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Pulmonary hypertension is recognized as a leading cause of morbidity and mortality in patients with sickle cell disease (SCD). We now report benchtop phenotyping from the explanted lungs of the first successful lung transplant in SCD. Pulmonary artery smooth muscle cells (PASMCs) cultured from the explanted lungs were analyzed for proliferate capacity, superoxide (O2 (•-)) production, and changes in key pulmonary arterial hypertension (PAH)-associated molecules and compared with non-PAH PASMCs. Upregulation of several pathologic processes persisted in culture in SCD lung PASMCs in spite of cell passage. SCD lung PASMCs showed growth factor- and serum-independent proliferation, upregulation of matrix genes, and increased O2 (•-) production compared with control cells. Histologic analysis of SCD-associated PAH arteries demonstrated increased and ectopically located extracellular matrix deposition and degradation of elastin fibers. Biomechanical analysis of these vessels confirmed increased arterial stiffening and loss of elasticity. Functional analysis of distal fifth-order pulmonary arteries from these lungs demonstrated increased vasoconstriction to an α1-adrenergic receptor agonist and concurrent loss of both endothelial-dependent and endothelial-independent vasodilation compared with normal pulmonary arteries. This is the first study to evaluate the molecular, cellular, functional, and mechanical changes in end-stage SCD-associated PAH.

The media has the ability to affect public opinion and policy direction. Prevalence of morbid obesity in Canada is increasing; as is the only effective long-term treatment, weight loss surgery (WLS). Limited research has explored media re/presentations of WLS. The purpose of this study was to examine national online news coverage (and reader comments) of WLS using content analysis. We sought to understand the dominant messages being conveyed within the news texts and reader comments, specifically whose voice was represented, who was the intended audience and what was the overall tone. Articles and comments were retrieved from the Canadian Broadcasting Corporation news web site and analysed using line-by-line techniques. Articles were predominantly 'positive/supportive' (63%) in tone and frequently presented the voices and opinions of 'experts' conveying a biomedical perspective. Comments were overwhelmingly 'negative' (56%) and often derogatory including such language as 'piggy' and 'fatty'. Comments were almost exclusively anonymous (99%) and were frequently directed at other commenters (33%) and 'fat' people (6%). The potentially problematic nature of media framing and reader comments, particularly as they could relate to weight-based stigmatization and discrimination is discussed.

Although right-ventricular function is an important determinant of cardio-pulmonary performance in health and disease, right ventricular myocardium mechanical behaviour has received relatively little attention. We present a novel experimental method for quantifying the mechanical behaviour of transmurally intact, viable right-ventricular myocardium. Seven murine right ventricular free wall (RVFW) specimens were isolated and biaxial mechanical behaviour measured, along with quantification of the local transmural myofibre and collagen fibre architecture. We developed a complementary strain energy function based method to capture the average biomechanical response. Overall, murine RVFW revealed distinct mechanical anisotropy. The preferential alignment of the myofibres and collagen fibres to the apex-to-outflow-tract direction was consistent with this also being the mechanically stiffer axis. We also observed that the myofibre and collagen fibre orientations were remarkably uniform throughout the entire RVFW thickness. Thus, our findings indicate a close correspondence between the tissue microstructure and biomechanical behaviour of the RVFW myocardium, and are a first step towards elucidating the structure–function of non-contracted murine RVFW myocardium in health and disease.

Right ventricular (RV) function is the major determinant of mortality in pulmonary arterial hypertension and male sex is a strong predictor of mortality in this disease. The effects of testosterone on RV structure and function in load stress are presently unknown. We tested whether testosterone levels affect RV hypertrophic responses, fibrosis, and function. Male C57BL/6 mice underwent castration or sham followed by pulmonary artery banding (PAB) or sham. After recovery, testosterone pellets were placed in a subset of the castrated mice and mice were maintained for at least two weeks, when they underwent hemodynamic measurements and tissues were harvested. Plasma levels of testosterone were reduced by castration and repleted by testosterone administration. In PAB, castration resulted in lower right ventricle/left ventricle + septum (RV/LV+S), and myocyte diameter (P < 0.05). Replacement of testosterone normalized these parameters and increased RV fibrosis (P < 0.05). Two weeks of PAB resulted in increased RV systolic pressure in all groups with decreased markers of RV systolic and diastolic function, specifically reduced ejection fraction and increased time constant, and dPdt minimum (P < 0.05), though there was minimal effect of testosterone on hemodynamic parameters. Survival was improved in mice that underwent castration with PAB compared with PAB alone (P < 0.05). Testosterone affects RV hypertrophic response to load stress through increased myocyte size and increased fibrosis in mice. Castration and testosterone replacement are not accompanied by significant alterations in RV in vivo hemodynamics, but testosterone deprivation appears to improve survival in PAB. Further study of the role of testosterone in RV dysfunction is warranted to better understand these findings in the context of human disease.

Arginase expression and activity have been noted to be heightened in conditions associated with erectile dysfunction, including aging. Previously, arginase inhibition by chronic administration of the arginase inhibitor 2-(S)-amino-6-boronohexanoic acid (ABH) has been shown to improve endothelial dysfunction in aged rats. The objective of this study was to assess whether chronic oral ABH administration affects cavernosal erectile function. Rats were divided into 4 groups: young control, young treated with arginase inhibitor, aged control, and aged treated with arginase inhibitor. Arginase activity was measured and presented as a proportion of young untreated rats. In vivo erectile responses to cavernous nerve stimulation were measured in all cohorts. The cavernous nerve was stimulated with a graded electrical stimulus, and the intracavernosal/mean arterial pressure ratios and total intracavernosal pressure were recorded. Arginase activity was elevated in the aged rats compared with young controls; however, arginase activity was significantly decreased in aged rats treated with ABH. With the addition of ABH, erectile responses improved in the aged rats (P.05). Oral inhibition of arginase with ABH results in improved erectile function in aged rats, resulting in erectile hemodynamics similar to young rats. This represents the first documentation of systemic arginase inhibition positively affecting corporal cavernosal function.

Although medical therapies for pulmonary arterial hypertension have greatly improved, it remains a chronic and fatal disease. For patients who are refractory to medical therapy, lung transplantation is an important treatment option. This review discusses issues pertaining to indications for transplant, preparation for transplant and listing, operative issues, and outcomes for patients with pulmonary arterial hypertension.

Erectile dysfunction (ED) is a common men's health problem characterized by the consistent inability to sustain an erection sufficient for sexual intercourse. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin and/or neurogenic dysfunction. The constitutive forms of nitric oxide synthase [NOS; endothelial NOS (eNOS) and neuronal NOS (nNOS)] are important enzymes involved in the production of nitric oxide (NO) and thus regulate penile vascular homeostasis. Given the impact of endothelial- and neuronal-derived NO in penile vascular biology, a great deal of research over the past decade has focused on the role of NO synthesis from the endothelium and nitrergic nerve terminal in normal erectile physiology as well as in disease states. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED. Therefore, molecular mechanisms involved in dysregulation of these NOS isoforms in the development of ED are essential to discovering the pathogenesis of ED in various disease states. This communication reviews the role of eNOS and nNOS in erectile physiology and discusses the alterations in eNOS and nNOS via post-translation modification in various vascular diseases of the penis.

OBJECTIVES: To investigate the expression of cGMP-dependent protein kinase 1 (PKG1)alpha and PKG1beta in the corpus cavernosum, and to evaluate the effect of adenoviral gene transfer of PKG1alpha to the erectile compartment on erectile function in a rat model of diabetes. MATERIALS AND METHODS: Diabetic (DM; induced by streptozotocin) male Sprague Dawley rats were transfected with adenoviruses (AdCMVbetagal or AdCMVPKG1alpha, in 10 rats each) 2 months after the induction of DM. Intracavernosal pressure (ICP) during stimulation of the cavernosal nerve (CN) was assessed, and compared with mean arterial pressure (MAP). Erectile tissue was harvested for Western blot analysis, immunohistochemistry and total PKG activity. Ten age-matched rats without DM served as the control. RESULTS: Compared to controls, AdCMVbetagal-transfected DM rats had significantly lower peak ICP responses, ICP/MAP ratios, and filling rates during CN stimulation. In DM rats transfected with AdCMVPKG1alpha, peak ICP, ICP/MAP ratios and filling rates were significantly better than in DM rats transfected with the reporter gene. As assessed by Western blot and immunohistochemistry, expression of PKG1alpha and PKG1beta was lower in corporal tissue from DM AdCMVbetagal-transfected rats than in controls. PKG1alpha expression was improved after AdCMVPKG1alpha gene therapy. Total PKG activity was lower in DM rat corporal tissue than in controls, and PKG1alpha gene transfer significantly improved DM corporal PKG activity to a value greater than in the control. CONCLUSION: PKG1alpha and PKG1beta activities are reduced in the erectile tissue of the diabetic rat, and gene transfer of PKG1alpha to the penis restored PKG activity and erectile function in vivo in diabetic rats. Gene therapy procedures targeting PKG1alpha might be an interesting future therapeutic approach to overcome diabetic erectile dysfunction resistant to oral pharmacotherapy.

The Archean Pilbara Craton contains five geologically distinct terranes – the East Pilbara, Karratha, Sholl, Regal and Kurrana Terranes – all of which are unconformably overlain by the 3.02- to 2.93-Ga De Grey Superbasin. The 3.53–3.17 Ga East Pilbara Terrane (EP) represents the ancient nucleus of the craton that formed through three distinct mantle plume events at 3.53–3.43, 3.35–3.29 and 3.27–3.24 Ga. Each plume event resulted in eruption of thick dominantly basaltic volcanic successions on older crust to 3.72 Ga, and melting of crust to generate first tonalite-trondhjemite-granodiorite (TTG), and then progressively more evolved granitic magmas. In each case, plume magmatism was accompanied by uplift and crustal extension. The combination of conductive heating from below, thermal blanketing from above, and internal heating of buried granitoids during these events led to episodes of partial convective overturn of upper and middle crust. These mantle melting events caused severe depletion of the subcontinental lithospheric mantle, making the EP a stable, buoyant, unsubductable continent by c. 3.2 Ga. Extension accompanying the latest event led to rifting of the protocontinent margins at between 3.2 and 3.17 Ga. After 3.2 Ga, horizontal tectonic forces dominated over vertical forces, as revealed by the geology of the three terranes (Karratha, Sholl and Regal) of the West Pilbara Superterrane. The c. 3.12-Ga Whundo Group of the Sholl Terrane is a fault bounded, 10-km-thick volcanic succession with geochemical characteristics of modern oceanic arcs (including boninites and evidence for flux melting) that indicate steep Archean subduction. At 3.07 Ga, the 3.12-Ga Sholl Terrane, 3.27-Ga Karratha Terrane and c. 3.2-Ga Regal Terrane accreted together and onto the EP during the Prinsep Orogeny. This was followed by development of the De Grey Superbasin – an intracontinental sag basin and widespread plutonism (2.99–2.93 Ga) as a result of orogenic relaxation and slab break off. Craton-wide compressional deformation at 2.95–2.93 Ga culminated with 2.91-Ga accretion of the 3.18 Ga Kurrana Terrane with the EP. This compression caused amplification of the dome-and-keel structure in the EP. Final cratonization was effected by emplacement of 2.89–2.83 Ga post-tectonic granites.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual intercourse. Basic science research on erectile physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin. The incidence of ED dramatically increases in men with diabetes mellitus, hypercholesterolemia, and cardiovascular disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the occurrence of ED in this cohort of men. This communication reviews the role of the vascular endothelium in erectile physiology and the influence of endothelial dysfunction in the pathogenesis of ED. Future pharmacological and gene therapy interventions to restore endothelial function may represent exciting new therapeutic strategies for the treatment of ED. Penile erection is a neurovascular phenomenon that depends upon neural integrity, a functional vascular system, and healthy cavernosal tissues (Giuliano et al, 1995). Normal erectile function involves 3 synergistic and simultaneous processes: 1) neurologically mediated increase in penile arterial inflow, 2) relaxation of cavernosal smooth muscle, and 3) restriction of venous outflow from the penis. The corpus cavernosum of the penis is composed of a meshwork of interconnected smooth muscle cells lined by vascular endothelium. Of note, endothelial cells and underlying smooth muscle also line the small resistance helicine arteries that supply blood to the corpus cavernosum during penile tumescence. Pathological alteration in the anatomy of the penile vasculature or impairment of any combination of neurovascular processes can result

The etiologies of erectile dysfunction (ED) after nerve-sparing radical prostatectomy have not been clearly elucidated. The aim of this study was to evaluate the effects of cavernous nerve injury on cavernous fibrosis, and to consider measures to prevent irreversible damage to the cavernous tissues. Twenty male Sprague-Dawley rats constituted the study population. The animals were divided into 2 groups; group 1 consisted of sham-operated rats (n = 10), and group 2 consisted of rats that underwent incision of both cavernous nerves (n = 10). Three months later, all rats underwent intracavernous papaverine injection (300 and 600 mg), and intracorporal pressures were recorded. Transforming growth factor-beta(1) (TGF-beta(1)) messenger RNA (mRNA) expression from rat penile tissue was measured using reverse transcriptase-polymerase chain reaction. Hypoxia-inducible factor-1alpha (HIF-1alpha), TGF-beta(1), and collagen I and III protein expressions were determined by Western blot analysis and immunohistochemical staining. Erectile function as studied with intracavernosal papaverine injection and histological analysis of penile cross-sections at 3 months was similar in both groups. TGF-beta(1) mRNA expression, HIF-1alpha, TGF-beta(1), and collagen I and III protein expressions were significantly greater in the neurotomy group. Immunohistochemical staining for TGF-beta(1), HIF-1alpha, and collagen III were qualitatively more positive in the neurotomy group, whereas collagen I staining was similar. This study demonstrates an increase in TGF-beta(1), HIF-1alpha, and collagen III synthesis in rat cavernosal smooth musculature after cavernous neurotomies. In theory, cavernous fibrosis may be reduced by employing various vasoactive agents or interventions that increase oxygenation to the corporal tissues during the postoperative period.

Background: Pulmonary hypertension (PH) has a poor outcome overwhelmingly related to right ventricular (RV) failure. Augmentation area index (AI) could capture hemodynamic effects of vessel stiffen...

Introduction: Misclassification of patients with pulmonary hypertension may occur due to reliance on automated pulmonary wedge pressure (PWP) measurements instead of end-expiration measurements. The long-term outcomes of patients who are misclassified are unclear. We performed a retrospective study to characterize misclassified patients and to assess their outcomes. Methods: Review of clinical and hemodynamic data was performed for all patients who underwent right heart catheterization at University of Pittsburgh Medical Center with a mean pulmonary arterial pressure>25mmHg and PWP

This paper reports on two cases of large volume pericardiocentesis followed by transient severe acute left ventricular (LV) systolic failure in the absence of any prior history of LV dysfunction. Acute LV volume overload due to inter‐ventricular volume mismatch is believed by most authors to be the cause for this phenomenon. Another plausible physiopathologic explanation is the acute increase in “wall stress” (Laplace's law) due to acute distention of the cardiac chambers secondary to a sudden increase in venous return at high filling pressures, combined with a “vacuum” effect of the evacuated pericardial space.

“Tremblers” (tresantes) were those Spartans who had fled from the enemy. Since the Spartan code of values required them to remain in their ranks until victory or death, those who survived a defeat were socially humiliated and marginalized. While the term is already attested in Tyrtaios, the formalization of their status is elusive: the episodes that refer to some kind of social degradation and/or legal punishment of one or more Spartan tremblers are rare, limited to the years between 480 and 331 BCE, and not reducible to a common pattern.

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine's natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to pro-apoptotic stimuli. Bulbispermine, haemanthamine, and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited notable growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion; they displayed similar potencies in both cell types, indicating that the induction of apoptosis is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.

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Latifundia (from Lat. latus=large and fundus= estate) is a term that does not occur often in Latin sources; the majority of the texts concerned date to the first century ce. Keywords: agriculture; Roman history

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