Showing papers by "Icahn School of Medicine at Mount Sinai published in 2001"

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

Abstract: The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Current concepts in mild cognitive impairment.

Abstract: The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.

Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy

Abstract: Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.

Abstract: Noonan syndrome (MIM 163950) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature and heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy). Webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses also are frequently associated with this disease. This syndrome is relatively common, with an estimated incidence of 1 in 1,000-2,500 live births. It has been mapped to a 5-cM region (NS1) [corrected] on chromosome 12q24.1, and genetic heterogeneity has also been documented. Here we show that missense mutations in PTPN11 (MIM 176876)-a gene encoding the nonreceptor protein tyrosine phosphatase SHP-2, which contains two Src homology 2 (SH2) domains-cause Noonan syndrome and account for more than 50% of the cases that we examined. All PTPN11 missense mutations cluster in interacting portions of the amino N-SH2 domain and the phosphotyrosine phosphatase domains, which are involved in switching the protein between its inactive and active conformations. An energetics-based structural analysis of two N-SH2 mutants indicates that in these mutants there may be a significant shift of the equilibrium favoring the active conformation. This implies that they are gain-of-function changes and that the pathogenesis of Noonan syndrome arises from excessive SHP-2 activity.

A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity

Abstract: Epidemiological studies have documented a reduced prevalence of Alzheimer's disease among users of nonsteroidal anti-inflammatory drugs (NSAIDs). It has been proposed that NSAIDs exert their beneficial effects in part by reducing neurotoxic inflammatory responses in the brain, although this mechanism has not been proved. Here we report that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ42 peptide (the 42-residue isoform of the amyloid-β peptide) produced from a variety of cultured cells by as much as 80%. This effect was not seen in all NSAIDs and seems not to be mediated by inhibition of cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs. Furthermore, short-term administration of ibuprofen to mice that produce mutant β-amyloid precursor protein (APP) lowered their brain levels of Aβ42. In cultured cells, the decrease in Aβ42 secretion was accompanied by an increase in the Aβ(1–38) isoform, indicating that NSAIDs subtly alter γ-secretase activity without significantly perturbing other APP processing pathways or Notch cleavage. Our findings suggest that NSAIDs directly affect amyloid pathology in the brain by reducing Aβ42 peptide levels independently of COX activity and that this Aβ42-lowering activity could be optimized to selectively target the pathogenic Aβ42 species.

Spontaneous intracerebral hemorrhage.

Abstract: Nontraumatic intracerebral hemorrhage is bleeding into the parenchyma of the brain that may extend into the ventricles and, in rare cases, the subarachnoid space. Each year, approximately 37,000 to 52,400 people in the United States have an intracerebral hemorrhage.1,2 This rate is expected to double during the next 50 years as a result of the increasing age of the population and changes in racial demographics. Intracerebral hemorrhage accounts for 10 to 15 percent of all cases of stroke and is associated with the highest mortality rate, with only 38 percent of affected patients surviving the first year.3 Depending on . . .

Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry's disease.

Abstract: Background Fabry's disease, lysosomal α-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. Methods We evaluated the safety and effectiveness of recombinant α-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant α-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. Results In the double-blind study, 20 of the 29 patients in the recom...

Utility of food-specific IgE concentrations in predicting symptomatic food allergy ☆ ☆☆

Abstract: Background: The double-blind, placebo-controlled food challenge is considered the gold standard for diagnosing food allergy. However, in a retrospective analysis of children and adolescents with atopic dermatitis and food allergy, discrete food-specific IgE concentrations were established that could predict clinical reactivity to egg, milk, peanut, and fish with greater than 95% certainty. Objective: The purpose of this investigation was to determine the utility of these 95% predictive decision points in a prospective evaluation of food allergy. Methods: Sera from 100 consecutive children and adolescents referred for evaluation of food allergy were analyzed for specific IgE antibodies to egg, milk, peanut, soy, wheat, and fish by using the Pharmacia CAP System FEIA. Food-specific IgE values were compared with history and the results of skin prick tests and food challenges to determine the efficacy of previously established 95% predictive decision points in identifying patients with increased probability of reacting during a specific food challenge. Results: One hundred children (62% male; median age, 3.8 years; range, 0.4-14.3 years) were evaluated for food allergy. The diagnosis of food allergy was established by means of history or oral food challenge. On the basis of the previously established 95% predictive decision points for egg, milk, peanut, and fish allergy, greater than 95% of food allergies diagnosed in this prospective study were correctly identified by quantifying serum food-specific IgE concentrations. Conclusion: In a prospective study of children and adolescents referred for evaluation of food allergy, previously established 95% predictive decision points of food-specific IgE antibody concentrations for 4 major food allergens were effective in predicting clinical reactivity. Quantification of food-specific IgE is a useful test for diagnosing symptomatic allergy to egg, milk, peanut, and fish in the pediatric population and could eliminate the need to perform double-blind, placebo-controlled food challenges in a significant number of children. (J Allergy Clin Immunol 2001;107:891-6.)

A novel influenza A virus mitochondrial protein that induces cell death

Abstract: While searching for alternative reading-frame peptides encoded by influenza A virus that are recognized by CD8+ T cells, we found an abundant immunogenic peptide encoded by the +1 reading frame of PB1. This peptide derives from a novel conserved 87-residue protein, PB1-F2, which has several unusual features compared with other influenza gene products in addition to its mode of translation. These include its absence from some animal (particularly swine) influenza virus isolates, variable expression in individual infected cells, rapid proteasome-dependent degradation and mitochondrial localization. Exposure of cells to a synthetic version of PB1-F2 induces apoptosis, and influenza viruses with targeted mutations that interfere with PB1-F2 expression induce less extensive apoptosis in human monocytic cells than those with intact PB1-F2. We propose that PB1-F2 functions to kill host immune cells responding to influenza virus infection.

Roles of the heat shock transcription factors in regulation of the heat shock response and beyond

Abstract: The heat shock response, characterized by increased expression of heat shock proteins (Hsps) is induced by exposure of cells and tissues to extreme conditions that cause acute or chronic stress. Hsps function as molecular chaperones in regulating cellular homeostasis and promoting survival. If the stress is too severe, a signal that leads to programmed cell death, apoptosis, is activated, thereby providing a finely tuned balance between survival and death. In addition to extracellular stimuli, several nonstressful conditions induce Hsps during normal cellular growth and development. The enhanced heat shock gene expression in response to various stimuli is regulated by heat shock transcription factors (HSFs). After the discovery of the family of HSFs (i.e., murine and human HSF1, 2, and 4 and a unique avian HSF3), the functional relevance of distinct HSFs is now emerging. HSF1, an HSF prototype, and HSF3 are responsible for heat-induced Hsp expression, whereas HSF2 is refractory to classical stressors. HSF4 is expressed in a tissue-specific manner; similar to HSF1 and HSF2, alternatively spliced isoforms add further complexity to its regulation. Recently developed powerful genetic models have provided evidence for both cooperative and specific functions of HSFs that expand beyond the heat shock response. Certain specialized functions of HSFs may even include regulation of novel target genes in response to distinct stimuli.

Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation.

Abstract: Background The conventional treatment strategy for patients with atrial fibrillation who are to undergo electrical cardioversion is to prescribe warfarin for anticoagulation for three weeks before cardioversion. It has been proposed that if transesophageal echocardiography reveals no atrial thrombus, cardioversion may be performed safely after only a short period of anticoagulant therapy. Methods In a multicenter, randomized, prospective clinical trial, we enrolled 1222 patients with atrial fibrillation of more than two days' duration and assigned them to either treatment guided by the findings on transesophageal echocardiography or conventional treatment. The composite primary end point was cerebrovascular accident, transient ischemic attack, and peripheral embolism within eight weeks. Secondary end points were functional status, successful restoration and maintenance of sinus rhythm, hemorrhage, and death. Results There was no significant difference between the two treatment groups in the rate of emboli...

Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow.

Abstract: Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs), Cerberus, Wnt inhibitory factor (WIF) and Dickkopf (Dkk). FRPs, Cerberus and WIF have all been shown to act by binding and sequestering Wnt. We report a novel mechanism of Wnt-signalling inhibition by human Dkk-1. Dkk-1 demonstrated no interaction with Wnt but bound a single cell surface site with high affinity (K(D) = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (M(r) 240K) with [(125)I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through beta-catenin is mediated by the Fz receptor and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow. Overproduction of the 200K LRP6 protein, but not of Fz, strikingly increased Dkk-1 binding as well as the amount of the 240K cross-linked complex, which was shown to be composed of Dkk-1 and LRP6. Moreover, Dkk-1 function was completely independent of Fz but LRP6 dramatically interfered with the Dkk-1 inhibition of Wnt signalling. Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz or Wnt sequestration through other mechanisms, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.

Coronary artery disease: pathogenesis and acute coronary syndromes.

Abstract: Atherosclerotic diseases and their thrombotic complications remain the leading causes of mortality and morbidity in Western society In the United States, cardiovascular disease is responsible for one in every 24 (414%) deaths and is the leading single cause of mortality Furthermore, the presence of atherosclerotic disease (defined as thickening of the arterial wall through the accumulation of lipids, macrophages, T-lymphocytes, smooth muscle cells, extracellular matrix, calcium and necrotic debris) is more prevalent, but by itself rarely fatal The crucial, final common process for the conversion of a nonocclusive, often clinically silent atherosclerotic lesion to a potentially fatal condition is often plaque disruption The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death Substantial clinical, experimental and postmortem evidence demonstrates the central role that a superimposed acute thrombosis on a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes Therefore, therapeutic approaches to date have focused on reducing such thrombotic complications of atherosclerotic plaques (ie, antiplatelet, anticoagulant and thrombolytic therapies) to reduce the resulting morbidity and mortality In this review, we will focus on the current theories of atherogenesis and how they impact on our understanding of acute coronary syndromes

Biology of Posttraumatic Stress Disorder

Abstract: Most biological findings in posttraumatic stress disorder (PTSD) are compatible with those of the chronic stress response, such as increased corticotropin-releasing factor (CRF) concentrations, catecholamine depletion within the central nervous system, and reduced hippocampal volume. However, over the last 10 years, biological observations have been made in PTSD that are different from what has been typically associated with chronic stress, notably certain hypothalamic-pituitary-adrenal (HPA) axis findings. In particular, urinary and plasma cortisol levels are considerably lower in PTSD patients than in non-PTSD trauma survivors and normal controls. Furthermore, the circadian pattern of cortisol release from the adrenal glands follows a greater dynamic range in PTSD than in patients with major depression or in normal controls. The reduction in cortisol levels results from an enhanced negative feedback by cortisol, which is secondary to an increased sensitivity of glucocorticoid receptors in target tissues. This HPA axis alteration contrasts with the well-known chronic stress cascade in which CRF release results in erosion of negative feedback and down-regulation of glucocorticoid receptors. Sensitization of the HPA axis is consistent with the clinical picture of hyperreactivity and hyperresponsiveness in PTSD.

Conduction Slowing and Sudden Arrhythmic Death in Mice With Cardiac-Restricted Inactivation of Connexin43

Abstract: Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1+/-0.13 versus 1.66+/-0.06; P:<0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.

Vital involvement of a natural killer cell activation receptor in resistance to viral infection.

Abstract: Natural killer (NK) cells are lymphocytes that can be distinguished from T and B cells through their involvement in innate immunity and their lack of rearranged antigen receptors. Although NK cells and their receptors were initially characterized in terms of tumor killing in vitro, we have determined that the NK cell activation receptor, Ly-49H, is critically involved in resistance to murine cytomegalovirus in vivo. Ly-49H requires an immunoreceptor tyrosine-based activation motif (ITAM)-containing transmembrane molecule for expression and signal transduction. Thus, NK cells use receptors functionally resembling ITAM-coupled T and B cell antigen receptors to provide vital innate host defense.

The Inner Life of Physicians and Care of the Seriously Ill

Abstract: Seriously ill persons are emotionally vulnerable during the typically protracted course of an illness. Physicians respond to such patients’ needs and emotions with emotions of their own, which may reflect a need to rescue the patient, a sense of failure and frustration when the patient’s illness progresses, feelings of powerlessness against illness and its associated losses, grief, fear of becoming ill oneself, or a desire to separate from and avoid patients to escape these feelings. These emotions can affect both the quality of medical care and the physician’s own sense of well-being, since unexamined emotions may also lead to physician distress, disengagement, burnout, and poor judgment. In this article, which is intended for the practicing, nonpsychiatric clinician, we describe a model for increasing physician selfawareness, which includes identifying and working with emotions that may affect patient care. Our approach is based on the standard medical model of risk factors, signs and symptoms, differential diagnosis, and intervention. Although it is normal to have feelings arising from the care of patients, physicians should take an active role in identifying and controlling those emotions.

Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment.

Abstract: OBJECTIVE: Novel antipsychotic medications have been reported to have beneficial effects on cognitive functioning in patients with schizophrenia. However, these effects have been assessed in studies with considerable variation in methodology. A large number of investigator-initiated and industry-sponsored clinical trials are currently underway to determine the effect of various novel antipsychotics on cognitive deficits in patients with schizophrenia. The ability to discriminate between high- and low-quality studies will be required to understand the true implications of these studies and their relevance to clinical practice. METHOD: This article addresses several aspects of research on cognitive enhancement in schizophrenia, emphasizing how the assessment of cognitive function in clinical trials requires certain standards of study design to lead to interpretable results. RESULTS: Novel antipsychotic medications appear to have preliminary promise for the enhancement of cognitive functioning. However, the ...

Clinical Evaluation of Once-Weekly Dosing of Epoetin Alfa in Chemotherapy Patients: Improvements in Hemoglobin and Quality of Life Are Similar to Three-Times-Weekly Dosing

Abstract: PURPOSE: To prospectively evaluate the effectiveness, safety, and clinical benefits of once-weekly epoetin alfa therapy as an adjunct to chemotherapy in anemic cancer patients. PATIENTS AND METHODS: A total of 3,012 patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this multicenter, open-label, nonrandomized study conducted in 600 United States community-based practices. Patients received epoetin alfa 40,000 U once weekly, which could be increased to 60,000 U once weekly after 4 weeks dependent on hemoglobin response. Treatment was continued for a maximum of 16 weeks. RESULTS: Among the 2,964 patients assessable for efficacy, epoetin alfa therapy resulted in significant increases in hemoglobin levels, decreases in transfusion requirements, and improvements in functional status and fatigue as assessed by the linear analog scale assessment (energy level, ability to perform daily activities, and overall quality of life) and the anemia subscale of the Functional Assessment of ...

Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac.

Abstract: The ability to taste the sweetness of carbohydrate-rich foodstuffs has a critical role in the nutritional status of humans. Although several components of bitter transduction pathways have been identified, the receptors and other sweet transduction elements remain unknown. The Sac locus in mouse, mapped to the distal end of chromosome 4 (refs. 7-9), is the major determinant of differences between sweet-sensitive and -insensitive strains of mice in their responsiveness to saccharin, sucrose and other sweeteners. To identify the human Sac locus, we searched for candidate genes within a region of approximately one million base pairs of the sequenced human genome syntenous to the region of Sac in mouse. From this search, we identified a likely candidate: T1R3, a previously unknown G protein-coupled receptor (GPCR) and the only GPCR in this region. Mouse Tas1r3 (encoding T1r3) maps to within 20,000 bp of the marker closest to Sac (ref. 9) and, like human TAS1R3, is expressed selectively in taste receptor cells. By comparing the sequence of Tas1r3 from several independently derived strains of mice, we identified a specific polymorphism that assorts between taster and non-taster strains. According to models of its structure, T1r3 from non-tasters is predicted to have an extra amino-terminal glycosylation site that, if used, would interfere with dimerization.

Failure of the ubiquitin-proteasome system in Parkinson's disease.

Abstract: Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by degeneration of dopamine-containing neurons in the midbrain. In cases of familial PD, mutations that lead to failure of the ubiquitin–proteasome system (UPS) have been identified. These genetic abnormalities do not occur in sporadic PD, but we propose that impairment of the UPS could also contribute to neurodegeneration in this disorder. We discuss evidence that failure of the UPS is a common aetiopathogenic factor that underlies the development of familial and sporadic PD, an idea that might help to explain clinical and pathological differences and similarities in these disorders.

Clinical imaging of the high-risk or vulnerable atherosclerotic plaque.

Abstract: The study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of disease progression and regression and aid in selecting appropriate treatments. Several invasive and noninvasive imaging techniques are available to assess atherosclerotic vessels. Most of the standard techniques identify luminal diameter, stenosis, wall thickness, and plaque volume; however, none can characterize plaque composition and therefore identify the high-risk plaques. We will present the different imaging modalities that have been used for the direct assessment of the carotid, aortic, and coronary atherosclerotic plaques. We will review in detail the use of high-resolution, multicontrast magnetic resonance for the noninvasive imaging of vulnerable plaques and the characterization of plaques in terms of their various components (ie, lipid, fibrous, calcium, or thrombus).

A thyroid hormone receptor that is required for the development of green cone photoreceptors.

Abstract: Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina. The mechanisms that control which opsin is expressed in a particular cone are poorly understood, but previous in vitro studies implicated thyroid hormone in cone differentiation. Thyroid hormone receptor beta 2 (TR beta 2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Tr beta 2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders.

Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy

Abstract: Background—This prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis Methods and Results—Sixty-two patients (37 men, 25 women; mean age ±SD 430±123 years) with recent onset (≤6 months of symptoms) of dilated cardiomyopathy and LVEF ≤040 were randomized to 2 g/kg IVIG or placebo All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16% The primary outcome was change in LVEF at 6 and 12 months after randomiz Overall, LVEF improved from 025±008 to 041±017 at 6 months (P<0001) and 042±014 (P<0001 versus baseline) at 12 months The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 014±012, placebo 014±014; 12 months: IVIG 016±012, placebo 015±016) Overall, 31 (56%) of 55 patients at 1 year had an increase in LV

Trp8, a transient receptor potential channel expressed in taste receptor cells

Abstract: The present invention relates to the discovery, identification and characterization of a transient receptor potential channel, referred to herein as TRP8, which is expressed in taste receptor cells and associated with the perception of bitter and sweet taste. The invention encompasses TRP8 nucleotides, host cell expression systems, TRP8 proteins, fusion proteins, polypeptides and peptides, antibodies to the TRP8 protein, transgenic animals that express a TRP8 transgene, and recombinant “knock-out” animals that do not express TRP8. The invention further relates to methods for identifying modulators of the TRP8-mediated taste response and the use of such modulators to either inhibit or promote the perception of bitterness or sweetness. The modulators of TRP8 activity may be used as flavor enhancers in foods, beverages and pharmaceuticals.

Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions A Longitudinal Study by High-Resolution, Noninvasive Magnetic Resonance Imaging

Abstract: Background This study was designed to investigate the effects of lipid-lowering by simvastatin on human atherosclerotic lesions. Methods and Results Eighteen asymptomatic hypercholesterolemic patie...