Search

Soluble prorenin receptor (sPRR), a component of the renin-angiotensin system (RAS), has been identified as a plasma biomarker for hypertension and cardiovascular diseases in humans. Despite studies showing that sPRR in the kidney is produced by tubular cells in the renal collecting duct (CD), its biological actions modulating cardiorenal function in physiological conditions remain unknown. Therefore, the objective of our study was to investigate whether CD-derived human sPRR (HsPRR) expression influences cardiorenal function and examine sex and circadian differences. Thus, we investigated the status of the intrarenal RAS, water and electrolyte balance, renal filtration capacity, and blood pressure (BP) regulation in CD-HsPRR and control (CTL) mice. CD-HsPRR mice were generated by breeding human sPRR-Myc-tag mice with Hoxb7/Cre mice. Renal sPRR expression increased in CD-HsPRR mice, but circulating sPRR and RAS levels were unchanged compared with CTL mice. Only female littermates expressing CD-HsPRR showed 1 ) increased 24-h BP, 2 ) an impaired BP response to an acute dose of losartan and attenuated angiotensin II (ANG II)-induced hypertension, 3 ) reduced angiotensin-converting enzyme activity and ANG II content in the renal cortex, and 4 ) decreased glomerular filtration rate, with no changes in natriuresis and kaliuresis despite upregulation of the β-subunit of the epithelial Na + channel in the renal cortex. These cardiorenal alterations were displayed only during the active phase of the day. Taken together, these data suggest that HsPRR could interact with ANG II type 1 receptors mediating sex-specific, ANG II-independent renal dysfunction and a prohypertensive phenotype in a sex-specific manner. NEW & NOTEWORTHY We successfully generated a humanized mouse model that expresses human sPRR in the collecting duct. Collecting duct-derived human sPRR did not change circulating sPRR and RAS levels but increased daytime BP in female mice while showing an attenuated angiotensin II-dependent pressor response. These findings may aid in elucidating the mechanisms by which women show uncontrolled BP in response to antihypertensive treatments targeting the RAS, improving approaches to reduce uncontrolled BP and chronic kidney disease incidences in women.

[Figure: see text].

Background: Regulation of renal hemodynamics and BP via tubuloglomerular feedback (TGF) may be an important adaptive mechanism during pregnancy. Because the β-splice variant of nitric oxide synthase 1 (NOS1β) in the macula densa is a primary modulator of TGF, we evaluated its role in normal pregnancy and gestational hypertension in a mouse model. We hypothesized that pregnancy upregulates NOS1β in the macula densa, thus blunting TGF, allowing the GFR to increase and BP to decrease., Methods: We used sophisticated techniques, including microperfusion of juxtaglomerular apparatus in vitro , micropuncture of renal tubules in vivo , clearance kinetics of plasma FITC-sinistrin, and radiotelemetry BP monitoring, to determine the effects of normal pregnancy or reduced uterine perfusion pressure (RUPP) on macula densa NOS1β/NO levels, TGF responsiveness, GFR, and BP in wild-type and macula densa-specific NOS1 knockout (MD-NOS1KO) mice., Results: Macula densa NOS1β was upregulated during pregnancy, resulting in blunted TGF, increased GFR, and decreased BP. These pregnancy-induced changes in TGF and GFR were largely diminished, with a significant rise in BP, in MD-NOS1KO mice. In addition, RUPP resulted in a downregulation in macula densa NOS1β, enhanced TGF, decreased GFR, and hypertension. The superimposition of RUPP into MD-NOS1KO mice only caused a modest further alteration in TGF and its associated changes in GFR and BP. Finally, in African green monkeys, renal cortical NOS1β expression increased in normotensive pregnancies, but decreased in spontaneous gestational hypertensive pregnancies., Conclusions: Macula densa NOS1β plays a critical role in the control of renal hemodynamics and BP during pregnancy., (Copyright © 2021 by the American Society of Nephrology.)

(Pro)renin receptor (PRR), a 350-amino acid receptor initially thought of as a receptor for the binding of renin and prorenin, is multifunctional. In addition to its role in the renin-angiotensin system (RAS), PRR transduces several intracellular signaling molecules and is a component of the vacuolar H + -ATPase that participates in autophagy. PRR is found in the kidney and particularly in great abundance in the cortical collecting duct. In the kidney, PRR participates in water and salt balance, acid-base balance, and autophagy and plays a role in development and progression of hypertension, diabetic retinopathy, and kidney fibrosis. This review highlights the role of PRR in the development and function of the kidney, namely, the macula densa, podocyte, proximal and distal convoluted tubule, and the principal cells of the collecting duct, and focuses on PRR function in body fluid volume homeostasis, blood pressure regulation, and acid-base balance. This review also explores new advances in the molecular mechanism involving PRR in normal renal health and pathophysiological states.

Blood pressure regulation in health and disease involves a balance between afferent and efferent signals from multiple organs and tissues. Although there are numerous reviews focused on the role of sympathetic nerves in different models of hypertension, few have revised the contribution of afferent nerves innervating adipose tissue and their role in the development of obesity-induced hypertension. Both clinical and basic research support the beneficial effects of bilateral renal denervation in lowering blood pressure. However, recent studies revealed that afferent signals from adipose tissue, in an adipose-brain-peripheral pathway, could contribute to the increased sympathetic activation and blood pressure during obesity. This review focuses on the role of adipose tissue afferent reflexes and briefly describes a number of other afferent reflexes modulating blood pressure. A comprehensive understanding of how multiple afferent reflexes contribute to the pathophysiology of essential and/or obesity-induced hypertension may provide significant insights into improving antihypertensive therapeutic approaches.

Controversy exists regarding the use of dose capping of weight-based unfractionated heparin (UFH) infusions in obese and morbidly obese patients. The primary objective of this study was to compare time to first therapeutic activated partial thromboplastin time (aPTT) in hospitalized patients receiving UFH for acute venous thromboembolism (VTE) among three body mass index (BMI) cohorts: non-obese (< 30 kg/m 2 ), obese (30-39.9 kg/m 2 ), and morbidly obese (⩾ 40 kg/m 2 ). In this single-center, retrospective cohort study, patients were included if they ⩾ 18 years of age, had a documented VTE, and were on an infusion of UFH for at least 24 hours. Weight-based UFH doses were calculated using actual body weight. A total of 423 patients met the inclusion criteria, with 230 (54.4%), 146 (34.5%), and 47 (11.1%) patients in the non-obese, obese, and morbidly obese cohorts, respectively. Median times to therapeutic aPTT were 16.4, 16.6, and 17.1 hours in each cohort. Within 24 hours, the cumulative incidence rates for therapeutic aPTT were 70.7% for the non-obese group, 69.9% for the obese group, and 61.7% for the morbidly obese group (obese vs non-obese: HR = 1.02, 95% CI: 0.82-1.26, p = 0.88; morbidly obese vs non-obese: HR = 0.87, 95% CI: 0.62-1.21, p = 0.41). There was no significant difference in major bleeding events between BMI groups (obese vs non-obese, p = 0.91; morbidly obese vs non-obese, p = 0.98). Based on our study, heparin dosing based on actual body weight without a dose cap is safe and effective.

Potent platelet inhibition is one of the most important medical interventions to prevent ischemic complications during and after percutaneous coronary intervention (PCI). Practice has evolved with the introduction of potent oral P2Y 12 inhibitors that provide quick, effective platelet inhibition, and the need for routine glycoprotein IIb/IIIa inhibitors (GPIs) has decreased. Additionally, a shorter duration of GPI infusion has been shown to be safe with adequate oral antiplatelet loading, but clinical outcome data are limited to eptifibatide. This single-center, retrospective cohort study analyzed in-hospital outcomes for patients who received adjunctive GPI therapy for PCI before and after an institution-wide switch to high-dose bolus tirofiban with shortened infusion from short-duration eptifibatide. The primary end point was a composite in-hospital outcome of major and minor bleeding and cardiovascular events (death, myocardial infarction, coronary artery bypass grafting, ischemic stroke, and target vessel revascularization). Secondary end points included bleeding and cardiovascular event types. A total of 357 and 446 patients received eptifibatide and tirofiban, respectively, from February 1, 2014 through September 30, 2017. Thirty five eptifibatide and 46 tirofiban patients experienced an in-hospital composite event (9.8% vs 10.3%, p = 0.81). There was no difference found between in-hospital bleeding (6.4% vs 5.4%, p = 0.52) or cardiovascular events (5.6% vs 6.5%, p = 0.60) with the use of eptifibatide or tirofiban, respectively. Multivariable analysis showed that patients with transradial access or an indication of unstable angina were less likely to experience an in-hospital composite event (OR 0.30 and 0.19, respectively, p <0.001 for both). In conclusion, the use of high-dose bolus tirofiban with shortened infusion versus short-duration eptifibatide was not associated with an increase of in-hospital bleeding or cardiovascular events., (Copyright © 2018. Published by Elsevier Inc.)

Background: Excessive perioperative fluid administration likely increases postoperative cardiovascular, infectious, and GI complications. Early administration of diuretics after elective surgery facilitates rapid mobilization of excess fluid, potentially leading to decreased bowel edema, more rapid return of bowel function, and reduced length of hospital stay., Objective: This study aimed to evaluate the benefit of early diuresis after elective colon and rectal surgery in the setting of an enhanced recovery after surgery practice., Design: This was a prospective study., Settings: The study was conducted at a quaternary referral center., Patients: A randomized, open-label, parallel-group trial was conducted in patients undergoing elective colon and rectal surgery at a single quaternary referral center., Intervention: The primary intervention was administration of intravenous furosemide plus enhanced recovery after surgery on postoperative day 1 and 2 versus enhanced recovery after surgery alone., Main Outcome Measures: The primary outcome was length of hospital stay. Secondary outcomes included 30-day readmission rate, time to stool output during hospitalization after surgery, and incidence of various complications within the first 48 hours of hospital stay., Results: In total, 123 patients were randomly assigned to receive either furosemide plus enhanced recovery after surgery (n = 62) or enhanced recovery after surgery alone (n = 61). Groups were evenly matched at baseline. At interim analysis, length of hospital stay was not superior in the intervention group (80.6 vs 99.6 hours, p = 0.564). No significant difference was identified in the rates of nasogastric tube replacement (1.6% vs 9.7%, p = 0.125). Time to return of bowel function was significantly longer in the intervention group (45.4 vs 48.8 hours, p = 0.048). The decision was made to end the study early because the conditional power of the study favored futility., Limitations: This was a single-center study., Conclusions: Early administration of furosemide does not significantly reduce the length of hospital stay after elective colon and rectal surgery in the setting of enhanced recovery after surgery practice. See Video Abstract at http://links.lww.com/DCR/A714.

Hypertension is a complex, multifactorial disease affecting an estimated 78 million adults in the United States. Despite scientific gains, the etiology of human essential hypertension is unknown and current experimental models do not recapitulate all the behavioral and physiological characteristics of the pathology. Researchers should assess the translational capacity of these models and look to other animal models for the discovery of new therapies. Chlorocebus aethiops sabaeus , the African Green Monkey (AGM), is a nonhuman primate that develops spontaneous hypertension and may provide a novel translational model for the study of hypertension and associated diseases. In a randomly selected group of 424 adult AGMs, 37% (157/424) exhibited systolic blood pressures (SBP) >140 mmHg (SBP: 172.0 ± 2.2 mmHg) and were characterized as hypertensive (HT). 44% (187/424) were characterized as normotensive with SBP <120 mmHg (NT, SBP: 99.6 ± 1.0 mmHg) and the remaining 18% (80/424) as borderline hypertensive (BHT, SBP: 130.6 ± 0.6 mmHg). When compared with NT animals, HT AGMs are older (8.7 ± 0.6 vs. 12.4 ± 0.7 yr, P < 0.05) with elevated heart rates (125.7 ± 2.0 vs. 137.7 ± 2.2 beats/min, P < 0.05). BHT animals had average heart rates of 138.2 ± 3.1 beats/min ( P < 0.05 compared with NT) and were 11.00 ± 0.9 yr old. NT and HT animals had similar levels of angiotensinogen gene expression, plasma renin activity, and renal cortical renin content ( P > 0.05). HT monkeys exhibit renal vascular remodeling (wall-to-lumen ratio NT 0.11 ± 0.01 vs. HT 0.15 ± 0.02, P < 0.05) and altered glomerular morphology (Bowman's capsular space: NT 30.9 ± 1.9% vs. HT 44.4 ± 3.1%, P < 0.05). The hypertensive AGM provides a large animal model that is highly similar to humans and should be studied to identify novel, more effective targets for the treatment of hypertension., (Copyright © 2017 the American Physiological Society.)

Little is known about the potential for ion channels to regulate cellular behaviors during tissue regeneration. Here, we utilized an amphibian tail regeneration assay coupled with a chemical genetic screen to identify ion channel antagonists that altered critical cellular processes during regeneration. Inhibition of multiple ion channels either partially (anoctamin1/Tmem16a, anoctamin2/Tmem16b, K V 2.1, K V 2.2, L-type Ca V channels and H/K ATPases) or completely (GlyR, GABA A R, K V 1.5 and SERCA pumps) inhibited tail regeneration. Partial inhibition of tail regeneration by blocking the calcium activated chloride channels, anoctamin1&2, was associated with a reduction of cellular proliferation in tail muscle and mesenchymal regions. Inhibition of anoctamin 1/2 also altered the post-amputation transcriptional response of p44/42 MAPK signaling pathway genes, including decreased expression of erk1/erk2. We also found that complete inhibition via voltage gated K + channel blockade was associated with diminished phagocyte recruitment to the amputation site. The identification of H + pumps as required for axolotl tail regeneration supports findings in Xenopus and Planaria models, and more generally, the conservation of ion channels as regulators of tissue regeneration. This study provides a preliminary framework for an in-depth investigation of the mechanistic role of ion channels and their potential involvement in regulating cellular proliferation and other processes essential to wound healing, appendage regeneration, and tissue repair., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Adult rats exposed to maternal separation (MatSep) are normotensive but display lower glomerular filtration rate and increased renal neuroadrenergic drive. The aim of this study was to determine the renal α-adrenergic receptor density and the renal vascular responsiveness to adrenergic stimulation in male rats exposed to MatSep. In addition, baroreflex sensitivity was assessed to determine a component of neural control of the vasculature. Using tissue collected from 4-mo-old MatSep and control rats, α 1 -adrenergic receptors (α 1 -ARs) were measured in renal cortex and isolated renal vasculature using receptor binding assay, and the α-AR subtype gene expression was determined by RT-PCR. Renal cortical α 1 -AR density was similar between MatSep and control tissues (B max = 44 ± 1 vs. 42 ± 2 fmol/mg protein, respectively); however, MatSep reduced α 1 -AR density in renal vasculature (B max = 47 ± 4 vs. 62 ± 4 fmol/mg protein, P < 0.05, respectively). In a separate group of rats, the pressor, bradycardic, and renal vascular constrictor responses to acute norepinephrine injection (NE, 0.03-0.25 μg/μl) were determined under anesthesia. Attenuated NE-induced renal vasoconstriction was observed in rats exposed to MatSep compared with control ( P < 0.05). A third group of rats was infused at steady state with the α 1 agonist phenylephrine (10 μg/min iv) and vasodilator sodium nitroprusside (5 μg/min iv). The difference between the change in heart rate/mean arterial pressure slopes was indicative of reduced baroreflex sensitivity in MatSep vs. control rats (-0.45 ± 0.04 vs. -0.95 ± 0.07 beats·min -1 ·mmHg -1 , P < 0.05). These data support the notion that reduced α-adrenergic receptor expression and function in the renal vasculature could develop secondary to MatSep-induced overactivation of the renal neuroadrenergic tone., (Copyright © 2017 the American Physiological Society.)

Soft tissue repair is a complex process that requires specific communication between multiple cell types to orchestrate effective restoration of physiological functions. Macrophages play a critical role in this wound healing process beginning at the onset of tissue injury. Understanding the signaling mechanisms involved in macrophage recruitment to the wound site is an essential step for developing more effective clinical therapies. Macrophages are known to respond to electrical fields, but the underlying cellular mechanisms mediating this response is unknown. This study demonstrated that low-amplitude sine-wave electrical stimulation (ES) initiates a soft tissue response in the absence of injury in Procambarus clarkii This cellular response was characterized by recruitment of macrophage-like hemocytes to the stimulation site indicated by increased hemocyte density at the site. ES also increased tissue collagen deposition compared to sham treatment (P < 0.05). Voltage-gated potassium (KV) channel inhibition with either 4-aminopyridine or astemizole decreased both hemocyte recruitment and collagen deposition compared to saline infusion (P < 0.05), whereas inhibition of calcium-permeable channels with ruthenium red did not affect either response to ES Thus, macrophage-like hemocytes in P. clarkii elicit a wound-like response to exogenous ES and this is accompanied by collagen deposition. This response is mediated by KV channels but independent of Ca(2+) channels. We propose a significant role for KV channels that extends beyond facilitating Ca(2+) transport via regulation of cellular membrane potentials during ES of soft tissue., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Student populations are diverse such that different types of learners struggle with traditional didactic instruction. Problem-based learning has existed for several decades, but there is still controversy regarding the optimal mode of instruction to ensure success at all levels of students' past achievement. The present study addressed this problem by dividing students into the following three instructional groups for an upper-level course in animal physiology: traditional lecture-style instruction (LI), guided problem-based instruction (GPBI), and open problem-based instruction (OPBI). Student performance was measured by three summative assessments consisting of 50% multiple-choice questions and 50% short-answer questions as well as a final overall course assessment. The present study also examined how students of different academic achievement histories performed under each instructional method. When student achievement levels were not considered, the effects of instructional methods on student outcomes were modest; OPBI students performed moderately better on short-answer exam questions than both LI and GPBI groups. High-achieving students showed no difference in performance for any of the instructional methods on any metric examined. In students with low-achieving academic histories, OPBI students largely outperformed LI students on all metrics (short-answer exam: P < 0.05, d = 1.865; multiple-choice question exam: P < 0.05, d = 1.166; and final score: P < 0.05, d = 1.265). They also outperformed GPBI students on short-answer exam questions (P < 0.05, d = 1.109) but not multiple-choice exam questions (P = 0.071, d = 0.716) or final course outcome (P = 0.328, d = 0.513). These findings strongly suggest that typically low-achieving students perform at a higher level under OPBI as long as the proper support systems (formative assessment and scaffolding) are provided to encourage student success., (Copyright © 2015 The American Physiological Society.)

Mitochondrial (Mt) dysfunction contributes to the pathophysiology of renal function and promotes cardiovascular disease such as hypertension. We hypothesize that renal Mt-genes derived from female spontaneously hypertensive rats (SHR) that exhibit hypertension have reduced expression specific to kidney cortex. After breeding a female Okamoto-Aoki SHR (SAP = 188mmHg) with Brown Norway (BN) males (SAP = 100 and 104 mmHg), hypertensive female progeny were backcrossed with founder BN for 5 consecutive generations in order to maintain the SHR mitochondrial genome in offspring that contain over increasing BN nuclear genome. Mt-protein coding genes (13 total) and nuclear transcription factors mediating Mt-gene transcription were evaluated in kidney, heart and liver of normotensive (NT: n = 20) vs. hypertensive (HT: n = 20) BN/SHR-mtSHR using quantitative real-time PCR. Kidney cortex, but not liver or heart Mt-gene expression was decreased ~2-5 fold in 12 of 13 protein encoding genes of HT BN/SHR-mtSHR. Kidney cortex but not liver mRNA expression of the nuclear transcription factors Tfam, NRF1, NRF2 and Pgc1α were also decreased in HT BN/SHR-mtSHR. Kidney cortical tissue of HT BN/SHR-mtSHR exhibited lower cytochrome oxidase histochemical staining, indicating a reduction in renal oxidative phosphorylation but not in liver or heart. These results support the hypothesis that renal cortex of rats with SHR mitochondrial genome has specifically altered renal expression of genes encoding mitochondrial proteins. This kidney-specific coordinated reduction of mitochondrial and nuclear oxidative metabolism genes may be associated with heritable hypertension in SHR.

Background: Although remodeling changes of the lower airway are well described, similar changes in the upper airway are less well known. Remodeling changes of the upper airway in chronic rhinosinusitis (CRS) relevant to different phenotypes and endotypes and their clinical characteristics are investigated., Methods: A cross-sectional study of adult patients with CRS was performed. Mucosal samples were taken during endoscopic sinus surgery (ESS). Histopathological analysis included eosinophil count, eosinophil activation (eosinophilic mucin), and remodeling changes. Mucosal damage was defined as ulceration, edema, and hypertrophic changes. Patient-reported outcomes (PROMs) were assessed using a Nasal Symptom Score (NSS) and Sino-Nasal Outcome Test (SNOT-22). Patients were subgrouped by presence of polyps (CRSwNP/CRSsNP) or tissue eosinophilia (>10/high power field). Subgroup analysis was performed when both eosinophilic chronic rhinosinusitis (eCRS) and eosinophil activation (eCRSwEA) were coexistent. Analysis between subgroups, pathology, and PROMs was also performed., Results: A total of 259 patients (age 48.5 ± 15.6 years, 45% female) were recruited; 53% CRSwNP, 51% eCRS. Remodeling changes were present in 85%, higher in both CRSwNP (90%, p = 0.006) and eCRS (91%, p = 0.004). Mucosal damage changes were common in eCRS (ulceration 18%, p = 0.003; edema 98%, p < 0.001; hypertrophic changes 25%, p = 0.007). NSS was worse in CRSwNP compared to CRSsNP (2.84 ± 1.1 vs 2.29 ± 1.1, p < 0.001) and eCRSwEA (2.95 ± 0.16 vs 2.51 ± 0.11, p = 0.04). "Loss of sense of smell or taste" was worse in patients with evidence of mucosal damage (p = 0.006)., Conclusion: Remodeling features are present in CRS. Tissue eosinophilia and evidence of eosinophil activation is closely associated with remodeling features of CRS, associated mucosal damage and clinical symptoms., (© 2015 ARS-AAOA, LLC.)

Transcriptional activation of major histocompatibility complex (MHC) I and II molecules by the cytokine, interferon γ (IFN-γ), is a key step in cell-mediated immunity against pathogens and tumors. Recent evidence suggests that suppression of MHC I and II expression on multiple tumor types plays important roles in tumor immunoevasion. One such tumor is malignant melanoma, a leading cause of skin cancer-related deaths. Despite growing awareness of MHC expression defects, the molecular mechanisms by which melanoma cells suppress MHC and escape from immune-mediated elimination remain unknown. Here, we analyze the dysregulation of the Janus kinase (JAK)/STAT pathway and its role in the suppression of MHC II in melanoma cell lines at the radial growth phase (RGP), the vertical growth phase (VGP) and the metastatic phase (MET). While RGP and VGP cells both express MHC II, MET cells lack not only MHC II, but also the critical transcription factors, interferon response factor (IRF) 1 and its upstream activator, signal transducer and activator of transcription 1 (STAT1). Suppression of STAT1 in vitro was also observed in patient tumor samples, suggesting STAT1 silencing as a global mechanism of MHC II suppression and immunoevasion.

In resource-limited settings, the lack of decentralized molecular diagnostic testing and sparse access to centralized medical facilities can present a critical barrier to timely diagnosis, treatment, and subsequent control and elimination of infectious diseases. Isothermal nucleic acid amplification methods, including reverse transcription loop-mediated isothermal amplification (RT-LAMP), are well-suited for decentralized point-of-care molecular testing in minimal infrastructure laboratories since they significantly reduce the complexity of equipment and power requirements. Despite reduced complexity, however, there is still a need for a constant heat source to enable isothermal nucleic acid amplification. This requirement poses significant challenges for laboratories in developing countries where electricity is often unreliable or unavailable. To address this need, we previously developed a low-cost, electricity-free heater using an exothermic reaction thermally coupled with a phase change material. This heater achieved acceptable performance, but exhibited considerable variability. Furthermore, as an enabling technology, the heater was an incomplete diagnostic solution. Here we describe a more precise, affordable, and robust heater design with thermal standard deviation <0.5°C at operating temperature, a cost of approximately US$.06 per test for heater reaction materials, and an ambient temperature operating range from 16°C to 30°C. We also pair the heater with nucleic acid lateral flow (NALF)-detection for a visual readout. To further illustrate the utility of the electricity-free heater and NALF-detection platform, we demonstrate sensitive and repeatable detection of HIV-1 with a ß-actin positive internal amplification control from processed sample to result in less than 80 minutes. Together, these elements are building blocks for an electricity-free platform capable of isothermal amplification and detection of a variety of pathogens.

Angiotensin II (AII) has been linked as a causal factor in several experimental models of hypertension (HT) including Okamoto spontaneously hypertensive rats (SHR). The transmission and expression of AII type 1 receptors (AT1r) in SHR and the development of genetic HT remain unknown. It is hypothesized that tissue-specific expression of renin-angiotensin system (RAS) genes derived from SHR are linked to HT in offspring of SHR crossed with Brown Norway (BN) rats. Hypertensive female progeny of BN/SHR matings was backcrossed with founder BN males to generate the F1 and five backcross generations (BN/SHR-mt(SHR)). Progeny were phenotyped according to normotension (NT: systolic arterial pressure [SAP] ≤ 124 mmHg), borderline hypertension (BHT: 124 ≤ SAP < 145 mmHg), and HT (SAP ≥ 145 mmHg). Six generations produced more HT (n = 88; 46%) than NT (n = 21; 11%) offspring. The mRNA expression of the RAS was evaluated in NT (n = 20) and HT (n = 20) BN/SHR-mt(SHR) across several generations. Quantitative real-time polymerase chain reaction analysis of kidney tissue showed increased expression of AII, type 1 receptors (Agtr1a) (∼2.5-fold) in HT versus NT rats, while other members of both the renal and systemic RAS pathway were not different. Western blot analysis from kidney homogenates showed that AT1r protein levels were higher (P < 0.05) in backcross generation 3 (BC3) HT versus NT rats. Evaluation of SAP as a function of AT1r expression by linear regression indicated positive correlation (P < 0.05) in kidney of BC3 BN/SHR-mt(SHR) rats. Thus, elevated kidney AT1r expression may be involved in the development of HT in BN/SHR-mt(SHR) rats.

Nasal obstruction is one of the most common presenting symptoms requiring medical attention at both the primary care physician and the otorhinolaryngologists' level. Nasal obstruction may be caused by anatomic, physiological, or neurologic factors. Complexity is added to this situation because, often, the causation may be multifactorial. Nasal obstruction is the primary symptom of persistent allergic rhinitis (AR) and affects up to 40% of the population. AR must be treated throughout the year; thus, treatment choices and patient compliance must be considered. It is interesting to note that AR directly affects an individual's quality of life, quality of sleep, and workplace efficiency. Therefore, the magnitude of costs to both the individual and the society must be recognized. Various medical therapies and surgical techniques will be described for the treatment of nasal obstruction.

Nasal obstruction is one of the most common presenting symptoms requiring medical attention at both the primary care physician and the otorhinolaryngologists' level. Nasal obstruction may be caused by anatomic, physiological, or neurologic factors. Complexity is added to this situation because, often, the causation may be multifactorial. Nasal obstruction is the primary symptom of persistent allergic rhinitis (AR) and affects up to 40% of the population. AR must be treated throughout the year; thus, treatment choices and patient compliance must be considered. It is interesting to note that AR directly affects an individual's quality of life, quality of sleep, and workplace efficiency. Therefore, the magnitude of costs to both the individual and the society must be recognized. Various medical therapies and surgical techniques will be described for the treatment of nasal obstruction.

This paper describes a rapid, high-throughput flow-through membrane immunoassay (FMIA) platform. A nitrocellulose membrane was spotted in an array format with multiple capture and control reagents for each sample detection area, and assay steps were carried out by sequential aspiration of sample and reagents through each detection area using a 96-well vacuum manifold. The FMIA provides an alternate assay format with several advantages over ELISA. The high surface area of the membrane permits high label concentration using gold labels, and the small pores and vacuum control provide rapid diffusion to reduce total assay time to ~30 min. All reagents used in the FMIA are compatible with dry storage without refrigeration. The results appear as colored spots on the membrane that can be quantified using a flatbed scanner. We demonstrate the platform for detection of IgM specific to lipopolysaccharides (LPS) derived from Salmonella Typhi. The FMIA format provides analytical results comparable to ELISA in less time, provides integrated assay controls, and allows compensation for specimen-to-specimen variability in background, which is a particular challenge for IgM assays.

Escherichia coli produces biofilms in response to the small molecule autoinducer-2 (AI-2), a product of the LuxS enzyme. LuxS is part of the activated methyl cycle and could also affect biofilm development by AI-2-independent effects on metabolism. A luxS deletion mutant of E. coli W3110 and an inducible plasmid-luxS-complemented strain were used to identify AI-2-independent phenotypes. Differential interference contrast microscopy revealed distinct surface colonization patterns. Confocal microscopy followed by quantitative image analysis determined differences in biofilm topography correlating with luxS expression; deletion mutant biofilms had a 'spreading' phenotype, whereas the complement had a 'climbing' phenotype. Addition of exogenous 4,5-dihydroxy-2,3-pentanedione (DPD), an AI-2 precursor, to the deletion mutant increased biofilm height and biomass, whereas addition of the methyl donor S-adenosyl methionine or aspartate prevented the luxS-complemented strain from producing a thick biofilm. The luxS-complemented strain autoaggregated, indicating that fimbriae production was inhibited, which was confirmed by transmission electron microscopy. DPD could not induce autoaggregation in the deletion mutant, demonstrating that fimbriation was an AI-2-independent phenotype. Carbon utilization was affected by LuxS, potentially contributing to the observed phenotypic differences. Overall, the work demonstrated that LuxS affected E. coli biofilm formation independently of AI-2 and could assist in adapting to diverse conditions., (© 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.)

Conventional microfluidic devices typically require highly precise pumps or pneumatic control systems, which add considerable cost and the requirement for power. These restrictions have limited the adoption of microfluidic technologies for point-of-care applications. Paper networks provide an extremely low-cost and pumpless alternative to conventional microfluidic devices by generating fluid transport through capillarity. We revisit well-known microfluidic devices for hydrodynamic focusing, sized-based extraction of molecules from complex mixtures, micromixing, and dilution, and demonstrate that paper-based devices can replace their expensive conventional microfluidic counterparts.

Agarose was used to stabilize fragile biofilms cultivated in parallel plate flow cells prior to imaging by confocal laser scanning microscopy. An essential element to the success of the procedure was the application of a ceramic heat pad to the flow cell to maintain agarose fluidity until the biofilm was enveloped. Quantitative digital image analysis demonstrated the effectiveness of this technique for generating reproducible measurements of a three-dimensional biofilm structure. The described method will also benefit researchers who transport their flow cell-cultivated biofilms to a core facility for imaging., (Copyright 2010 Elsevier B.V. All rights reserved.)

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO(2) in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of pO(2) values measured in control tumours were <5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of pO(2) values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.

As part of an effort to create a point-of-care diagnostic system for the developing world, we present a microfluidic flow-through membrane immunoassay with on-card dry reagent storage. By preserving reagent function, the storage and reconstitution of anhydrous reagents enables the devices to remain viable in challenging, unregulated environmental conditions. The assay takes place on a disposable laminate card containing both a porous membrane patterned with capture molecules and a fibrous pad containing an anhydrous analyte label. To conduct the assay, the card is placed in an external pumping and imaging instrument capable of delivering sample and rehydrated reagent to the assay membrane at controlled flow rates to generate quantitative results. Using the malarial antigen Plasmodium falciparum histidine-rich protein II (PfHRP2) as a model, we demonstrate selection of dry storage conditions, characterization of reagent rehydration, and execution of an automated on-card assay. Gold-antibody conjugates dried in a variety of sugar matrices were shown to retain 80-96% of their activity after 60 days of storage at elevated temperatures, and the release profile of the reconstituted reagent was characterized under flow in microfluidic channels. The system gave a detection limit in the sub-nanomolar range in under nine minutes, showing the potential to expand into quantitative, multi-analyte analysis of human blood samples.

Purpose: Radioimmunotherapy has been approved for relapsed follicular lymphoma (FL), including rituximab-refractory FL. This study was designed to determine the CR rate with short-course chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (CHOP-R) followed by 90-Y ibritumomab tiuxetan (RIT) with extended rituximab as first-line treatment., Experimental Design: Between March 2004 and February 2007, 60 patients with stage II to IV symptomatic or bulky FL from a single institution supported by a large community network entered this phase II trial. Patients received CHOP-R for three treatment cycles before RIT followed by four additional weekly treatments with rituximab. Response was determined using fusion [(18) F] fluorodeoxyglucose-positron emission tomography (PET)-computed tomography (CT) imaging., Results: Of the 60 patients entering this trial, 55 patients completed all protocol therapy. The median follow up was 19.7 months (range, 0.26-35.9 months). For intent-to-treat analysis, the complete response (CR) rate after CHOP-R, as assessed by CT and PET imaging, was 40% and 46%, respectively. After RIT, the CR rate improved, as assessed by CT and PET imaging, to 82% and 89%, respectively. Ten patients have progressed, including eight from best response of CR. Seven of 18 patients who were PET positive after CHOP-R progressed compared with 3 of 37 patients who were PET negative (P=0.010)., Conclusions: In patients with previously untreated, symptomatic or bulky FL, short-course chemoimmunotherapy and consolidation RIT and extended rituximab resulted in a high CR rate. Failure to achieve an early PET CR after CHOP-R indicated high risk of relapse.

The human cytomegalovirus tegument protein pp71 localizes to the nucleus immediately upon infection, and functions to initiate viral gene expression. Analysis of a series of random insertion mutations revealed that sequences within the mid region (MR) of pp71 are important for localization to the nucleus. Fusion of MR sequences with eGFP revealed that amino acids 94 to 300 were sufficient to target proteins to the nucleus. Random substitution mutagenesis within this domain resulted in two double substitution mutants, pp71P203T/T223M and pp71T228M/L275Q, with a predominantly cytoplasmic localization. Disruption of nuclear targeting resulted in relocalization of the fusion proteins to a distinct perinuclear region. Using tandem mass spectrometry, we determined that threonine 223 can be phosphorylated. Mutation of this residue to a phosphomimetic amino acid resulted in abrogation of nuclear targeting. These results strongly suggest that the intracellular trafficking of pp71 is regulated by phosphorylation.

1. Accumulating evidence in both humans and animals indicates that acute increases in plasma osmolality elevate sympathetic nerve activity (SNA). In addition, plasma hyperosmolality (or hypernatraemia) can produce sustained increases in SNA and arterial blood pressure (ABP) through stimulation of forebrain osmoreceptors. 2. Although an abundance of information exists regarding the osmoregulatory circuits for thirst and secretion of antidiuretic hormone, much less is known about those pathways and synaptic mechanisms linking osmotic perturbations and SNA. To date, the available evidence suggests that osmosensitive sites within the forebrain lamina terminalis, such as the organum vasculosum of the lamina terminalis, are key elements that link plasma hypertonicity to elevated SNA. 3. The major efferent target of osmosensitive regions in the forebrain lamina terminalis is the hypothalamic paraventricular nucleus (PVH). Evidence from a number of studies indicates that the PVH contributes to both acute and chronic osmotically driven increases in SNA. In turn, PVH neurons increase SNA through a direct vasopressinergic spinal pathway and/or a glutamatergic pathway to bulbospinal sympathetic neurons of the rostral ventrolateral medulla. 4. Future studies are needed to: (i) define the contribution of various osmosensitive regions of the forebrain lamina terminalis to acute and chronic osmotically driven increases in SNA; (ii) identify the cellular mechanisms and neural circuitry linking plasma osmolality and SNA; and (iii) define whether such mechanisms contribute to elevated SNA in salt-sensitive hypertension.

We describe a technology, the NanoString nCounter gene expression system, which captures and counts individual mRNA transcripts. Advantages over existing platforms include direct measurement of mRNA expression levels without enzymatic reactions or bias, sensitivity coupled with high multiplex capability, and digital readout. Experiments performed on 509 human genes yielded a replicate correlation coefficient of 0.999, a detection limit between 0.1 fM and 0.5 fM, and a linear dynamic range of over 500-fold. Comparison of the NanoString nCounter gene expression system with microarrays and TaqMan PCR demonstrated that the nCounter system is more sensitive than microarrays and similar in sensitivity to real-time PCR. Finally, a comparison of transcript levels for 21 genes across seven samples measured by the nCounter system and SYBR Green real-time PCR demonstrated similar patterns of gene expression at all transcript levels.

Background: A novel magnetic guidance system has been developed that allows the operator to remotely navigate an electrophysiology mapping/ablation catheter to precise locations in the heart for treatment of tachyarrhythmias. To date, this new technology has not been directly compared with the conventional approach., Objective: To compare the use of the magnetic guidance system to the conventional approach for ablation of atrioventricular nodal reentry tachycardia., Methods: Between November 2002 and October 2004, 28 patients with atrioventricular nodal reentry tachycardia treated with the magnetic guidance system were retrospectively compared with 28 matched control patients., Results: Patients treated using the magnetic guidance system had similar procedure durations and fluoroscopy times compared with the matched controls. The only statistically significant difference between the groups was a longer time between insertion of the ablation catheter and placement of the first radiofrequency lesion in the magnetic guidance system cohort (23.3 +/- 12.0 vs. 10.5 +/- 13.9, p=0.001), possibly due to the research protocol. However, there was a trend toward a shorter total time that radiofrequency energy was applied in the magnetic guidance system cohort (5.2 +/- 4.5 vs. 8.0 +/- 7.2, p=0.087). There were no major complications or recurrences after at least 3 months of follow-up among the patients treated with the magnetic guidance system., Conclusion: The magnetic guidance system appears to have similar, and possibly improved, clinical efficacy compared with conventional catheter navigation for the treatment of atrioventricular nodal reentrant tachycardia.

Background: Atrioventricular (AV) delay optimization can be an important determinant of the response to cardiac resynchronization therapy (CRT) in patients with medically refractory heart failure and a ventricular conduction delay., Objectives: The purpose of this study was to compare two Doppler echocardiographic methods of AV delay optimization after CRT., Methods: Forty consecutive patients (age 59 +/- 12 years) with severe heart failure, New York Heart Association class 3.1 +/- 0.4, QRS duration 177 +/- 23 ms, and left ventricular ejection fraction 26% +/- 6% referred for CRT were studied using two-dimensional Doppler echocardiography. In each patient, the acute improvement in stroke volume with CRT in response to two methods of AV delay optimization was compared. In the first method, the AV delay that produced the largest increase in the aortic velocity time integral (VTI) derived from continuous-wave Doppler (aortic VTI method) was measured. In the second method, the AV delay that optimized the timing of mitral valve closure to occur simultaneously with the onset of left ventricular systole was calculated from pulsed Doppler mitral waveforms at a short and long AV delay interval (mitral inflow method)., Results: The optimized AV delay determined by the aortic VTI method resulted in an increase in aortic VTI of 19% +/- 13% compared with an increase of 12% +/- 12% by the mitral inflow method (P <.001). The optimized AV delay by the aortic VTI method was significantly longer than the optimized AV delay calculated from the mitral inflow method (119 +/- 34 ms vs 95 +/- 24 ms, P <.001). There was no correlation in the AV delay determined by the two methods (r = 0.03)., Conclusion: AV delay optimization by Doppler echocardiography for patients with severe heart failure treated with a CRT device yields a greater systolic improvement when guided by the aortic VTI method compared with the mitral inflow method.

Acute episodes of severe renal ischemia result in acute renal failure (ARF). These episodes are followed by a characteristic recovery and repair response, whereby tubular morphology and renal function appear completely restored within approximately 1 mo. However, the chronic effects of such an injury have not been well studied. Male rats were subjected to 60-min bilateral ischemia followed by reperfusion, yielding a characteristic injury. Postischemic animals manifested severe diuresis, peaking at 1 wk postinjury (volume: >45 ml/day, ARF vs. 18 ml/day, sham; P < 0.05). Urine flow subsequently declined but remained significantly elevated vs. sham animals for a 40-wk period. The prolonged alteration in urinary concentrating ability was attributable, in part, to a diminished capacity to generate a hypertonic medullary interstitium. By week 16, proteinuria developed in the post-ARF group and progressed for the duration of the study. Histological examination revealed essentially normal tubular morphology at 4 and 8 wk postinjury but the development of tubulointerstitial fibrosis at 40 wk. Transforming growth factor (TGF)-beta1 expression was elevated at 40 wk, but not at 4 and 8 wk postinjury. Microfil analysis revealed an approximately 30-50% reduction in peritubular capillary density in the inner stripe of the outer medulla at 4, 8, and 40 wk in post-ARF groups vs. sham animals. In addition, post-ARF rats manifested a significant pressor response to a low dose of ANG II (15 ng x kg(-1) x min(-1)). We hypothesize that severe ischemic injury results in a permanent alteration of renal capillary density, contributing to a urinary concentrating defect and the predisposition toward the development of renal fibrosis.

Hypertension is elicited by chronic, low dose intracerebroventricular (ICV) angiotensin II (AII) infusion in rats raised from weaning on relatively high sodium chloride diet (250 mEq kg(-1) food). This experimental model of hypertension is dependent upon renal innervation and associated with neurogenic sodium retention. The present study determined whether this neurogenic ICV AII hypertension is mediated by central alpha-adrenoceptors. Rats were weaned at 21 days of age and fed a 1.5% (250 mg kg(-1) food) sodium chloride diet for 10-12 weeks. At adulthood, animals were instrumented with central nervous system (CNS) lateral ventricular cannulas, femoral artery and vein catheters and housed in metabolic pens for chronic study. Low dose ICV AII infusion (20 ng min(-1)) increased mean arterial pressure (MAP) from 121 +/- 4 to 140 +/- 6 mm Hg on the day of ICV infusion. This increase in arterial pressure was associated with 3 consecutive days of decreased urinary sodium excretion. Subsequent ICV alpha-adrenoceptor blockade with phentolamine (AII + phentolamine) abolished the pressor and antinatriuretic responses to low dose chronic ICV AII infusion. Resumption of ICV AII infusion alone increased in MAP toward pre-alpha-adrenergic blockade values (133 +/- 5 mm Hg) on day 8. Following cessation of ICV AII infusion, arterial pressure and sodium excretion returned to values not significantly different from control. This model of hypertension was not dependent on circulating plasma renin activity (PRA), since PRA decreased during ICV AII infusion. These data confirm that low dose ICV AII causes hypertension and sodium retention in rats raised from weaning on moderately elevated sodium intake. We conclude that AII mediated neurogenic hypertension and antinatriuresis is elicited by stimulation of AT1 receptors on neurons which interact with noradrenergic cell bodies in cardiovascular and autonomic centers that may modulate renal sympathetic outflow via alpha-adrenoceptors.

Purpose: Experiments were conducted to elucidate the relationship between the changes in oxygen partial pressure (pO2) and blood flow in heated tumors with an ultimate goal of using mild temperature hyperthermia (MTH) to increase tumor oxygenation., Methods and Materials: The blood flow and pO2 in the R3230 adenocarcinoma grown (subcutaneously) in the right hind limbs of Fischer rats were measured immediately or 24 h after heating at 40.5 degrees-43.5 degrees C for 30 or 60 min. The blood flow was measured with the radioactive microsphere method and the tumor pO2 was measured polarographically using an Eppendorf pO2 histograph., Results: The tumor PO2 significantly increased immediately and 24 h after heating for 30 min at 40.5 degrees-43.5 degrees C or for 60 min at 40.5 degrees and 41.5 degrees C. On the other hand, in tumors heated at 42.5 degrees C for 60 min, the tumor pO2 immediately after heating was similar to the control value whereas that 24 h after heating was about threefold greater than the control tumor pO2. Heating at 43.5 degrees C for 60 min resulted in a significant decline in pO2 immediately after and 24 h after heating. The increase in tumor pO2 immediately after heating appeared to be due to an increase in tumor blood flow. However, the changes in tumor pO2 and tumor blood flow 24 h after heating, particularly after high thermal doses (e.g., 60 min heating at 42.5 degrees or 43.5 degrees C), were not correlated., Conclusion: Heating at mild temperatures (i.e., 40.5 degrees-42.5 degrees C for 30-60 min), caused thermal dose-dependent increases in pO2 in the R3230 AC tumors of Fischer rats during 0-24 h after heating. Such an increase in tumor oxygenation after MTH appeared to be due to an increase in tumor blood flow.

CNS angiotensin II (AII) hypertension is induced by chronic, low dose intracerebroventricular (ICV) AII infusion only in rats raised on a relatively high sodium chloride diet (250 meq kg(-1)food) from weaning. This experimental model of hypertension is dependent upon renal sympathetic innervation and associated with neurogenic sodium retention. This study determined whether AT1 and/or AT2 receptor subtypes in the CNS mediate this neurogenic ICV AII hypertension. Rats were weaned at 21 days of age and fed a 1.5% sodium chloride diet for 10-12 weeks. At adulthood, animals were instrumented with CNS lateral ventricular cannulas, femoral arterial and vein catheters and housed in metabolic pens for chronic study. Low dose ICV AII infusion (20 ng min(-1) )increased mean arterial pressure by 12+/-2 mm Hg and decreased urinary sodium excretion for three consecutive days. Subsequent ICV AT1 blockade with losartan abolished both the pressor and antinatriuretic responses to low dose ICV AII. In contrast, ICV AT2 receptor blockade with PD 123319 did not affect either angiotensin induced pressor or antinatriuretic responses. Following cessation of ICV AII infusion, arterial pressure and sodium excretion returned to values not significantly different from control in both groups of rats. These data confirm that low dose ICV AII causes hypertension and sodium retention in rats raised from early age on moderately elevated sodium intakes. This AII mediated neurogenic hypertension and antinatriuresis is transduced by activation of CNS AT1 receptors and not by activation of central AT2 receptors.

Chronic elevation of sodium intake may affect the sensitivity of the central nervous system to intracerebroventricular (I.C.V.) angiotensin II (Ang II) infusion. Experiments were conducted to determine the influence of raising Sprague-Dawley rats from 2 to 3 weeks of age on low (5.0 mmol/L per kg food), normal (50 mmol/L per kg food), or high (250 mmol/L per kg food) NaCl diets on renal and cardiovascular responses to low-dose I.C.V. Ang II infusion. At 12 weeks of age, Sprague-Dawley rats were instrumented for chronic study, including brain lateral ventricular cannulation. Artificial cerebrospinal fluid was infused (0.25 microL/min I.C.V.) during control and recovery, whereas Ang II (20 ng/min) was infused for 5 days. During the experiment, respective sodium intakes were infused intravenously over 24 hours. In rats fed high sodium, control mean arterial pressure was 115+/-2 mm Hg and increased to 132+/-4 mm Hg by day 5 of I.C.V. Ang II infusion. This increase in arterial pressure was associated with significant (P<.05) decreases in sodium excretion, leading to the retention of 5.4+/-0.6 mmol/L total sodium over the 5 days of Ang II infusion. In rats raised on low and normal sodium intakes from weaning and in 10-week-old rats exposed to a high sodium diet for only 2 weeks, arterial pressure was not increased and sodium was not retained during I.C.V. Ang II infusion at 20 ng/min. In rats raised on the high sodium diet, bilateral renal denervation abolished the arterial hypertension and reduced the sodium retention over 5 days of I.C.V. Ang II infusion. Thus, chronic elevation of sodium intake increases the hypertensive response to low-dose I.C.V. Ang II infusion, which is dependent on intact renal nerves. We conclude that elevated postnatal NaCl intake enhances the pressor sensitivity of the brain to Ang II.

This retrospective study evaluates the efficacy of megestrol acetate in patients with hormone refractory metastatic adenocarcinoma of the prostate. Data are presented from 14 patients with advanced prostatic adenocarcinoma who were treated with 160-320 mg of megestrol acetate daily. Each patient was either asymptomatic or had minimal cancer-related symptoms. Disease response was monitored by prostate-specific antigen levels. The response rate was 14%, with two patients having a partial response. No complete responses were observed. The median time to disease progression was 2 months. Our findings when considered together with results from previously published data demonstrate little activity of megestrol acetate in patients with hormone refractory prostate cancer. Therefore, we cannot recommend megestrol acetate as an effective second-line therapy.

Individuals with essential hypertension have been characterized by increased renal sympathetic vascular tone with decreased plasma volume and normal cardiac output compared with normotensive individuals. We used a servo-controlled intrarenal infusion system to evaluate the hemodynamic, renal excretory, and plasma hormonal responses to 28-day, low-level elevations in the intrarenal adrenergic neurotransmitter norepinephrine. In uninephrectomized dogs (n = 6), servo-controlled norepinephrine infusion increased mean arterial pressure from 95.6 +/- 3.1 to 115.7 +/- 4.9 mm Hg on day 1 without concomitant reductions in renal blood flow. Arterial hypertension was sustained and renal vascular resistance increased during the 28 days of servo-controlled norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine (1.49 +/- 0.23 to 0.47 +/- 0.25 mg/d) necessary to maintain renal blood flow constant. Arterial pressure returned to control values with the cessation of servo-controlled norepinephrine, whereas renal blood flow and renal vascular resistance remained slightly decreased and increased, respectively. Cumulative sodium balance exhibited a net 177 +/- 37 mmol sodium loss over the 28 days of norepinephrine infusion, indicating that the hypertension did not result from sodium retention or expansion of extracellular fluid volume. Intrarenal norepinephrine did not change plasma epinephrine, norepinephrine, or vasopressin concentrations. Atrial natriuretic factor, however, increased at 7 and 14 days of servo-controlled norepinephrine, and plasma renin activity increased on day 14 of norepinephrine infusion. We conclude that low-level elevation of intrarenal adrenergic neurotransmitter produces sustained arterial hypertension that is independent of expansion in extracellular fluid volume, increases in circulating catecholamines or plasma renin activity, or reductions in renal blood flow. This hypertension may be associated with increased renal vascular sensitivity to norepinephrine and/or other renal vasoactive factors.

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO2 in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 +/- 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO(2) measured within 10-15 min after heating for 30 min at 42.5 degrees C was about three-fold greater than that in the control tumours. About 62% of PO(2) values measured in control tumours were < 5 mm Hg. After heating at 42.5 degrees C for 30 min, 37% of PO(2) values were < 5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.

Purpose: The vascular thermal adaptation in the R3230 adenocarcinoma, skin and muscle in the legs of Fischer rats was studied., Methods and Materials: The legs of Fischer rats bearing the R3230 AC adenocarcinoma (subcutaneously) were heated once or twice with a water bath, and the blood flow in the tumor, skin and muscle of the legs was measured with the radioactive microsphere method., Results: The blood flow in control R3230 AC tumors was 23.9 ml/100 g/min. The tumor blood flow increased about 1.5 times in 30 min and then markedly decreased upon heating at 44.5 degrees C for 90 min. In the tumors preheated 16 h earlier at 42.5 degrees C for 60 min, reheating at 44.5 degrees C increased the tumor blood flow by 2.5-fold in 30 min. Contrary to the decline in blood flow following an initial increase during the 44.5 degrees C heating without preheating, the tumor blood flow remained elevated throughout the 90 min reheating at 44.5 degrees C. These results indicated that thermal adaptation or thermotolerance developed in the tumor vasculatures after the preheating at 42.5 degrees C for 60 min. The magnitude of vascular thermal adaptation in the tumors 24 h and 48 h after the preheating, as judged from the changes in blood flow, were smaller than that 16 h after the preheating. Heating at 42.5 degrees C for 60 min induced vascular thermal adaptation also in the skin and muscle, which peaked in 48 h and 24 h, respectively, after the heating., Conclusion: Heating at 42.5 degrees C for 1 h induced vascular thermal adaptation in the R3230 AC tumor, skin, and muscle of rats that peaked 16-48 h after the heating. When the tumor blood vessels were thermally adapted, the tumor blood flow increased upon heating at temperatures that would otherwise reduce the tumor blood flow. Such an increase in tumor blood flow may hinder raising the tumor temperature while it may increase tumor oxygenation.

Epidemiologic and experimental data support a role for 1,25-dihydroxyvitamin D(3) in the growth regulation of prostate cancer. We conducted a phase II clinical trial evaluating calcitriol (1,25(OH)(2)D(3)) in patients with hormone refractory prostate cancer. We enrolled 14 patients in this study. 1,25(OH)(2)D(3) was initiated at a daily oral dose of 0.5 μg and escalated to 1.5 μg daily. No objective responses were observed. However, in two patients decreases of 25% and 45% in prostate specific antigen levels were seen. Hypercalcemia was the predominant toxicity. We conclude that 1,25(OH)(2)D(3) given in this manner is inactive in advanced prostate cancer. Dose escalation of oral 1,25(OH)(2)D(3) is limited by hypercalcemia.

Approximately 200,000 men will be diagnosed with prostate cancer in 1994. While localized disease is potentially curable with surgery or radiation therapy, metastatic disease is incurable. The most frequent site of metastasis is bone. Spinal cord compression occurs in approximately 7% of men with prostate cancer. Back pain often heralds the diagnosis of spinal cord compression. In prostate cancer patients with back pain or signs of myelopathy or radiculopathy, plain radiographs of the spine and magnetic resonance imaging should be performed. Early diagnosis is of utmost importance. The neurologic status prior to treatment is the major determinant influencing outcome. Following diagnosis, corticosteroid therapy should begin immediately. Hormonal therapy should be instituted in those patients who have not previously undergone hormonal manipulation. The standard approach to definitive therapy is radiation. Surgical decompression plays a role in patients with severe myelopathy, spinal instability, and in those patients whose neurologic status deteriorates during or after radiation therapy.

Introduction: The spontaneously hypertensive rat (SHR) has been shown to possess elevated efferent sympathetic nerve activity, and renal denervation delays the development of hypertension in this genetic strain. Evidence that the renal sympathetic nerves have direct effects on tubular function suggests that one of the mechanisms for increasing arterial pressure in the SHR might involve neurally mediated sodium retention., Aims and Methods: The present study examined the relationships between renal sympathetic tone, daily sodium balance and the development of hypertension in SHR over a 4-week period. Conscious, unrestrained, 7-week-old SHR with innervated or denervated kidneys were placed on a fixed sodium intake by intravenous infusion (5.72 mumol/day per 100 g body weight). Urinary sodium excretion was determined once a day for 28 consecutive days; systolic blood pressure (SBP) and body weight were monitored twice a week., Results: Renal denervation delayed the onset of and retarded the development of hypertension. Despite the difference in SBP, daily sodium balance was equal in the innervated and the denervated SHR. The positive sodium balances exhibited by both groups are attributed to the rapid growth observed during the time course of the experiment. The growth rate was also similar in the two groups., Conclusion: The present data indicate that, although the renal nerves may mediate enhanced transient tubular sodium reabsorption, sodium retention does not contribute directly to the development of hypertension in the SHR. Rather, it appears that the elevation of arterial pressure might occur as a requirement to excrete excess sodium and thus maintain a daily sodium balance.

Objective: To determine whether shorter compression durations combined with fixed increased compression velocity during mechanical high-impulse CPR (HI-CPR) improve resuscitation hemodynamics, compared with mechanical standard CPR (SCPR)., Methods: A porcine model of ventricular fibrillation was used, with each animal serving as its own control. Twelve anesthetized swine (20-25 kg each) were instrumented for hemodynamic monitoring. Ventricular fibrillation was induced and followed, after 3 minutes, by mechanical SCPR (50% duty cycle) for 10 minutes. Mechanical HI-CPR was then applied, with compression durations varied randomly at 2-minute intervals for 20% (COM20), 30% (COM30), and 40% (COM40) of the CPR cycle. A 2-minute mechanical SCPR control phase completed the experiment., Results: Hemodynamic measurements were significantly better for COM20 and COM30 vs SCPR, including, respectively: mean arterial pressure (MAP), 45 +/- 8 and 43 +/- 7 vs 36 +/- 7 torr; coronary perfusion pressure (CPP), 21 +/- 6 and 21 +/- 8 vs 16 +/- 6 torr; and end-tidal CO2 (ETCO2), 7 +/- 2 and 6.6 +/- 2 vs 5 +/- 1.4 torr. MAP, CPP, and ETCO2 during COM40 were not significantly different from those during SCPR, and there was no difference between COM20 and COM30 for any hemodynamic parameter. Aortic flow velocity was significantly better in COM20, COM30, and COM40 vs SCPR: 2.3 +/- 0.7, 2.1 +/- 0.9, and 1.95 +/- 0.9 vs 1.3 +/- 0.5 cm/sec, respectively., Conclusion: In a swine model of mechanical HI-CPR, shorter compression durations combined with fixed increased compression velocity significantly improve resuscitation hemodynamics, compared with those afforded by mechanical SCPR.

Purpose: The effect of pentoxifylline (PTX) on the blood flow in experimental rodent tumors was investigated., Methods and Materials: When the R3230 AC adenocarcinoma implanted in the leg of Fischer 344 rats grew to about 1 g, the effect of PTX on the blood flow in the tumor and in the skin and muscle was determined with the microsphere method using 85Sr labelled 25 microns diameter microspheres. The SCK mammary carcinoma was induced subcutaneously in the leg or foot of A/J mice and the effect of PTX on the tumors was investigated: the blood perfusion in the leg tumors (7 mm in diameter) was determined with the 86Rb uptake method and that in the foot tumors (5 mm diameter) was determined with the laser Doppler flow (LDF) method., Results: The blood flow in the R3230 AC adenocarcinoma significantly increased when measured 30 min after an IP injection of 50 mg/kg PTX while the blood flow in the normal skin and muscle remained unchanged. The 86Rb uptake in the SCK tumor slightly increased 30 min after an IP injection of 50 mg/kg PTX. The LDF in the SCK tumors grown in the foot began to increase 5-10 min after an injection of 25 mg/kg PTX reaching 1.5-2.0 times in 20-30 min and it returned to the original level at 60 min., Conclusion: The results in the present study together with our previous observation that PTX increases the tumor pO2 in rodent tumors strongly suggest that PTX may be useful for increasing the radiosensitivity of human tumors.

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

Objectives: The purpose of this prospective study was to test the hypothesis that the elimination of inducible repetitive atrioventricular (AV) node reentry despite the persistence of slow AV pathway conduction is a valid end point for radiofrequency catheter ablation procedures in patients with supraventricular tachycardia due to AV node reentry., Background: Although modification of AV node physiology by radiofrequency current can eliminate AV node reentrant tachycardia, therapeutic end points that are definitive of a satisfactory result in patients undergoing modification of the slow AV pathway have not been established. Applications of radiofrequency current at selected sites may eliminate all evidence of slow pathway conduction or sufficiently modify the refractory properties of the slow pathway to preclude sustained arrhythmias. Accordingly, total abolition of dual AV node physiology may not be necessary to prevent arrhythmia recurrence., Methods: Radiofrequency catheter ablation of the slow AV pathway was attempted in 59 patients with typical AV node reentry. Tissue ablation was performed with a continuous wave of 500-kHz radiofrequency current. Twenty-five to 35 W was applied for 60 s at the site selected for tissue destruction., Results: Dual AV node physiology was eliminated completely in 35 patients (59%), persisted without inducible AV node reentry in 13 patients (22%) and persisted with inducible single AV reentrant beats in 11 patients (19%). In patients with persistent dual AV node physiology, the maximal difference between the effective refractory period of the fast and slow pathways was reduced from 104 +/- 62 ms before the procedure to 37 +/- 37 ms after AV conduction had been modified (p < 0.001). During a mean follow-up interval of 15 months (range 4 to 28), only one patient (2%) had a recurrence of the tachycardia., Conclusions: Results demonstrate that when complete elimination of dual AV node physiology is difficult, modification of slow pathway conduction to the extent that repetitive AV node reentry cannot be induced is a definitive end point that portends a good prognosis.

Renal sympathetic stimulation of plasma renin activity (PRA) and sodium reabsorption was examined in conscious dogs before and during intrarenal angiotensin II (ANG II)-type 1 receptor blockade with losartan (Dup-753) and converting enzyme inhibition. In uninephrectomized dogs, renal function and PRA responses to 14% blood volume depletion (BVD) were measured. BVD was utilized to activate renal sympathetic outflow in the absence of hypotension. In eight vehicle-treated dogs, 14% BVD increased PRA from 1.38 +/- 0.32 to 2.79 +/- 0.66 ng ANG I.ml-1 x h-1 and decreased urinary sodium excretion (UNaV) from 85.1 +/- 11.3 to 45.4 +/- 7.5 mueq/min. During losartan (n = 6) and captopril (n = 5) infusion, plasma renin responses were enhanced in response to 14% BVD (1.93 +/- 0.48 to 5.74 +/- 2.25 and 3.03 +/- 0.73 to 9.19 +/- 1.94 ng ANG I.ml-1 x h-1, respectively), whereas antinatriuretic responses were similar to vehicle-infused dogs. Thus, neurogenic antinatriuresis is not mediated by secondary generation of ANG II, since UNaV decreased similarly to control in all conditions of ANG II blockade. Tonic intrarenal and/or circulating ANG II synthesis of dogs on a normal sodium diet inhibit neurogenic stimulation of renin release, since PRA responses were enhanced after blockade of ANG II.