of α- and ß-adrenergic signaling in phenotypic targeting: significance in benign and malignant urologic disease.

The urinary tract is highly innervated by autonomic nerves which are essential in urinary tract development, the production of growth factors, and the control of homeostasis. These neural signals may become dysregulated in several genitourinary (GU) disease states, both benign and malignant. Accordingly, the autonomic nervous system is a therapeutic target for several genitourinary pathologies including cancer, voiding dysfunction, and obstructing nephrolithiasis. Adrenergic receptors (adrenoceptors) are G-Protein coupled-receptors that are distributed throughout the body. The major function of α1-adrenoceptors is signaling smooth muscle contractions through GPCR and intracellular calcium influx. Pharmacologic intervention of α-and ß-adrenoceptors is routinely and successfully implemented in the treatment of benign urologic illnesses, through the use of α-adrenoceptor antagonists. Furthermore, cell-based evidence recently established the antitumor effect of α1-adrenoceptor antagonists in prostate, bladder and renal tumors by reducing neovascularity and impairing growth within the tumor microenvironment via regulation of the phenotypic epithelial-mesenchymal transition (EMT). There has been a significant focus on repurposing the routinely used, Food and Drug Administration-approved α1-adrenoceptor antagonists to inhibit GU tumor growth and angiogenesis in patients with advanced prostate, bladder, and renal cancer. In this review we discuss the current evidence on (a) the signaling events of the autonomic nervous system mediated by its cognate α- and ß-adrenoceptors in regulating the phenotypic landscape (EMT) of genitourinary organs; and (b) the therapeutic significance of targeting this signaling pathway in benign and malignant urologic disease. Video abstract.

The effects of muscle mass and muscle quality on cardio-metabolic risk in peripubertal girls: a longitudinal study from childhood to early adulthood.

BACKGROUND: Increased cardio-metabolic risk is well documented in children and adolescents with obesity and normal weight obesity (NWO). However, the associations of muscle mass and muscle quality with cardio-metabolic risk, independent of weight status from childhood to adulthood, has not been examined. METHODS: A total of 236 girls were followed from pre-puberty to early adulthood. Fat mass (FM) and lean mass (LM) of the whole body were assessed by a dual-energy X-ray absorptiometry; muscle cross-sectional area (mCSA), muscle density (mDen; skeletal muscle fat content) of the lower leg by the peripheral quantitative computerized tomography; and blood glucose, insulin, triglycerides and high-density lipoprotein cholesterol by enzymatic photometric methods. Study participants were categorized based on body mass index (BMI) and percentage body fat (%BF) as overweight and/or obese (BMI⩾30 with %BF⩾30), normal weight obese (BMI 18.5-24.9 with %BF⩾30) and normal weight lean (BMI 18.5-24.9 with %BF <30). RESULTS: Girls with overweight and/or obesity from age of 11 to age 18 had greater LM and larger mCSA, but lower mDen and skeletal muscle mass index than the normal-weight girls (P<0.001 for all). Girls with NWO had similar mCSA and muscle mass but lower mDen and skeletal muscle index (SMI) than their normal-weight lean peers from childhood to early adulthood (P<0.001 all). In all girls, mDen and SMI were inversely associated with cardio-metabolic risk score (r2=0.012, P<0.05 and r2=0.201, P<0.001, respectively). However, after adjusting for whole-body FM or android abdominal FM, all associations disappeared. CONCLUSIONS: Skeletal muscle size and muscle mass are not associated with cardio-metabolic risk factors during pubertal growth after adjusting for measures of adiposity. Ectopic fat accumulation in the skeletal muscle and increased adiposity, particularly in the abdominal area in childhood, are significant contributors to increased cardio-metabolic risk in adulthood, irrespective of body weight status.

Distant effects of nitric oxide inhalation in lavage-induced lung injury in anaesthetised pigs.

BACKGROUND: Inhalation of nitric oxide (INO) exerts both local and distant effects. INO in healthy pigs causes down-regulation of endogenous nitric oxide (NO) production and vasoconstriction in lung regions not reached by INO, especially in hypoxic regions, which augments hypoxic pulmonary vasoconstriction. In contrast, in pigs with endotoxemia-induced lung injury, INO causes increased NO production in lung regions not reached by INO. The aim of this study was to investigate whether INO exerts distant effects in surfactant-depleted lungs. METHODS: Twelve pigs were anaesthetised, and the left lower lobe (LLL) was separately ventilated. Lavage injury was induced in all lung regions, except the LLL. In six pigs, 40 ppm INO was given to the LLL (INO group), and the effects on endogenous NO production and blood flow in the lavage-injured lung regions were studied. Six pigs served as a control group. NO concentration in exhaled air (ENO), NO synthase (NOS) activity and cyclic guanosine monophosphate (cGMP) in lung tissue, and regional pulmonary blood flow were measured. RESULTS: The calcium (Ca(2+) )-dependent NOS activity was lower (P < 0.05) in the lavage-injured lung regions in the INO group than in the control group. There were no measurable differences between the groups for Ca(2+) -independent NOS activity, cGMP, ENO, or regional pulmonary blood flow. CONCLUSIONS: Regional INO did not increase endogenous NO production in lavage-injured lung regions not directly reached by INO, but instead down-regulated the constitutive calcium-dependent nitric oxide synthase activity, indicating that NO may inhibit its own synthesis.

Low bone mineral density is associated with increased risk for myocardial infarction in men and women.

UNLABELLED: The association between bone mineral density (BMD) and myocardial infarction (MI) was investigated in 6,872 men and women. For both men and women, lower BMD in the femoral neck and hip was associated with increased risk of MI largely independent of smoking, hypertension, hypertriglyceridemia, and diabetes. INTRODUCTION: The relationship between BMD and cardiovascular disease is not completely understood. The objective of this prospective study was to investigate the risk of MI in relation to bone mineral density and to determine if cardiovascular risk factors could explain this association. METHODS: Dual energy X-ray absorptiometry was performed in 5,490 women and 1,382 men to determine total hip and femoral neck BMD (in grams per square centimeters) and estimate femoral neck volumetric BMD (in grams per cubic centimeters). During a mean follow-up time of 5.7 years, 117 women and 79 men suffered an initial MI. RESULTS: After adjustment for age and BMI, lower BMD of the femoral neck and total hip was associated with increased risk of MI for both women [hazard ratio (HR) = 1.33, 95% confidence interval (CI) 1.08-1.66 per standard deviation (SD) decrease in femoral neck BMD] and men (HR = 1.74, 95% CI 1.34-2.28 per SD decrease in total hip BMD). After additional adjustment for smoking, hypertension, hypertriglyceridemia, and diabetes, the associations were slightly attenuated in men (HR = 1.42-1.88 in the age and BMI-adjusted model versus 1.33-1.77 in the fully adjusted model) while similar attenuations were seen in women (HR = 1.06-1.25 versus 1.05-1.22). CONCLUSION: Lower BMD was associated with an increase in MI risk for both men and women. Women had consistently lower HRs compared to men in all models. Adjusting for smoking, hypertension, hypertriglyceridemia, and diabetes did not distinctively weaken these associations.

Lactation is associated with greater maternal bone size and bone strength later in life.

SUMMARY: The association between lactation and bone size and strength was studied in 145 women 16 to 20 years after their last parturition. Longer cumulative duration of lactation was associated with larger bone size and strength later in life. INTRODUCTION: Pregnancy and lactation have no permanent negative effect on maternal bone mineral density but may positively affect bone structure in the long term. We hypothesized that long lactation promotes periosteal bone apposition and hence increasing maternal bone strength. METHODS: Body composition, bone area, bone mineral content, and areal bone mineral density of whole body and left proximal femur were assessed using DXA, and cross-sectional area and volumetric bone mineral density of the left tibia shaft were measured by pQCT in 145 women (mean age 48 years, range 36-60 years) 16 to 20 years after their last parturition. Hip (HSI) and tibia strength indexes (TBSI) were calculated. Medical history and lifestyle factors including breastfeeding patterns and durations were collected via a self-administered questionnaire. Weight change during each pregnancy was collected from personal maternity tracking records. RESULTS: Sixteen to 20 years after the last parturition, women who had breastfed in total more than 33 months in their life, regardless of the number of children, had greater bone strength estimates of the hip (HSI = 1.92 vs. 1.61) and the tibia (TBSI = 5,507 vs. 4,705) owing to their greater bone size than mothers who had breastfed less than 12 months (p < 0.05 for all). The differences in bone strength estimates were independent of body height and weight, menopause status, use of hormone replacement therapy, and present leisure time physical activity level. CONCLUSION: Breastfeeding is beneficial to maternal bone strength in the long run.

Risk of hernia formation after radical prostatectomy: a comparison between open and robot-assisted laparoscopic radical prostatectomy within the prospectively controlled LAPPRO trial.

PURPOSE: In addition to incisional hernia, inguinal hernia is a recognized complication to radical retropubic prostatectomy. To compare the risk of developing inguinal and incisional hernias after open radical prostatectomy compared to robot-assisted laparoscopic prostatectomy. METHOD: Patients planned for prostatectomy were enrolled in the prospective, controlled LAPPRO trial between September 2008 and November 2011 at 14 hospitals in Sweden. Information regarding patient characteristics, operative techniques and occurrence of postoperative inguinal and incisional hernia were retrieved using six clinical record forms and four validated questionnaires. RESULTS: 3447 patients operated with radical prostatectomy were analyzed. Within 24 months, 262 patients developed an inguinal hernia, 189 (7.3%) after robot-assisted laparoscopic prostatectomy and 73 (8.4%) after open radical prostatectomy. The relative risk of having an inguinal hernia after robot-assisted laparoscopic prostatectomy was 18% lower compared to open radical retropubic prostatectomy, a non-significant difference. Risk factors for developing an inguinal hernia after prostatectomy were increased age, low BMI and previous hernia repair. The incidence of incisional hernia was low regardless of surgical technique. Limitations are the non-randomised setting. CONCLUSIONS: We found no difference in incidence of inguinal hernia after open retropubic and robot-assisted laparoscopic radical prostatectomy. The low incidence of incisional hernia after both procedures did not allow for statistical analysis. Risk factors for developing an inguinal hernia after prostatectomy were increased age and BMI.

Abdominal and gynoid adiposity and the risk of stroke.

BACKGROUND: Previous studies have indicated that fat distribution is important in the development of cardiovascular disease (CVD). We investigated the association between fat distribution, as measured by dual energy X-ray absorptiometry (DXA), and the incidence of stroke. METHODS: A cohort of 2751 men and women aged ≥40 years was recruited. Baseline levels of abdominal, gynoid and total body fat were measured by DXA. Body mass index (BMI, kg m(-2)) was calculated. Stroke incidence was recorded using the regional stroke registry until subjects reached 75 years of age. RESULTS: During a mean follow-up time of 8 years and 9 months, 91 strokes occurred. Of the adiposity indices accessed abdominal fat mass was the best predictor of stroke in women (hazard ratio (HR)=1.66, 95% confidence interval (CI)=1.23-2.24 per standard deviation increase), whereas the ratio of gynoid fat to total fat mass was associated with a decreased risk of stroke (HR=0.72, 95% CI=0.54-0.96). Abdominal fat mass was the only of the adiposity indices assessed that was found to be a significant predictor of stroke in men (HR=1.49, 95% CI=1.06-2.09). The associations between abdominal fat mass and stroke remained significant in both women and men after adjustment for BMI (HR=1.80, 95% CI=1.06-3.07; HR=1.71, 95% CI=1.13-2.59, respectively). However, in a subgroup analyses abdominal fat was not a significant predictor after further adjustment for diabetes, smoking and hypertension. CONCLUSION: Abdominal fat mass is a risk factor for stroke independent of BMI, but not independent of diabetes, smoking and hypertension. This indicates that the excess in stroke risk associated with abdominal fat mass is at least partially mediated through traditional stroke risk factors.

Learning curve for robotic assisted laparoscopic prostatectomy: a multi-institutional study of 3794 patients.

AIM: The aim of this study was to define the learning curve for positive surgical margin (PSM) rate and operative time (OT) for robotic assisted laparoscopic radical prostatectomy (RALP); while the learning curve appears shorter for surgical safety for RALP compared to other surgical modalities, this has not been well established for the above parameters. METHODS: We performed a retrospective cohort study of 3794 patients who underwent RALP between Jan 2003 and Sep 2009 by three surgeons (DL, PW, AKT) from three centers (UPenn, Karolinska, Cornell). Mean overall PSM rates and mean overall OT were calculated for all three surgeons at intervals of 50 RALPs per surgeon, and learning curves for these means were fit using a loess method. R version 2.71 was used for all statistical analysis. RESULTS: The learning curve for PSM rates for all patients demonstrated improvements continued with increasing surgeon experience, with over 1600 cases required to get a PSM rate <10%. When pT3 patients were evaluated, the learning curve started to plateau after 1000-1500 cases. Mean OT plateaued after 750 cases though with further surgical experience the OTs started to climb again. CONCLUSION: The learning curve for RALP is not as short as previously thought, and a large number of cases are needed to get PSM rates and OTs to a minimum. This suggests that RALP should be performed by high volume surgeons in order to optimize patient outcomes.

Oncologic outcomes of patients with incidental prostate cancer who underwent RARC: a comparison between nerve sparing and non-nerve sparing approach.

BACKGROUND: Incidental Prostate cancer (iPCa) is a relatively common finding during histopathological evaluation of radical cystectomy (RC) specimens. To reduce the high impact of RC on erectile function, several sexual-preserving techniques have been proposed. The aim of this study was to evaluate and compare the oncologic outcomes of patients with iPCa who underwent nerve spring and no-nerve sparing robot-assisted radical cystectomy (RARC). METHODS: The clinicopathologic data of male patients who underwent RARC at our institution between 2006 and 2016 were retrospectively analysed. Patients with iPCa at definitive pathological examinations were stratified in two groups, according to the preservation of the neurovascular bundles (nerve sparing vs no nerve sparing). Significant PCa was defined as any Gleason score ≥ 3 + 4. Biochemical recurrence (BR) was defined as a sustained PSA level > 0.2 ng/mL on two or more consecutive appraisals. BR rate was assessed only in patients with incidental prostate cancer and at least 2 years of follow-up. Differences in categorical and continuous variables were analysed using the chi-squared test and the Mann-Withney U test, respectively. Biochemical recurrence curves were generated using the Kaplan-Meier method and compared with the Log-rank test. RESULTS: Overall, 343 male patients underwent RARC for bladder cancer within the study period. Nerve-sparing surgery was performed in 143 patients (41%), of these 110 had at least 2 years of follow up after surgery. Patients who underwent nerve-sparing surgery were significantly younger (p < 0.001). Clinically significant PCa was found in 24% of patients. No significant differences regarding preoperative PSA value (p = 0.3), PCa pathological stage (p = 0.5), Gleason score (p = 0.3) and positive surgical margin rates (p = 0.3) were found between the two groups. After a median follow-up of 51 months only one patient, in the no-nerve-sparing group had developed a biochemical recurrence (p = 0.4). CONCLUSIONS: In our series most of the iPca detected in RC specimens can be considered as insignificant with a low rate of BR (0.9%). Nerve-sparing RARC is a safe procedure which did not affect oncological outcomes of patients with iPCa.

Abdominal and gynoid adipose distribution and incident myocardial infarction in women and men.

OBJECTIVE: The relationships between objectively measured abdominal and gynoid adipose mass with the prospective risk of myocardial infarction (MI) has been scarcely investigated. We aimed to investigate the associations between fat distribution and the risk of MI. SUBJECTS: Total and regional fat mass was measured using dual-energy X-ray absorptiometry (DEXA) in 2336 women and 922 men, of whom 104 subsequently experienced an MI during a mean follow-up time of 7.8 years. RESULTS: In women, the strongest independent predictor of MI was the ratio of abdominal to gynoid adipose mass (hazard ratio (HR)=2.44, 95% confidence interval (CI) 1.79-3.32 per s.d. increase in adipose mass), after adjustment for age and smoking. This ratio also showed a strong association with hypertension, impaired glucose tolerance and hypertriglyceridemia (P<0.01 for all). In contrast, the ratio of gynoid to total adipose mass was associated with a reduced risk of MI (HR= 0.57, 95% CI 0.43-0.77), and reduced risk of hypertension, impaired glucose tolerance and hypertriglyceridemia (P<0.001 for all). In men, gynoid fat mass was associated with a decreased risk of MI (HR=0.69, 95% CI 0.48-0.98), and abdominal fat mass was associated with hypertriglyceridemia (P for trend 0.02). CONCLUSION: In summary, fat distribution was a strong predictor of the risk of MI in women, but not in men. These different results may be explained by the associations found between fat distribution and hypertension, impaired glucose tolerance and hypertriglyceridemia.

Prostate cancer screening in men aged 50 to 69 years (STHLM3): A prospective population-based diagnostic study. Grönberg H, Adolfsson J, Aly M, Nordström T, Wiklund P, Brandberg Y, Thompson J, Wiklund F, Lindberg J, Clements M, Egevad L, Eklund M.Lancet Oncol. 2015 Dec;16(16):1667-76. [Epub 2015 Nov 10]. doi: 10.1016/S1470-2045(15)00361-7.

BACKGROUND: The prostate-specific antigen (PSA) test is used to screen for prostate cancer but has a high false-positive rate that translates into unnecessary prostate biopsies and overdiagnosis of low-risk prostate cancers. We aimed to develop and validate a model to identify high-risk prostate cancer (with a Gleason score of at least 7) with better test characteristics than that provided by PSA screening alone. METHODS: The Stockholm 3 (STHLM3) study is a prospective, population-based, paired, screen-positive, diagnostic study of men without prostate cancer aged 50 to 69 years randomly invited by date of birth from the Swedish Population Register kept by the Swedish Tax Agency. Men with prostate cancer at enrolment were excluded from the study. The predefined STHLM3 model (a combination of plasma protein biomarkers [PSA, free PSA, intact PSA, hK2, MSMB, MIC1], genetic polymorphisms [232 SNPs], and clinical variables [age, family, history, previous prostate biopsy, prostate exam]), and PSA concentration were both tested in all participants enrolled. The primary aim was to increase the specificity compared with PSA without decreasing the sensitivity to diagnose high-risk prostate cancer. The primary outcomes were number of detected high-risk cancers (sensitivity) and the number of performed prostate biopsies (specificity). The STHLM3 training cohort was used to train the STHLM3 model, which was prospectively tested in the STHLM3 validation cohort. Logistic regression was used to test for associations between biomarkers and clinical variables and prostate cancer with a Gleason score of at least 7. This study is registered with ISCRTN.com, number ISRCTN84445406. FINDINGS: The STHLM3 model performed significantly better than PSA alone for detection of cancers with a Gleason score of at least 7 (P<0.0001), the area under the curve was 0·56 (95% CI: 0·55-0·60) with PSA alone and 0·74 (95% CI: 0·72-0·75) with the STHLM3 model. All variables used in the STHLM3 model were significantly associated with prostate cancers with a Gleason score of at least 7 (P<0·05) in a multiple logistic regression model. At the same level of sensitivity as the PSA test using a cutoff of≥3ng/ml to diagnose high-risk prostate cancer, use of the STHLM3 model could reduce the number of biopsies by 32% (95% CI: 24-39) and could avoid 44% (35-54) of benign biopsies. INTERPRETATION: The STHLM3 model could reduce unnecessary biopsies without compromising the ability to diagnose prostate cancer with a Gleason score of at least 7, and could be a step towards personalised risk-based prostate cancer diagnostic programmes. FUNDING: Stockholm County Council (Stockholms Läns Landsting).

Early mortality risk stratification after SARS-CoV-2 infection / Estratificación de riesgo de mortalidad temprana en infección por SARS-CoV-2

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Pursuing Quality in the Application of Bladder Cancer Quality of Life Research.

Patient-reported outcomes (PRO), including health-related quality of life (HRQOL) measures, represent important means for evaluating patients' health outcomes and for guiding health care decisions made by patients, practitioners, investigators, and policy makers. In spite of the large number of studies examining HRQOL in patients with bladder cancer, very few review articles investigated this topic. Because these review studies report mixed results, incorporating bladder cancer HRQOL measures into standard urological practice is not a viable option. In this non-systematic review of the literature and commentary we note some general concerns regarding PRO research, but our primary focus is on the HRQOL methodology within the context of two types of bladder cancer: muscle invasive and non-muscle invasive bladder cancer. Considering bladder cancer HRQOL as the interaction of four areas of the assessment process (i.e., what model of HRQOL to choose, what instruments are available to fit the choice, how interpretation of the resulting data fits the model, and how to derive some utility from the chosen model) and the two types of disease (i.e., muscle invasive and non-muscle invasive) may move us toward a better understanding of bladder cancer HRQOL. Establishing a useful model of perceived general health or specific symptoms is the first and most important step in developing the responsive bladder cancer HRQOL measures necessitated by clinical settings.

Mitogen activated protein kinase inhibition by PD98059 blocks nerve growth factor stimulated axonal outgrowth from adult mouse dorsal root ganglia in vitro.

Nerve growth factor stimulated axonal outgrowth from explanted mouse dorsal root ganglia is dependent on mitogen activated protein kinase. PD98059 ([2-(2'amino-3'-methoxyphenyl)-oxanaphthalen-4-one]) blocks mitogen activated protein kinase by inhibiting its immediate upstream activator, mitogen activated protein kinase kinase (also known as MEK). Here we used PD98059 to study the role of mitogen activated protein kinase in the axonal outgrowth of adult dorsal root ganglia explants. Whereas PD98059 at 50 microM left spontaneous axonal outgrowth unaffected, it markedly inhibited nerve growth factor stimulated axon growth when assessed after two days in culture. A mitogen activated protein kinase assay and immunoblotting using antibodies discriminating between activated and inactivated kinase, both confirmed that PD98059 reduced the amount of activated enzyme in nerve growth factor stimulated preparations, while the total amounts of the kinase remained unchanged. Immunohistochemistry revealed the presence of neuronal mitogen activated protein kinase kinase and mitogen activated protein kinase itself. The latter enzyme was found to be activated in the growing axons, as seen by whole-mount labelling. At the ganglionic level activated mitogen activated protein kinase was preferentially detected in satellite cells. The results show that nerve growth factor stimulated axonal outgrowth in vitro from adult mouse dorsal root ganglia utilizes the mitogen activated protein kinase pathway.