ABSTRACT
Testicular choriocarcinomas comprise less than 1% of all testicular tumors and are often highly vascular with early hematogenous metastasis. Choriocarcinoma syndrome (CS) is a rare entity distinguished by diffuse tumor burden and often fatal bleeding from metastatic sites. Most reported cases describe pulmonary hemorrhage secondary to initiation of chemotherapy. We present a fatal case of a young, previously healthy male with overwhelming gastrointestinal bleeding as the presenting sign of CS. Our case demonstrates that CS should be considered in the differential diagnosis for refractory anemia due to gastrointestinal hemorrhage in a young male with a testicular mass.
ABSTRACT
OBJECTIVE: To compare the frequency of postoperative encounters in the 30-day and 90-day postoperative periods for various bladder outlet obstruction surgical therapies. MATERIALS AND METHODS: All patients who underwent transurethral resection of the prostate (TURP), GreenLight laser photovaporization of the prostate (GL-PVP) (American Medical Systems Inc.), and holmium laser enucleation of the prostate (HoLEP) from January 1, 2012 to December 31, 2014 were followed for 6 months postoperatively. All postoperative encounters such as patient calls or questions, catheter exchanges or removals, and hospital-based readmissions or emergency department visits were recorded in the electronic medical record. RESULTS: Two hundred and ninety-one consecutive patients underwent outlet procedures during the study period: TURP (N = 199; mean age, 71 years; mean body mass index [BMI], 28.5), HoLEP (N = 60; mean age, 68 years; mean BMI, 28.1), or GL-PVP (N = 32; mean age, 72 years; mean BMI, 29.3). No statistically significant difference was observed for age, BMI, preoperative American Urological Association symptom score, or preoperative maximum flow velocity between the 3 groups. Thirty-day postoperative encounters differed significantly between the 3 surgery types (P < .001). Specifically, there were fewer encounters within 30 days of surgery for TURP compared to both HoLEP (≥1 encounter: TURP = 48.7%, HoLEP = 66.7%; P = .006) and GL-PVP (≥1 encounter: TURP = 48.7%, GL-PVP = 93.7%; P < .001). The number of encounters within 90 days postoperatively was also significantly lower for TURP patients (P < .001). CONCLUSION: TURP results in fewer postoperative encounters in both the 30-day and 90-day postoperative periods compared to HoLEP and GL-PVP. Laser prostate therapies may place increased burden on clinic staff during the 30-day and 90-day postoperative periods.
Subject(s)
Minimally Invasive Surgical Procedures/adverse effects , Office Visits/trends , Postoperative Complications/epidemiology , Prostatic Hyperplasia/surgery , Risk Assessment/methods , Transurethral Resection of Prostate/adverse effects , Urinary Bladder Neck Obstruction/etiology , Aged , Aged, 80 and over , Follow-Up Studies , Humans , Incidence , Laser Therapy/adverse effects , Laser Therapy/methods , Male , Middle Aged , Minimally Invasive Surgical Procedures/methods , Prognosis , Prostatic Hyperplasia/complications , Retrospective Studies , Time Factors , Transurethral Resection of Prostate/methods , Treatment Outcome , United States/epidemiology , Urinary Bladder Neck Obstruction/surgeryABSTRACT
RATIONALE: Chronic inflammation is a major contributor to the progressive pathology of hypertension, and T-cell activation is required for the genesis of hypertension. However, the precise role of myeloid cells in this process is unclear. OBJECTIVE: To characterize and understand the role of peripheral myeloid cells in the development of hypertension. METHODS AND RESULTS: We examined myeloid cells in the periphery of hypertensive mice and found that increased numbers of CD11b(+)Gr1(+) myeloid cells in blood and the spleen are a characteristic of 3 murine models of experimental hypertension (angiotensin II, L-NG-nitroarginine methyl ester, and high salt). These cells express surface markers and transcription factors associated with immaturity and immunosuppression. Also, they produce hydrogen peroxide to suppress T-cell activation. These are characteristics of myeloid-derived suppressor cells (MDSCs). Depletion of hypertensive MDSCs increased blood pressure and renal inflammation. In contrast, adoptive transfer of wild-type MDSCs to hypertensive mice reduced blood pressure, whereas the transfer of nicotinamide adenine dinucleotide phosphate oxidase 2-deficient MDSCs did not. CONCLUSION: The accumulation of MDSCs is a characteristic of experimental models of hypertension. MDSCs limit inflammation and the increase of blood pressure through the production of hydrogen peroxide.
Subject(s)
Blood Pressure , Hypertension/immunology , Myeloid Cells/immunology , Nephritis/immunology , Adoptive Transfer , Angiotensin II , Animals , Antigens, Ly/metabolism , CD11b Antigen/metabolism , Cells, Cultured , Disease Models, Animal , Hydrogen Peroxide/metabolism , Hypertension/metabolism , Hypertension/physiopathology , Hypertension/prevention & control , Immune Tolerance , Inflammation Mediators/metabolism , Lymphocyte Activation , Male , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/metabolism , Myeloid Cells/transplantation , NADPH Oxidase 2 , NADPH Oxidases/deficiency , NADPH Oxidases/genetics , NG-Nitroarginine Methyl Ester , Nephritis/metabolism , Nephritis/physiopathology , Nephritis/prevention & control , Signal Transduction , Sodium, Dietary , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Time FactorsABSTRACT
Hypertension is associated with neuroinflammation and increased sympathetic tone. Interference with neuroinflammation by an anti-inflammatory reagent or overexpression of interleukin-10 in the brain was found to attenuate hypertension. However, the cellular mechanism of neuroinflammation, as well as its impact on neurogenic regulation of blood pressure, is unclear. Here, we found that hypertension, induced by either angiotensin II or l-N(G)-nitro-l-arginine methyl ester, is accompanied by microglial activation as manifested by microgliosis and proinflammatory cytokine upregulation. Targeted depletion of microglia significantly attenuated neuroinflammation, glutamate receptor expression in the paraventricular nucleus, plasma vasopressin level, kidney norepinephrine concentration, and blood pressure. Furthermore, when microglia were preactivated and transferred into the brains of normotensive mice, there was a significantly prolonged pressor response to intracerebroventricular injection of angiotensin II, and inactivation of microglia eliminated these effects. These data demonstrate that microglia, the resident immune cells in the brain, are the major cellular factors in mediating neuroinflammation and modulating neuronal excitation, which contributes to the elevated blood pressure.
Subject(s)
Blood Pressure/physiology , Hypertension/physiopathology , Microglia/physiology , Sympathetic Nervous System/physiology , Angiotensin II/adverse effects , Animals , Apoptosis/drug effects , Diphtheria Toxin/administration & dosage , Diphtheria Toxin/pharmacology , Disease Models, Animal , Hypertension/chemically induced , Infusions, Intraventricular , Mice , Mice, Inbred C57BL , Microglia/drug effects , NG-Nitroarginine Methyl Ester/adverse effectsABSTRACT
Hypertension is a major risk factor for cardiovascular disease. While the cause of hypertension is multifactorial, renal dysregulation of salt and water excretion is a major factor. All components of the renin-angiotensin system are produced locally in the kidney, suggesting that intrarenal generation of angiotensin II plays a key role in blood pressure regulation. Here, we show that two mouse models lacking renal angiotensin converting enzyme (ACE) are protected against angiotensin II and l-NAME induced hypertension. In response to hypertensive stimuli, mice lacking renal ACE do not produce renal angiotensin II. These studies indicate that the intrarenal renin-angiotensin system works as an entity separate from systemic angiotensin II generation. Renal ACE appears necessary for experimental hypertension.
Subject(s)
Angiotensin II/metabolism , Hypertension/metabolism , Kidney/metabolism , Animals , Humans , Peptidyl-Dipeptidase A/metabolism , Renin-Angiotensin System/physiologyABSTRACT
The existence of a complete and functional renin-angiotensin system along the nephron is widely recognized. However, its precise role in blood pressure control and, by extension, hypertension is still uncertain. While most investigators agree that overexpressing RAS components along the nephron results in hypertension, two important issues remain: whether the local RAS works as a separate entity or represents an extension of the systemic RAS and whether locally generated angiotensin II has specific renal effects on blood pressure that are distinct from systemic angiotensin II. This review addresses these issues while emphasizing the unique role of local angiotensin II in the response of the kidney to hypertensive stimuli and the induction of hypertension.
Subject(s)
Angiotensin II/biosynthesis , Blood Pressure/physiology , Hypertension/metabolism , Kidney/metabolism , Renin-Angiotensin System/physiology , Animals , Humans , Hypertension/physiopathologyABSTRACT
The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na(+)/H(+) exchanger 3, Na(+)/Pi co-transporter 2, phosphorylated Na(+)/K(+)/Cl(-) cotransporter, and phosphorylated Na(+)/Cl(-) cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na(+) channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition.
Subject(s)
Hypertension/metabolism , Kidney/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Peptidyl-Dipeptidase A/physiology , Angiotensin II/metabolism , Animals , Blood Pressure , Glomerular Filtration Rate , Hypertension/drug therapy , Male , Mice , Mice, Inbred C57BL , NG-Nitroarginine Methyl Ester/chemistry , Natriuresis , Nitric Oxide/metabolism , Phosphorylation , Promoter Regions, Genetic , Protein Processing, Post-Translational , Renin/blood , Symporters/metabolismABSTRACT
While it is well known that angiotensin converting enzyme (ACE) plays an important role in blood pressure control, ACE also has effects on renal function, hematopoiesis, reproduction, and aspects of the immune response. ACE 10/10 mice overexpress ACE in myelomonocytic cells. Macrophages from these mice have an increased polarization towards a pro-inflammatory phenotype that results in a very effective immune response to challenge by tumors or bacterial infection. In a mouse model of Alzheimer's disease (AD), the ACE 10/10 phenotype provides significant protection against AD pathology, including reduced inflammation, reduced burden of the neurotoxic amyloid-ß protein and preserved cognitive function. Taken together, these studies show that increased myelomonocytic ACE expression in mice alters the immune response to better defend against many different types of pathologic insult, including the cognitive decline observed in an animal model of AD.
Subject(s)
Alzheimer Disease/genetics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Hypertension/metabolism , Monocytes/enzymology , Peptidyl-Dipeptidase A/genetics , Animals , Disease Models, Animal , Humans , Hypertension/drug therapy , Hypertension/genetics , Peptidyl-Dipeptidase A/metabolismABSTRACT
Angiotensin-converting enzyme (ACE) plays an important role in blood pressure control. ACE also has effects on renal function, reproduction, hematopoiesis, and several aspects of the immune response. ACE 10/10 mice overexpress ACE in monocytic cells; macrophages from ACE 10/10 mice demonstrate increased polarization toward a proinflammatory phenotype. As a result, ACE 10/10 mice have a highly effective immune response following challenge with melanoma, bacterial infection, or Alzheimer disease. As shown in ACE 10/10 mice, enhanced monocytic function greatly contributes to the ability of the immune response to defend against a wide variety of antigenic and non-antigenic challenges.
Subject(s)
Granulocyte Precursor Cells/enzymology , Granulocyte Precursor Cells/immunology , Immunity, Cellular/genetics , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Animals , Mice , Mice, KnockoutABSTRACT
Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid ß protein (Aß), particularly neurotoxic Aß(1-42). Angiotensin-converting enzyme (ACE) can degrade Aß(1-42), and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE(10/10) mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP(SWE)/PS1(ΔE9) mouse model of AD (ADâº). Evaluation of brain tissue from these ADâºACE(10/10) mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Aß(1-42) were reduced compared with those in AD⺠mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aß levels in ADâºACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, ADâºACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aß plaques. At 11 and 12 months of age, the ADâºACE(10/WT) and ADâºACE(10/10) mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.
Subject(s)
Alzheimer Disease/enzymology , Amyloid beta-Peptides/metabolism , Myeloid Cells/enzymology , Peptidyl-Dipeptidase A/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Astrocytes/physiology , Cell Movement , Cerebral Cortex/blood supply , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Cognition , Female , Humans , Macrophages/physiology , Male , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Ramipril/pharmacology , SolubilityABSTRACT
Angiotensin-converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity.
Subject(s)
Peptidyl-Dipeptidase A/physiology , Animals , Cytokines/genetics , Cytokines/metabolism , Endothelial Cells/metabolism , Gene Expression , Histocompatibility Antigens Class I/chemistry , Histocompatibility Antigens Class I/immunology , Humans , Hypertension/etiology , Immunity/physiology , Immunologic Memory , Kidney/metabolism , Kidney/physiology , Mice , Mice, Knockout , Peptides , Peptidyl-Dipeptidase A/chemistry , Phenotype , Protein Interaction Domains and MotifsABSTRACT
Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors.
Subject(s)
Peptidyl-Dipeptidase A/physiology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , History, 20th Century , Humans , Peptidyl-Dipeptidase A/chemistry , Peptidyl-Dipeptidase A/history , Polymorphism, Genetic , Protein Structure, Tertiary , Renin/physiologyABSTRACT
-Angiotensin-converting enzyme (ACE) is composed of the N- and C-terminal catalytic domains. To study the role of the ACE domains in the inflammatory response, N-knockout (KO) and C-KO mice, models lacking 1 of the 2 ACE domains, were analyzed during angiotensin II-induced hypertension. At 2 weeks, N-KO mice have systolic blood pressures that averaged 173±4.6 mm Hg, which is more than 25 mm Hg higher than the blood pressures observed in wild-type or C-KO mice (146±3.2 and 147±4.2 mm Hg). After 3 weeks, blood pressure differences between N-KO, C-KO, and wild-type were even more pronounced. Macrophages from N-KO mice have increased expression of tumor necrosis factor α after stimulation with either lipopolysaccharide (about 4-fold) or angiotensin II (about 2-fold), as compared with C-KO or wild-type mice. Inhibition of the enzyme prolyl oligopeptidase, responsible for the formation of acetyl-SerAspLysPro and other peptides, eliminated the blood pressure difference and the difference in tumor necrosis factor α expression between angiotensin II-treated N-KO and wild-type mice. However, this appears independent of acetyl-SerAspLysPro. These data establish significant differences in the inflammatory response as a function of ACE N- or C-domain catalytic activity. They also indicate a novel role of prolyl oligopeptidase in the cytokine regulation and in the blood pressure response to experimental hypertension.
Subject(s)
Angiotensin II/adverse effects , Cytokines/metabolism , Hypertension/chemically induced , Hypertension/physiopathology , Peptidyl-Dipeptidase A/deficiency , Animals , Blood Pressure/physiology , Disease Models, Animal , Hypertension/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Peptidyl-Dipeptidase A/genetics , Protein Structure, Tertiary , Tumor Necrosis Factor-alpha/metabolismABSTRACT
MOTIVATION: Progress in systems biology depends on developing scalable informatics tools to predictively model, visualize, and flexibly store information about complex biological systems. Scalability of these tools, as well as their ability to integrate within larger frameworks of evolving tools, is critical to address the multi-scale and size complexity of biological systems. RESULTS: Using current software technology, such as self-generation of database and object code from UML schemas, facilitates rapid updating of a scalable expert assistance system for modeling biological pathways. Distribution of key components along with connectivity to external data sources and analysis tools is achieved via a web service interface. AVAILABILITY: All sigmoid modeling software components and supplementary information are available through: http://www.igb.uci.edu/servers/sb.html.
Subject(s)
Expert Systems , Models, Biological , Systems Biology/statistics & numerical data , Computational Biology , Computer Communication Networks , Computer Simulation , Databases, Factual , Internet , Metabolic Networks and Pathways , Signal Transduction , Software , User-Computer InterfaceABSTRACT
Mitogen-activated protein kinase (MAPK) cascades are ubiquitous signal transduction modules in eukaryotes that are of great interest and importance. Here, we summarize some useful methods for the analysis of MAPK signaling, including methods to (1) detect MAPK activation in cells, with an emphasis on using phosphorylation-state-specific antibodies raised against mammalian phosphopeptide sequences to detect the activation of MAPKs in other species; (2) estimate the cellular concentrations of MAPKs and other proteins of interest; (3) detect and quantify the stable physical association of MAPKs with their substrates and regulators, and estimate the relevant dissociation constants; (4) delineate the MAPK-binding regions or domains of MAPK-interacting proteins, with particular emphasis on the identification and verification of MAPK-docking sites. These procedures are broadly applicable to many organisms, including both yeast and mammalian cells.
Subject(s)
Mitogen-Activated Protein Kinases/analysis , Mitogen-Activated Protein Kinases/metabolism , Molecular Biology/methods , Amino Acid Sequence , Animals , Antibody Specificity , Binding Sites , Buffers , Cell Extracts/chemistry , Enzyme Activation , Humans , Immunoprecipitation , Mitogen-Activated Protein Kinases/immunology , Molecular Sequence Data , Phosphorylation , Proteins/isolation & purificationABSTRACT
Aging appears to cease at late ages, when mortality rates roughly plateau in large-scale demographic studies. This anomalous plateau in late-life mortality has been explained theoretically in two ways: (1) as a strictly demographic result of heterogeneity in life-long robustness between individuals within cohorts, and (2) as an evolutionary result of the plateau in the force of natural selection after the end of reproduction. Here we test the latter theory using cohorts of Drosophila melanogaster cultured with different ages of reproduction for many generations. We show in two independent comparisons that populations that evolve with early truncation of reproduction exhibit earlier onset of mortality-rate plateaus, in conformity with evolutionary theory. In addition, we test two population genetic mechanisms that may be involved in the evolution of late-life mortality: mutation accumulation and antagonistic pleiotropy. We test mutation accumulation by crossing genetically divergent, yet demographically identical, populations, testing for hybrid vigor between the hybrid and nonhybrid parental populations. We found no difference between the hybrid and nonhybrid populations in late-life mortality rates, a result that does not support mutation accumulation as a genetic mechanism for late-life mortality, assuming mutations act recessively. Finally, we test antagonistic pleiotropy by returning replicate populations to a much earlier age of last reproduction for a short evolutionary time, testing for a rapid indirect response of late-life mortality rates. The positive results from this test support antagonistic pleiotropy as a genetic mechanism for the evolution of late-life mortality. Together these experiments comprise the first corroborations of the evolutionary theory of late-life mortality.