Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A

Natriuretic peptides, produced in the heart, bind to the natriuretic peptide receptor A (NPRA) and cause vasodilation and natriuresis important in the regulation of blood pressure. We here report that mice lacking a functional Npr1 gene coding for NPRA have elevated blood pressures and hearts exhibiting marked hypertrophy with interstitial fibrosis resembling that seen in human hypertensive heart disease. Echocardiographic evaluation of the mice demonstrated a compensated state of systemic hypertension in which cardiac hypertrophy and dilatation are evident but with no reduction in ventricular performance. Nevertheless, sudden death, with morphologic evidence indicative in some animals of congestive heart failure and in others of aortic dissection, occurred in all 15 male mice lacking Npr1 before 6 months of age, and in one of 16 females in our study. Thus complete absence of NPRA causes hypertension in mice and leads to cardiac hypertrophy and, particularly in males, lethal vascular events similar to those seen in untreated human hypertensive patients.

In vivo detection and imaging of phosphatidylserine expression during programmed cell death

One of the earliest events in programmed cell death is the externalization of phosphatidylserine, a membrane phospholipid normally restricted to the inner leaflet of the lipid bilayer. Annexin V, an endogenous human protein with a high affinity for membrane bound phosphatidylserine, can be used in vitro to detect apoptosis before other well described morphologic or nuclear changes associated with programmed cell death. We tested the ability of exogenously administered radiolabeled annexin V to concentrate at sites of apoptotic cell death in vivo. After derivatization with hydrazinonicotinamide, annexin V was radiolabeled with technetium 99m. In vivo localization of technetium 99m hydrazinonicotinamide-annexin V was tested in three models: fuminant hepatic apoptosis induced by anti-Fas antibody injection in BALB/c mice; acute rejection in ACI rats with transplanted heterotopic PVG cardiac allografts; and cyclophosphamide treatment of transplanted 38C13 murine B cell lymphomas. External radionuclide imaging showed a two- to sixfold increase in the uptake of radiolabeled annexin V at sites of apoptosis in all three models. Immunohistochemical staining of cardiac allografts for exogenously administered annexin V revealed intense staining of numerous myocytes at the periphery of mononuclear infiltrates of which only a few demonstrated positive apoptotic nuclei by the terminal deoxynucleotidyltransferase-mediated UTP end labeling method. These results suggest that radiolabeled annexin V can be used in vivo as a noninvasive means to detect and serially image tissues and organs undergoing programmed cell death.

Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor

The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone–ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone–ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

Cyclooxygenase-2 inhibition prevents delayed death of CA1 hippocampal neurons following global ischemia

The inducible isoform of the enzyme cyclooxygenase-2 (COX2) is an immediate early gene induced by synaptic activity in the brain. COX2 activity is an important mediator of inflammation, but it is not known whether COX2 activity is pathogenic in brain. To study the role of COX2 activity in ischemic injury in brain, expression of COX2 mRNA and protein and the effect of treatment with a COX2 inhibitor on neuronal survival in a rat model of global ischemia were determined. Expression of both COX2 mRNA and protein was increased after ischemia in CA1 hippocampal neurons before their death. There was increased survival of CA1 neurons in rats treated with the COX2-selective inhibitor SC58125 {1-[(4-methylsulfonyl) phenyl]-3-trifluoro-methyl-5-[(4-fluoro)phenyl] pyrazole} before or after global ischemia compared with vehicle controls. Furthermore, hippocampal prostaglandin E2 concentrations 24 h after global ischemia were decreased in drug-treated animals compared with vehicle-treated controls. These results suggest that COX2 activity contributes to CA1 neuronal death after global ischemia.

Anxiety and depression symptoms in liver encephalopathy : are they psychiatric or organic?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

The works of Percy Bysshe Shelley in verse and prose, now first brought together with many pieces not before published;

Poetry: v. 1. Alastor, and other poems. Mont Blanc, Laon and Cythna (or The revolt of Islam) Rosalind and Helen; with other poems.--v. 2. The Cenci. Prometheus unbound, with other poems. Oedipus Tyrannus, tr. from the original Doric. Epipsychidion.--v. 3. Adonais; an elegy on the death of Keats. Hellas, or a lyrical drama.

A discourse on the life, character, and public services of Ambrose Spenser, late Chief justice of the Supreme court of New York : delivered ... before the bar of the city of Albany, 1849.

With this are bound: Potter, H. A sermon occasioned by the death of the Hon. Ambrose Spencer, and Sprague, W. B. A discourse commemorative of the late Hoh. Ambrose Spenser.

Select tales. Being a compilation of singular, interesting, remarkable and authentic narratives, ancient and modern. Selected principally from the most esteemed and popular literary works, European and American, the greater part of which have never before been offered to the public in book form.

14th. A remarkable vision of Charles the eleventh of Sweden.--15th. An awful and authentic narrative of the monster Benito de Soto, the pirate of the Morning Star.--16th. The first and last sacrifice.--17th. The tiger's cave; or, The melancholy and tragical fate of Captains Wharton and Lincoln.--18th. The first and last love.--19th. The Scottish landlady, and her lodgers ... by Mr. Galt.--20th. Traditionary anecdotes of the Countess of Stair.--21st. First and last love.--Agnes Fitzroy.--22nd. The death of Alice Bland ... by the author of the Tales of a pilgrim--23d. Herby and his twelve wives.--24th. The murder hole.--25th. A remarkable trial of murders.

The history and proceedings of the House of Commons from the Restoration to the present time. Containing the most remarkable motions, speeches, resolves, reports and conferences to be met with in that interval: as also the most exact estimates of the charge of government, state of the public revenue, the rise and growth of the national debt, expence of the war, proceedings on ways and means, speeches and messages from the throne, addresses, and remonstrances, also the numbers pro and con upon every division &c. Many of which curious particulars were never before printed. Collected from the best authorities, compared with the journals of the House, and illustrated with a great variety of historical and explanatory notes. Together with a large appendix, containing exact lists of every Parliament, the names of the speakers, their several posts under the government, and other valuable, supplemental pieces.

Includes indexes.

Hearings relating to Madison Guaranty S & L and the Whitewater Development Corporation, Washington, DC phase : hearings before the Committee on Banking, Housing, and Urban Affairs, United States Senate, One Hundred Third Congress, second session.

Shipping list no.: 95-0029-P (v. 1), 95-0027-P (v. 2), 95-0194-P (v. 3, 11), 95-0187-P (v. 4, 9, 14), 95-0177-P (v. 5, 8, 13, 17), 95-0205-P (v. 6), 95-0176-P (v. 10, 15-16, 18), 95-0121-P (v. 12), 95-0188-P (v. 19), 95-0185-P (v. 20-21, 23), 95-0199-P (v. 22), 95-0195-P (v. 24).

Phobic anxiety in 11 nations: Part I: Dimensional constancy of the five-factor model

The Fear Survey Schedule-III (FSS-III) was administered to a total of 5491 students in Australia, East Germany, Great Britain, Greece, Guatemala, Hungary, Italy, Japan, Spain, Sweden, and Venezuela, and submitted to the multiple group method of confirmatory analysis (MGM) in order to determine the cross-national dimensional constancy of the five-factor model of self-assessed fears originally established in Dutch, British, and Canadian samples. The model comprises fears of bodily injury-illness-death, agoraphobic fears, social fears, fears of sexual and aggressive scenes, and harmless animals fears. Close correspondence between the factors was demonstrated across national samples. In each country, the corresponding scales were internally consistent, were intercorrelated at magnitudes comparable to those yielded in the original samples, and yielded (in 93% of the total number of 55 comparisons) sex differences in line with the usual finding (higher scores for females). In each country, the relatively largest sex differences were obtained on harmless animals fears. The organization of self-assessed fears is sufficiently similar across nations to warrant the use of the same weight matrix (scoring key) for the FSS-III in the different countries and to make cross-national comparisons feasible. This opens the way to further studies that attempt to predict (on an a priori basis) cross-national variations in fear levels with dimensions of national cultures. (C) 2002 Elsevier Science Ltd. All rights reserved.

Factors associated with the wish to hasten death: a study of patients with terminal illness

Background. There is considerable debate regarding the clinical issues surrounding the wish to hasten death (WTHD) in the terminally ill. The clinical factors contributing to the WTHD need further investigation among the terminally ill in order to enhance understanding of the clinical assessment and treatment needs that underlie this problem. A more detailed understanding may assist with the development of appropriate therapeutic interventions. Method. A sample of terminally ill cancer patients (N=256) recruited from an in-patient hospice unit, home palliative care service and a general hospital palliative care consulting service from Brisbane Australia between 1998-2001 completed a questionnaire assessing psychological (depression and anxiety), social (family relationship, social support, level of burden on others) and the impact of physical symptoms. The association between these factors and the WTHD was investigated. Results. A high WTHD was reported by 14% of patients. A discriminant function analysis revealed that the following variables were associated with a high WTHD (P

Do the Genetic or Environmental Determinants of Anxiety and Depression Change with Age? A Longitudinal Study of Australian Twins

Because the determinants of anxiety and depression in late adolescence and early adulthood may differ from those in later life, we investigated the temporal stability and magnitude of genetic and environmental correlates of symptoms of anxiety and depression across the life span. Data were collected from a population-based Australian sample of 4364 complete twin pairs and 777 singletons aged 20 to 96 years who were followed-up over three studies between 1980 and 1996. Each study contained the 14-item self-report DSSI/sAD scale which was used to measure recently experienced symptoms of anxiety and depression. Symptom scores were then divided and assigned to age intervals according to each subject's age at time of participation. We fitted genetic simplex models to take into account the longitudinal nature of the data. For male anxiety and depression, the best fitting simplex models comprised a single genetic innovation at age 20 which was transmitted, and explained genetic variation in anxiety and depression at ages 30, 40, 50 and 60. Most of the lifetime genetic variation in female anxiety and depression could also be explained by innovations at age 20 which were transmitted to all other ages; however, there were also smaller age-dependent genetic innovations at 30 for anxiety and at 40 and 70 for depression. Although the genetic determinants of anxiety and depression appear relatively stable across the life-span for males and females, there is some evidence to support additional mid-life and late age gene action in females for depression. The fact that mid-life onset for anxiety occurs one decade before depression is also consistent with a causal relationship (anxiety leading to depression) between these conditions. These findings have significance for large scale depression prevention projects.

Phobic anxiety in 11 nations: part II. Hofstede's dimensions of national cultures predict national-level variations

Hofstede's dimensions of national cultures termed Masculinity-Femininity (MAS) and Uncertainty Avoidance (UAI) (Hofstede, 2001) are proposed to be of relevance for understanding national-level differences in self-assessed fears. The potential predictive role of national MAS was based on the classical work of Fodor (Fodor, 1974). Following Fodor, it was predicted that masculine (or tough) societies in which clearer differentiations are made between gender roles (high MAS) would report higher national levels of fears than feminine (or soft/modest) societies in which such differentiations are made to a clearly lesser extent (low MAS). In addition, it was anticipated that nervous-stressful-emotionally-expressive nations (high UAI) would report higher national levels of fears than calm-happy and low-emotional countries (low UAI), and that countries high on both MAS and UAI would report the highest national levels of fears. A data set comprising 11 countries (N > 5000) served as the basis for analyses. As anticipated, (a) high MAS predicted higher national levels of Agoraphobic fears and of Bodily Injury-Illness-Death fears; (b) higher scores on both UAI and MAS predicted higher national scores on Bodily Injury-Illness-Death fears, fears of Sexual and Aggressive Scenes, and Harmless Animals fears; (c) higher UAI predicted higher national levels of Harmless Animals, Bodily Injury-Illness-Death, and Agoraphobic fears. (C) 2003 Elsevier Ltd. All rights reserved.

Prevalence and patterns of anxiety and depression in patients undergoing elective percutaneous transluminal coronary angioplasty

Background The use of elective percutaneous transluminal coronary angioplasty (PTCA) as a treatment for coronary heart disease is increasing. Despite this, little is known about the prevalence and patterns of anxiety and depression experienced by patients undergoing and recovering from this procedure. Anxiety and depression are factors known to negatively influence recovery after a cardiac event. Objective The purpose of this study was to (1) describe the levels of anxiety and depression reported by patients pre- and postelective PTCA, and (2) determine associations evident between anxiety and depression and the sociodemographic and clinical variables of gender, marital status, history of acute myocardial infarction, and attendance at cardiac rehabilitation. Methods In this descriptive, repeated-measures investigation, patients (n = 140) were requested to complete the Spielberger State Trait Anxiety Inventory and Cardiac Depression Scale (CDS) at three time points: 0(1) before admission for elective PTCA (T1); (2) 6 to 8 weeks (T2) after PTCA; and (3) 6 to 8 months (T3) after PTCA. Results A typical participant was male (75%), of European ethnicity (90%), aged 62 years (standard deviation = 10.7) with single or double vessel disease, and had attended cardiac rehabilitation in the past. At T1, 16% of men and 24% of women had state anxiety scores comparable to those experienced by neuropsychiatric patients. Trait anxiety scores remained relatively constant over time; higher scores at T1 were associated with past acute myocardial infarction. CDS scores at T2 and T3 were significantly lower than those at T1. However, an unexpected increase in CDS scores occurred at T3, compared with T2. At T3, 14% of men and 10% of women were depressed, relative to T1. Conclusion The findings lend support for the closer surveillance of emotional status in this population. Specialist nurses have the potential to play a greater role in identifying those at risk of developing anxiety and depression. However, this unmet need will remain unmet until specialist nurses who spend the most face-to-face time with patients are equipped with the skills and resources to systematically identify those “at risk.”