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.

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.

Effect of formoterol with or without budesonide in repeated low-dose allergen challenge.

The use of combination therapy in mild asthma is debated. The current authors evaluated the effects of formoterol alone and a formoterol/budesonide combination inhaler on asthma deterioration induced by repeated low-dose allergen exposure. In total, 15 subjects with intermittent allergic asthma inhaled low doses of allergen on seven consecutive weekdays in a three-period, crossover, double-blind, double-dummy comparison between formoterol 4.5 microg Turbuhaler, budesonide 160 microg/formoterol 4.5 microg Turbuhaler and placebo, each taken as two puffs 30 min after allergen dosing. The outcome variables were: provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second (PD(20)), exhaled nitric oxide fraction (F(eNO)), sputum eosinophils and prostaglandin D(2), and diary card recordings of symptoms (on a scale of 0-10), short-acting beta(2)-agonist use and evening forced expiratory volume in one second (FEV(1)). With placebo treatment, allergen exposure caused significant increases in airway hyperresponsiveness (geometric mean (coefficient of variation) PD(20): 397 (98) microg before versus 168 (82) microg after), F(eNO) (mean+/-sd 46+/-31 ppb before versus 73+/-46 ppb after) and asthma symptom score (mean+/-sd 0.39+/-0.55 before versus 0.68+/-0.67 after). Budesonide/formoterol abolished these changes and significantly improved baseline FEV(1). Formoterol alone, while providing symptom relief, was no better than placebo in protecting against the allergen-induced increase in airway inflammation. Signs of deteriorating asthma, provoked by low-dose allergen, are prevented by short-term use of budesonide/formoterol but not by temporary use of formoterol alone.

Cerebral perfusion in the elderly with nocturnal blood pressure fall.

Cerebrovascular disease may be linked with vascular autoregulation in aging. The aim of this study was to examine relation between nocturnal blood pressure (BP) fall and cerebral blood flow (CBF) changes in elderly men. The prospective 'Men born in 1914' cohort study has been in progress since 1968 and included 809 subjects. After 14 years from the last follow up, 97 subjects reached the age of 82 and underwent CBF measurement and 24 h ambulatory blood pressure monitoring. Diastolic BP at night decreased in 84 subjects with median 12.7% and increased in 13 subjects with median 3.7%. Relative diastolic BP fall at night was negatively associated to CBF in temporal and infero-parietal areas. Higher proportion of subjects with increasing systolic BP during the 14-year period was observed in the subgroup with extreme nocturnal diastolic BP dip, irrespectively of BP values or prevalence of hypertension. Extreme nocturnal diastolic BP fall in a cohort of elderly men is correlated with focal changes in CBF. Further studies could explain if increasing BP in the elderly is a cause or result of pathological autoregulation, and if antihypertensive treatment increases nocturnal BP dip.

Ultrasound characteristics of subdermally implanted Implanon contraceptive rods.

This study was designed to define sonographic characteristics and the optimal sonographic technique for localization of the single rod Implanon system. Diagnostic ultrasonography was performed in eight women who had the Implanon rod implanted in the medial aspect of the upper arm. All implants were scanned in the longitudinal and transverse direction using 3.5 MHz, 5 MHz, and 7.5 MHz linear array transducers. Scanning was performed both directly against the skin and with 2 and 4 cm Kiteco ultrasound stand-off pads. Each image obtained was evaluated for detectability of the Implanon rod and the grade of acoustic shadowing produced by the Implanon rod by two independent observers. Discrepancies in evaluation were adjudicated by a third observer. The Implanon rod implant was not directly identified using the transducer and standoff pad combinations. Implanon rods were indirectly identified as a result of the posterior acoustic shadow cast by the Implanon. Best demonstration was achieved with the 5 or 7.5 MHz transducer and a 2 cm stand-off pad in the transverse direction. Appropriate ultrasonographic technique and familiarity with posterior acoustic shadowing patterns generated by the implant provide a noninvasive method for localization of nonpalpable, single rod implants prior to removal.

PIP: Although the single-rod Implanon subdermal implant system is easier to insert and remove than the six-rod Norplant system, localization of one rod can be difficult in cases where external palpation is not possible. The sonographic characteristics and optimal sonographic technique for localization of the single rod Implanon contraceptive system were investigated in a study of eight US women who had a rod implanted in the medial aspect of the upper arm. All implants were scanned in the longitudinal and transverse direction through use of 3.5 MHz, 5 MHz, and 7.5 MHz linear array transducers. Scanning was performed both directly against the skin and with 2 cm and 4 cm Kiteco ultrasound stand-off pads. Each image was evaluated for detectability of the contraceptive rod and the grade of acoustic shadowing. In no instance was the Implanon rod identified through the transducer and stand-off pad combination. Rods were indirectly identified by their posterior acoustic shadow. The best demonstration of the rod was achieved with the 5 or 7 MHz transducer and a 2 cm stand-off pad placed between the transducer and the skin surface, with scanning in the transverse direction. These findings suggest that ultrasonography provides a noninvasive method for localization of implants prior to removal. However, since all eight rods in this series were readily palpable and in ideal subdermal location without associated scar tissue, these results cannot be extrapolated to patients with nonpalpable devices, excessive subcutaneous fat, or excessive scar tissue.

How to interpret differing cerebral blood flow patterns estimated with 99Tcm-HMPAO and 99Tcm-ECD SPET in a healthy population.

Two radiopharmaceuticals, 99Tcm-hexamethyl propylene amine oxime (99Tcm-HMPAO) and 99Tcm-ethyl cysteinate dimer (99Tcm-ECD), are currently used to determine cerebral blood flow. 99Tcm-ECD is, by virtue of its greater stability, superseding 99Tcm-HMPAO for routine examinations. Since the clinical assessment of 99Tcm-ECD images is usually based on experience with 99Tcm-HMPAO, we used both radiopharmaceuticals to compare regional cerebral blood flow in the same individuals. Eleven healthy subjects aged 67.1 +/- 6.3 years (mean +/- S.D.) underwent 99Tcm-ECD followed by 99Tcm-HMPAO single photon emission tomography. Cerebral blood flow was quantified in cortical and central regions of interest (basal ganglia, ventricles, white matter) in relation to cerebellar uptake. The intra-subject comparison of cerebral blood flow in the cortical areas revealed higher levels of perfusion in the posterior parietal, parieto-occipital and temporo-occipital areas using 99Tcm-ECD. In contrast to the cortical areas, cerebral blood flow in the central areas was greater using 99Tcm-HMPAO, especially in the centrum semiovale, basal ganglia, frontal white matter and frontal horns. This difference in cerebral blood flow when imaging healthy individuals with 99Tcm-ECD and 99Tcm-HMPAO should be taken into account in clinical practice when changing from one radiopharmaceutical to the other.

Experimental methods and modeling techniques for description of cell population heterogeneity.

With the continuous development, in the last decades, of analytical techniques providing complex information at single cell level, the study of cell heterogeneity has been the focus of several research projects within analytical biotechnology. Nonetheless, the complex interplay between environmental changes and cellular responses is yet not fully understood, and the integration of this new knowledge into the strategies for design, operation and control of bioprocesses is far from being an established reality. Indeed, the impact of cell heterogeneity on productivity of large scale cultivations is acknowledged but seldom accounted for. In order to include population heterogeneity mechanisms in the development of novel bioprocess control strategies, a reliable mathematical description of such phenomena has to be developed. With this review, we search to summarize the potential of currently available methods for monitoring cell population heterogeneity as well as model frameworks suitable for describing dynamic heterogeneous cell populations. We will furthermore underline the highly important coordination between experimental and modeling efforts necessary to attain a reliable quantitative description of cell heterogeneity, which is a necessity if such models are to contribute to the development of improved control of bioprocesses.

Studies on the control of antibody synthesis. VIII. Selection for high affinity antibody production in the secondary response.

Priming with haptenic determinants can augment the antibody response to a new haptenic determinant presented on a different carrier to which the original haptens are also coupled. This augmentation may be accompanied by a slight increase in the affinity of the antibody formed. However, only if the test hapten is present on the original priming antigen is there a selection for high affinity antibody-forming cells and a marked increase in the affinity of the antihapten antibody produced upon boosting is seen. The data are consistent with the assumption that antibody affinity is primarily controlled by the selection of B lymphocytes by antigen, while additional factors may be involved in controlling the magnitude of the response.

Immunoglobulin deficiency in children with a sudden overwhelming infection.

BACKGROUND: A small percentage of previously healthy children develop a sudden overwhelming infection (SOI) that rapidly progresses and results in shock and, occasionally, death. Some of these children may have an undetected Ig deficiency. OBJECTIVE: The aim of this study was to evaluate the incidence of Ig deficiency in children with a SOI. METHODS: A case series study was conducted in a university hospital and included 18 children who either died in the emergency room or required admission to the pediatric intensive care unit secondary to a SOI. Two age-matched control groups included children hospitalized to regular floor beds with an infectious process (infected control group) or a noninfectious process (noninfected control group). Serum left from the initial blood draw, before fluid resuscitation, was collected and stored at -70 degrees C. Total IgG, IgG subclasses, IgM, and IgA were assayed by rate nephelometry in a blinded fashion. RESULTS: In the study group, one of six children under 1 year of age had low Ig levels in comparison with two of nine control patients. In those children over the age of 1 year, 8 of 12 patients (67%) had low Ig levels as compared with 2 of 19 controls (11%) by Fisher's exact test, P = .002. Of those patients with Ig deficiencies, three of eight had isolated IgG deficiency, two of eight had combined IgG and IgA deficiency, three of eight had combined IgG and IgM deficiency. CONCLUSIONS: Children over the age of 1 year who present with a SOI have a significantly higher incidence of Ig deficiencies compared with age-matched controls.

Orthostatic hypotension in Alzheimer's disease: result or cause of brain dysfunction?

In Alzheimer's disease (AD), an association was found between autonomic dysfunction and frontal hypoperfusion in brain during orthostatic testing. To ascertain whether frontal hypoperfusion is dependent on longitudinal effects of hemodynamic disturbances, or contributes to them, we studied the relationship between the presence of orthostatic hypotension (OH) and resting cerebral blood flow (CBF) in late stages of AD. Twelve women with senile dementia of Alzheimer type (SDAT), and 15 non-demented women (mean age 82.6 years, SD 3.8 vs 81.8 years, SD 3.5) were examined with the orthostatic test. Four of 12 patients with SDAT, and 9 controls had OH (defined as systolic blood pressure fall > or = 20 mmHg). CBF was determined under resting conditions using 600 Mbq 99mTc HMPAO single photon emission computerized tomography (SPECT), and quantified in cortical areas in relation to cerebellum. In patients with SDAT and OH, CBF was lower in frontal and parieto-frontal cortical areas than in SDAT patients without OH. The former group was younger and had a shorter dementia duration. No significant differences in CBF were observed between controls with vs without OH. No differences in SDAT patients with or without OH were observed in the Berger dementia scale or Katz' ADL index. No difference in incidence of symptoms related to autonomic disturbances (diarrhea, obstipation, dysphagia, vertigo) was observed in either the SDAT or control group with regard to OH presence. We conclude that during the course of AD, OH can contribute to frontal brain changes and may exacerbate the disease. The further involvement of frontal dysfunction in aggravating blood pressure dysregulation in the elderly is discussed.

A study of regional cerebral blood flow using 99mTc-HMPAO-SPECT in elderly women with senile dementia of Alzheimer's type.

Thirteen women with senile dementia of Alzheimer's type (SDAT) according to NINCDS-ADRDA and 21 age-matched control women, aged 75-96 years, were investigated with clinical examination, dementia rating scales and single photon emission computed tomography (SPECT) using 99mTc-hexamethylpropyleneamine oxime (HM-PAO) as a tracer of regional cortical blood flow. The aim was to study whether typical SPECT findings of SDAT were seen also in the very old having the disease for a longer period. Neuropsychological assessment with vocabulary and spatial tests was performed in the control women, and the results were divided in three subgroups, normal, borderline and abnormal. Regional perfusion values, expressed as a ratio between cortical and cerebellar HM-PAO uptake, were lower in frontal, temporoparietal and occipital cortices in SDAT patients than in controls. The SDAT patients had the lowest uptake in the posterior temporoparietal region (0.67 +/- 0.06) and the corresponding value in the controls (0.79 +/- 0.05) differed significantly, p < 0.0001. The interhemispheric ratio between right and left posterior temporoparietal regions was 0.99 +/- 0.05. Nine of the control women (43%) had pathological SPECT with hemispheric asymmetries in 6 cases and bilateral temporooccipital reductions in 3 women. The neuropsychological assessment matched the findings in 7 of these women. One of the control women was judged as pathological and 10 women as borderline according to the spatial and vocabulary tests. Four of the 10 women with borderline results had normal SPECT. The sensitivity of the assessment to detect abnormalities compared to SPECT was 78% if borderline and abnormal results were expressed as true-positive cases. The specificity was 67%.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral blood flow in white matter is correlated with systolic blood pressure and EEG in senile dementia of the Alzheimer type.

The presence and functional significance of white matter lesions in the ageing brain and in dementia as well as their relation to blood pressure are often discussed. The aim of this study was to evaluate cerebral blood flow in white matter (WMCBF) and its relation to systemic blood pressure and multichannel EEG. WMCBF was measured in 24 elderly women with senile dementia of Alzheimer's type (SDAT, median age 85.5, range 68-93) and 20 age-matched controls (median age 86.0, range 79-93) using 99mTc-HMPAO single photon emission CT. A significant low WMCBF could be observed in all analysed regions in SDAT subjects compared to controls, with the greatest decline in the posterior region (parietotemporo-occipital area). Correlations between quantified EEG from the posterior regions and WMCBF were seen. Systolic blood pressure was significantly lower in the SDAT group and was positively correlated with WMCBF in the posterior and anterior brain regions. Whether low systemic blood pressure is the result of crerebral dysfunction is unclear.