Showing papers by "University of Medicine and Dentistry of New Jersey published in 2005"
TL;DR: Cross-validate the Female Sexual Function Index in several samples of women with mixed sexual dysfunctions and develop diagnostic cut-off scores for potential classification of women's sexual dysfunction and discuss the results in terms of potential strengths and weaknesses of the FSFI.
Abstract: The Female Sexual Function Index (FSFI) is a brief, multidimensional scale for assessing sexual function in women. The scale has received initial psychometric evaluation, including studies of reliability, convergent validity, and discriminant validity (Meston, 2003; Rosen et al., 2000). The present study was designed to cross-validate the FSFI in several samples of women with mixed sexual dysfunctions (N = 568) and to develop diagnostic cut-off scores for potential classification of women's sexual dysfunction. Some of these samples were drawn from our previous validation studies (N = 414), and some were added for purposes of the present study (N = 154). The combined data set consisted of multiple samples of women with sexual dysfunction diagnoses (N = 307), including female sexual arousal disorder (FSAD), hypoactive sexual desire disorder (HSDD), female sexual orgasm disorder (FSOD), dyspareunia/vaginismus (pain), and multiple sexual dysfunctions, in addition to a large sample of nondysfunctional controls...
1,958 citations
TL;DR: It is found that telomere length decreased steadily with age at a mean rate of 27 bp per year, and the pro-ageing effects of obesity and cigarette smoking are emphasised.
1,248 citations
TL;DR: The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process, and that p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.
Abstract: Cell growth and proliferation requires an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular and extracellular stresses. Alteration of the coordination often causes cancer. In mammals, the mTOR (mammalian target of rapamycin) protein kinase is the central node in nutrient and growth factor signaling, and p53 plays a critical role in sensing genotoxic and other stresses. The results presented here demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream targets, including autophagy, a tumor suppression process. Moreover, the mechanisms by which p53 regulates mTOR involves AMP kinase activation and requires the tuberous sclerosis (TSC) 1/TSC2 complex, both of which respond to energy deprivation in cells. In addition, glucose starvation not only signals to shut down mTOR, but also results in the transient phosphorylation of the p53 protein. Thus, p53 and mTOR signaling machineries can cross-talk and coordinately regulate cell growth, proliferation, and death.
1,195 citations
TL;DR: It is reported that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca2+ in astrocytes, and this finding identifies astroCytes as a proximal target for the treatment of epileptic disorders.
Abstract: Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity using tetrodotoxin (TTX) and voltage-gated Ca2+ channel blockers Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca2+ in astrocytes Two-photon imaging of live exposed cortex showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca2+ signaling Our results show an unanticipated key role for astrocytes in seizure activity As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders
775 citations
TL;DR: Evidence is provided that the enzymes responsible for the modifications of histones function in a coordinated pattern to control gene expression in the short term and, through the transferral of these modifications by inheritance to their progeny, in the long term.
773 citations
TL;DR: Increasing amount of data suggest that AChRs and PPARs are involved in AD-induced neuroinflammation and in this regard, future therapy may focus on their specific targeting in the AD brain.
684 citations
TL;DR: While iron supplementation may improve pregnancy outcome when the mother is iron deficient it is also possible that prophylactic supplementation may increase risk when theMother does not have iron deficiency or IDA, and iron supplements and increased iron stores have recently been linked to maternal complications.
623 citations
Duke University1, Veterans Health Administration2, University of California, San Francisco3, University of Texas at Austin4, VCU Medical Center5, University of Chicago6, University of Medicine and Dentistry of New Jersey7, University of Texas Medical Branch8, California Pacific Medical Center9, University of California, San Diego10, New York University11
TL;DR: Colonoscopy was more sensitive than other tests, as currently undertaken, for detection of colonic polyps and cancers, and have important implications for diagnostic use of colon imaging tests.
621 citations
TL;DR: It is reported that in humans, the 600 kDa RNF20/40 complex is the E3 ligase and UbcH6 is the ubiquitin E2-conjugating enzyme for H2B-Lys120 monoubiquitination, and the hPAF complex is recruited to transcriptionally active genes in vivo.
515 citations
TL;DR: High-resolution crystal structures obtained for collagen model peptides confirm the supercoiled triple helix conformation, and provide new information on hydrogen bonding patterns, hydration, sidechain interactions, and ligand binding.
Abstract: The molecular conformation of the collagen triple helix confers strict amino acid sequence constraints, requiring a (Gly-X-Y)n repeating pattern and a high content of imino acids. The increasing family of collagens and proteins with collagenous domains shows the collagen triple helix to be a basic motif adaptable to a range of proteins and functions. Its rodlike domain has the potential for various modes of self-association and the capacity to bind receptors, other proteins, GAGs, and nucleic acids. High-resolution crystal structures obtained for collagen model peptides confirm the supercoiled triple helix conformation, and provide new information on hydrogen bonding patterns, hydration, sidechain interactions, and ligand binding. For several peptides, the helix twist was found to be sequence dependent, and such variation in helix twist may serve as recognition features or to orient the triple helix for binding. Mutations in the collagen triple-helix domain lead to a variety of human disorders. The most common mutations are single-base substitutions that lead to the replacement of one Gly residue, breaking the Gly-X-Y repeating pattern. A single Gly substitution destabilizes the triple helix through a local disruption in hydrogen bonding and produces a discontinuity in the register of the helix. Molecular information about the collagen triple helix and the effect of mutations will lead to a better understanding of function and pathology.
510 citations
TL;DR: Testing the hypothesis that chronically ischemic myocardium induces autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which could protect against the consequences of further ischemia found this mechanism to be a homeostatic mechanism.
Abstract: We tested the hypothesis that chronically ischemic (IS) myocardium induces autophagy, a cellular degradation process responsible for the turnover of unnecessary or dysfunctional organelles and cytoplasmic proteins, which could protect against the consequences of further ischemia. Chronically instrumented pigs were studied with repetitive myocardial ischemia produced by one, three, or six episodes of 90 min of coronary stenosis (30% reduction in baseline coronary flow followed by reperfusion every 12 h) with the non-IS region as control. In this model, wall thickening in the IS region was chronically depressed by ≈37%. Using a nonbiased proteomic approach combining 2D gel electrophoresis with in-gel proteolysis, peptide mapping by MS, and sequence database searches for protein identification, we demonstrated increased expression of cathepsin D, a protein known to mediate autophagy. Additional autophagic proteins, cathepsin B, heat shock cognate protein Hsc73 (a key protein marker for chaperone-mediated autophagy), beclin 1 (a mammalian autophagy gene), and the processed form of microtubule-associated protein 1 light chain 3 (a marker for autophagosomes), were also increased. These changes, not evident after one episode, began to appear after two or three episodes and were most marked after six episodes of ischemia, when EM demonstrated autophagic vacuoles in chronically IS myocytes. Conversely, apoptosis, which was most marked after three episodes, decreased strikingly after six episodes, when autophagy had increased. Immunohistochemistry staining for cathepsin B was more intense in areas where apoptosis was absent. Thus, autophagy, triggered by ischemia, could be a homeostatic mechanism, by which apoptosis is inhibited and the deleterious effects of chronic ischemia are limited.
TL;DR: The effects of a strict low-carbohydrate diet, which included the diet supplements recommended by Dr. Atkins, on energy intake and expenditure, body weight and body water, glucose metabolism, and insulin sensitivity in obese patients with type 2 diabetes in the controlled environment of a clinical research center are determined.
Abstract: In a small group of obese, diabetic patients, 2 weeks of a low-carbohydrate diet led to spontaneous reduction in energy intake because, despite the carbohydrate restriction, the participants did no...
TL;DR: Results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.
Abstract: Diabetes leads to vascular leakage, glial dysfunction, and neuronal apoptosis within the retina. The goal of the studies reported here was to determine the role that retinal microglial cells play in diabetic retinopathy and assess whether minocycline can decrease microglial activation and alleviate retinal complications. Immunohistochemical analyses showed that retinal microglia are activated early in diabetes. Furthermore, mRNAs for interleukin-1beta and tumor necrosis factor-alpha, proinflammatory mediators known to be released from microglia, are also increased in the retina early in the course of diabetes. Using an in vitro bioassay, we demonstrated that cytokine-activated microglia release cytotoxins that kill retinal neurons. Furthermore, we showed that neuronal apoptosis is increased in the diabetic retina, as measured by caspase-3 activity. Minocycline represses diabetes-induced inflammatory cytokine production, reduces the release of cytotoxins from activated microglia, and significantly reduces measurable caspase-3 activity within the retina. These results indicate that inhibiting microglial activity may be an important strategy in the treatment of diabetic retinopathy and that drugs such as minocycline hold promise in delaying or preventing the loss of vision associated with this disease.
University of Medicine and Dentistry of New Jersey1, Saint Thomas - West Hospital2, University of California, San Diego3, University of Minnesota4, Johns Hopkins University5, University of North Carolina at Chapel Hill6, Rutgers University7, Stanford University8, University Medical Center New Orleans9, Brigham and Women's Hospital10, Boston University11, Lahey Hospital & Medical Center12, Aristotle University of Thessaloniki13, Hospital of the University of Pennsylvania14, Harvard University15, Yale University16, University of Southern California17, University of Milan18, Mayo Clinic19, SUNY Downstate Medical Center20, Columbia University21
TL;DR: A risk stratification algorithm developed by the First Princeton Consensus Panel corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED, and increasing evidence supports the role of lifestyle intervention in ED.
Abstract: Recent studies have highlighted the relation between erectile dysfunction (ED) and cardiovascular disease. In particular, the role of endothelial dysfunction and nitric oxide in ED and atherosclerotic disease has been elucidated. Given the large number of men receiving medical treatment for ED, concerns regarding the risk for sexual activity triggering acute cardiovascular events and potential risks of adverse or unanticipated drug interactions need to be addressed. A risk stratification algorithm was developed by the First Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. Patients were assigned to 3 categories: low, intermediate (including those requiring further evaluation), and high risk. This consensus study from the Second Princeton Consensus Conference corroborates and clarifies the algorithm and emphasizes the importance of risk factor evaluation and management for all patients with ED. The panel reviewed recent safety and drug interaction data for 3 phosphodiesterase (PDE)-5 inhibitors (sildenafil, tadalafil, vardenafil), with emphasis on the safety of these agents in men with ED and concomitant cardiovascular disease. Increasing evidence supports the role of lifestyle intervention in ED, specifically weight loss and increased physical activity, particularly in patients with ED and concomitant cardiovascular disease. Special management recommendations for patients taking PDE-5 inhibitors who present at the emergency department and other emergency medical situations are described. Finally, further research on the role of PDE-5 inhibition in treating patients with other medical or cardiovascular disorders is recommended.
TL;DR: In this paper, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months.
Abstract: The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes The observed decreases in IL-8, IFN-gamma-inducible protein-10 (CXCL10), and MIP-3alpha (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein Decreases in T cell-inflammatory gene expression (IFN-gamma, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques
TL;DR: The quantity of research and quality of scholarship on the SHIM provide testimony to its positive impact on understanding and improving male sexual function and it is likely to remain influential in coming years.
Abstract: The Sexual Health Inventory for Men (SHIM) is a widely used scale for screening and diagnosis of erectile dysfunction (ED) and severity of ED in clinical practice and research. In reviewing the SHIM-related literature, we sought to provide a compendium of studies in which the SHIM was used, to provide a systematic framework for organizing and evaluating the studies, and to provide a status report on the SHIM and its impact on the management of male sexual dysfunction. Using a Medline search, we found that the SHIM was an integral measure in at least 21 studies on the prevalence of ED, 23 studies on the efficacy of ED interventions, and eight other (mainly correlational) studies. The quantity of research and quality of scholarship on the SHIM provide testimony to its positive impact on understanding and improving male sexual function. These scientific contributions are likely to remain influential in coming years.
TL;DR: These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans.
Abstract: Background— Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition. Methods and Results— We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study. Over 10.1 to 12.8 years, the relative changes in telomere length were correlated with the homeostasis model assessment of insulin resistance (r=−0.531, P<0.001) and changes in the body mass index (r=−0.423, P<0.001). Conclusions— These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans.
TL;DR: This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition ofPARP.
Abstract: Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
TL;DR: A new BP category "prehypertension" is defined for systolic and diastolic BP: 120 to 139mm Hg and 85 to 89 mm Hg, respectively, which is a continuum to hypertension and is a risk factor for cardiovascular disease.
Abstract: Background and Purpose— The Joint National Committee on High Blood Pressure identified a new category of blood pressure in adults termed prehypertension. Our objective was to determine the long-term risk of cardiovascular diseases associated with this new category in a well-defined cohort of adults. Methods— We evaluated the association of prehypertension (120 to 139/80 to 89 mm Hg) and hypertension (>140/90 mm Hg) with the incidence of atherothrombotic brain infarction (ABI), all strokes, myocardial infarction (MI), and coronary artery disease (CAD) using pooled repeated measures and Cox proportional hazards analyses during follow-up after adjusting for age, gender, obesity, diabetes mellitus, hypercholesterolemia, cigarette smoking, and study period in a cohort of 5181 persons who participated in the Framingham Study. Results— Among the 11 116 person observations with a mean follow-up period of 9.9±1.0 years, prehypertension was not associated with an increased risk for ABI (relative risk [RR], 2.2; 95%...
TL;DR: It is shown that DJ-1 protects against oxidative stress-induced cell death, but that its relatively modest ability to quench reactive oxygen species is insufficient to account for its more robust cytoprotective effect.
Abstract: Investigations into the cellular and molecular biology of genes that cause inherited forms of Parkinson's disease, as well as the downstream pathways that they trigger, shed considerable light on our understanding the fundamental determinants of life and death in dopaminergic neurons. Homozygous deletion or missense mutation in DJ-1 results in autosomal recessively inherited Parkinson's disease, suggesting that wild-type DJ-1 has a favorable role in maintaining these neurons. Here, we show that DJ-1 protects against oxidative stress-induced cell death, but that its relatively modest ability to quench reactive oxygen species is insufficient to account for its more robust cytoprotective effect. To elucidate the mechanism of this cell-preserving function, we have screened out the death protein Daxx as a DJ-1-interacting partner. We demonstrate that wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1, and therefore, from triggering the ensuing death pathway. All these steps are impaired by the disease-causing L166P mutant isoform of DJ-1. These findings suggest that the regulated sequestration of Daxx in the nucleus and keeping apoptosis signal-regulating kinase 1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function.
TL;DR: An algorithm was derived to relate the amino acid sequence of a collagen triple helix to its thermal stability, based on the triple helical stabilization propensities of individual residues and their intermolecular and intramolecular interactions, as quantitated by melting temperature values of host-guest peptides.
TL;DR: There are systematic differences in poly(A) site usage among human tissues, and both trans-acting factors and cis-regulatory elements may be involved in regulating alternative polyadenylation in different tissues.
Abstract: Background
Alternative polyadenylation is one of the mechanisms in human cells that give rise to a variety of transcripts from a single gene. More than half of the human genes have multiple polyadenylation sites (poly(A) sites), leading to variable mRNA and protein products. Previous studies of individual genes have indicated that alternative polyadenylation could occur in a tissue-specific manner.
TL;DR: In determining the propriety of any specific procedure or test, the geneticist should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen.
TL;DR: Decreased quinolinic acid and neopterin in cerebrospinal fluid are paradoxical and suggest dysmaturation of metabolic pathways and absence of concurrent infection, respectively, in autism.
TL;DR: Using the yeast Saccharomyces cerevisiae, an in vivo assay is established that directly identifies specific regions and residues of eEF1A responsible for actin interactions and bundling, demonstrating for the first time a direct consequence of e EF1A on cytoskeleton organization in vivo and the physiological significance of this interaction.
Abstract: The binding of eukaryotic translation elongation factor 1A (eEF1A) to actin is a noncanonical function that may link two distinct cellular processes, cytoskeleton organization and gene expression. Using the yeast Saccharomyces cerevisiae, we have established an in vivo assay that directly identifies specific regions and residues of eEF1A responsible for actin interactions and bundling. Using a unique genetic screen, we isolated a series of eEF1A mutants with reduced actin bundling activity. These mutations alter actin cytoskeleton organization but not translation, indicating that these are separate functions of eEF1A. This demonstrates for the first time a direct consequence of eEF1A on cytoskeletal organization in vivo and the physiological significance of this interaction.
TL;DR: Cells can migrate with inhibited lamellipodia, and it is suggested that TM is a major regulator of F-actin functional specialization in migrating cells.
Abstract: The actin cytoskeleton is locally regulated for functional specializations for cell motility. Using quantitative fluorescent speckle microscopy (qFSM) of migrating epithelial cells, we previously defined two distinct F-actin networks based on their F-actin–binding proteins and distinct patterns of F-actin turnover and movement. The lamellipodium consists of a treadmilling F-actin array with rapid polymerization-dependent retrograde flow and contains high concentrations of Arp2/3 and ADF/cofilin, whereas the lamella exhibits spatially random punctae of F-actin assembly and disassembly with slow myosin-mediated retrograde flow and contains myosin II and tropomyosin (TM). In this paper, we microinjected skeletal muscle αTM into epithelial cells, and using qFSM, electron microscopy, and immunolocalization show that this inhibits functional lamellipodium formation. Cells with inhibited lamellipodia exhibit persistent leading edge protrusion and rapid cell migration. Inhibition of endogenous long TM isoforms alters protrusion persistence. Thus, cells can migrate with inhibited lamellipodia, and we suggest that TM is a major regulator of F-actin functional specialization in migrating cells.
TL;DR: A model for RNAP II transcription is proposed in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule ofRNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation.
Abstract: The prevailing view of the RNA polymerase II (RNAP II) transcription cycle is that RNAP II is recruited to the promoter, transcribes a linear DNA template, then terminates transcription and dissociates from the template. Subsequent rounds of transcription are thought to require de novo recruitment of RNAP II to the promoter. Several recent findings, including physical interaction of 3′-end processing factors with both promoter and terminator regions, challenge this concept. Here we report a physical association of promoter and terminator regions of the yeast BUD3 and SEN1 genes. These interactions are transcription-dependent, require the Ssu72 and Pta1 components of the CPF 3′-end processing complex, and require the phosphatase activity of Ssu72. We propose a model for RNAP II transcription in which promoter and terminator regions are juxtaposed, and that the resulting gene loops facilitate transcription reinitiation by the same molecule of RNAP II in a manner dependent upon Ssu72-mediated CTD dephosphorylation.
TL;DR: For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age, a phenomenon which might relate to telomere elongation in sperm from older men.
Abstract: Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young ( 50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.
TL;DR: It is demonstrated that adenosine receptor occupancy increasesIL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL- 10 mRNA levels, indicating a posttranscriptional mechanism.
Abstract: Adenosine receptor ligands have anti-inflammatory effects and modulate immune responses by up-regulating IL-10 production by immunostimulated macrophages. The adenosine receptor family comprises G protein-coupled heptahelical transmembrane receptors classified into four types: A 1 , A 2A , A 2B , and A 3 . Our understanding of the signaling mechanisms leading to enhanced IL-10 production following adenosine receptor occupancy on macrophages is limited. In this study, we demonstrate that adenosine receptor occupancy increases IL-10 production by LPS-stimulated macrophages without affecting IL-10 promoter activity and IL-10 mRNA levels, indicating a posttranscriptional mechanism. Transfection experiments with reporter constructs containing sequences corresponding to the AU-rich 3′-untranslated region (UTR) of IL-10 mRNA confirmed that adenosine receptor activation acts by relieving the translational repressive effect of the IL-10 3′-UTR. By contrast, adenosine receptor activation failed to liberate the translational arrest conferred by the 3′-UTR of TNF-α mRNA. The IL-10 3′-UTR formed specific complexes with proteins present in cytoplasmic extracts of RAW 264.7 cells. Adenosine enhanced binding of proteins to a region of the IL-10 3′-UTR containing the GUAUUUAUU nonamer. The stimulatory effect of adenosine on IL-10 production was mediated through the A 2B receptor, because the order of potency of selective agonists was 5′- N -ethylcarboxamidoadenosine (NECA) > N 6 -(3-iodobenzyl)-adenosine-5′- N -methyluronamide (IB-MECA) > 2-chloro- N 6 -cyclopentyladenosine (CCPA) = 2- p -(2-carboxyethyl)phenethylamino-5′- N -ethyl-carboxamidoadenosine (CGS-21680). Also, the selective A 2B antagonist, alloxazine, prevented the effect of adenosine. Collectively, these studies identify a novel pathway in which activation of a G protein-coupled receptor augments translation of an anti-inflammatory gene.
TL;DR: Evidence-based treatment algorithms for major depressive mood disorders should include dichotomization according to suicide risk, as assessed by interview, and ECT should be considered earlier than at its conventional "last resort" position.
Abstract: OBJECTIVE: This study assessed the incidence, severity, and course of expressed suicidal intent in depressed patients who were treated with ECT. The data are from the first phase of an ongoing, collaborative multicenter study, the overall aim of which was to compare continuation ECT with pharmacotherapy in the prevention of relapse after a successful course of ECT. METHOD: Suicidal intent, as expressed by patients during an interview, was scored at baseline and before each ECT session with item 3 on the 24-item Hamilton Depression Rating Scale in 444 patients with unipolar depression. RESULTS: One hundred thirty-one patients (29.5%) reported suicidal thoughts and acts (score of 3 or 4) at baseline. Scores decreased to 0 after 1 week (three ECT sessions) in 38.2% of the patients, after 2 weeks (six ECT sessions) in 61.1%, and in 80.9% at the end of the course of treatment. CONCLUSIONS: Expressed suicidal intent in depressed patients was rapidly relieved with ECT. Evidence-based treatment algorithms for maj...