Home About us Contact
|
Home About us Contact | ||
|
|
||
Major Clinical Problem (major + clinical_problem)
Selected AbstractsRole of Transthoracic Echocardiography in Atrial FibrillationECHOCARDIOGRAPHY, Issue 4 2000RICHARD W. ASINGER M.D. Atrial fibrillation is a major clinical problem that is predicted to be encountered more frequently as the population ages. The clinical management of atrial fibrillation has become increasingly complex as new therapies and strategies have become available for ventricular rate control, conversion to sinus rhythm, maintenance of sinus rhythm, and prevention of thromboembolism. Clinical and transthoracic echocardiographic features are important in determining etiology and directing therapy for atrial fibrillation. Left atrial size, left ventricular wall thickness, and left ventricular function have independent predictive value for determining the risk of developing atrial fibrillation. Left atrial size may have predictive value in determining the success of cardioversion and maintaining sinus rhythm in selected clinical settings but has less value in the most frequently encountered group, patients with nonvalvular atrial fibrillation, in whom the duration of atrial fibrillation is the most important feature. When selecting pharmacological agents to control ventricular rate, convert to sinus rhythm, and maintain normal sinus rhythm, transthoracic echocardiography (TTE) allows noninvasive evaluation of left ventricular function and hence guides management. The combination of clinical and transthoracic echocardiographic features also allows risk stratification for thromboembolism and hemorrhagic complications in atrial fibrillation. High-risk clinical features for thromboembolism supported by epidemiological observations, results of randomized clinical trials, and meta-analyses include rheumatic valvular heart disease, prior thromboembolism, congestive heart failure, hypertension, older (> 75 years old) women, and diabetes. Small series of cases also suggest those with hyperthyroidism and hypertrophic cardiomyopathy are at high risk. TTE plays a unique role in confirming or discovering high-risk features such as rheumatic valvular disease, hypertrophic cardiomyopathy, and decreased left ventricular function. Validation of the risk stratification scheme used in the Stroke Prevention in Atrial Fibrillation-III trial is welcomed by clinicians who are faced daily with balancing the benefit and risks of anticoagulation to prevent thromboembolism inpatients with atrial fibrillation. [source] Drug Resistance in Epilepsy: Putative Neurobiologic and Clinical MechanismsEPILEPSIA, Issue 6 2005Dieter Schmidt Summary:, Drug-resistant epilepsy with uncontrolled severe seizures despite state-of-the-art medical treatment continues to be a major clinical problem for up to one in three patients with epilepsy. Although drug resistance may emerge or remit in the course of epilepsy or its treatment, in most patients, drug resistance seems to be continuous and to occur de novo. Unfortunately, current antiepileptic drugs (AEDs) do not seem to prevent or to reverse drug resistance in most patients, but add-on therapy with novel AEDs is able to exert a modest seizure reduction in as many as 50% of patients in short-term clinical trials, and a few become seizure free during the trial. It is not known why and how epilepsy becomes drug resistant, while other patients with seemingly identical seizure types can achieve seizure control with medication. Several putative mechanisms underlying drug resistance in epilepsy have been identified in recent years. Based on experimental and clinical studies, two major neurobiologic theories have been put forward: (a) removal of AEDs from the epileptogenic tissue through excessive expression of multidrug transporters, and (b) reduced drug-target sensitivity in epileptogenic brain tissue. On the clinical side, genetic and clinical features and structural brain lesions have been associated with drug resistance in epilepsy. In this article, we review the laboratory and clinical evidence to date supporting the drug-transport and the drug-target hypotheses and provide directions for future research, to define more clearly the role of these hypotheses in the clinical spectrum of drug-resistant epilepsy. [source] Trends in peptic ulcer pharmacotherapyFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2004Bülent Sivri Abstract Considering the diseases of the stomach and duodenum, peptic ulcer has been the one with a significant clinical impact. The pathophysiology of peptic ulcer has centred on an imbalance between aggressive and protective factors. The discovery of Helicobacter pylori as a cause of peptic ulcer has changed our approach greatly towards this disease. Despite the decreasing frequency of H. pylori -induced peptic ulcers, peptic ulcer remains a major clinical problem partly because nonsteroidal anti-inflammatory drug (NSAID)-related ulcers and hospital admissions for ulcer complications associated with NSAIDs have increased in frequency. The interaction between H. pylori and NSAIDs is one of the most controversial issues in peptic ulcer. In this article, current concepts of peptic ulcer etiopathogenesis and the management of peptic ulcer according to the etiology were reviewed. [source] A new strategy for studying In Vitro the drug susceptibility of clinical isolates of human hepatitis B virusHEPATOLOGY, Issue 4 2004David Durantel Resistance of hepatitis B virus (HBV) to antivirals has become a major clinical problem. Our objective was to develop a new method for the cloning of naturally occurring HBV genomes and a phenotypic assay capable of assessing HBV drug susceptibility and DNA synthesis capacity in vitro. Viral DNA was extracted from sera and was amplified by polymerase chain reaction, and amplicons were cloned into vectors that enable, after cell transfection, the initiation of the intracellular HBV replication cycle. Single or multiple clones were used to transfect Huh7 cells. The viral DNA synthesis capacity and drug susceptibility were determined by measuring the level of intracellular DNA intermediate, synthesized in absence or presence of antiviral, using Southern blot analysis. We have developed, calibrated, then used this phenotypic assay to determine the drug susceptibility of HBV quasispecies isolated throughout the course of therapy from patients selected according to their mutation profile. A multiclonal and longitudinal analysis enabled us to measure the variation of drug susceptibility of different viral quasispecies by comparison of IC50/IC90s with standards. The presence of famciclovir- or lamivudine-induced mutations in the viral population caused a change in viral DNA synthesis capacity and drug susceptibility in vitro, demonstrating the clinical relevance of the assay. In conclusion, our phenotypic assay enables the in vitro characterization of DNA synthesis capacity and drug susceptibility of HBV quasispecies isolated from patients. This assay should allow a better monitoring of patients undergoing antiviral therapy, as well as the screening of novel drugs on emerging resistant strains. (Hepatology 2004;40:855,864). [source] NF-,B inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutantsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2009Nadia Lounnas Abstract The Bcr-Abl inhibitor imatinib is the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Nevertheless, resistance to imatinib emerges as CML progresses to an acute deadly phase implying that physiopathologically relevant cellular targets should be validated to develop alternative therapeutic strategies. The NF-,B transcription factor that exerts pro-survival actions is found abnormally active in numerous hematologic malignancies. In the present study, using Bcr-Abl-transfected BaF murine cells, LAMA84 human CML cell line and primary CML, we show that NF-,B is active downstream of Bcr-Abl. Pharmacological blockade of NF-,B by the IKK2 inhibitor AS602868 prevented survival of BaF cells expressing either wild-type, M351T or T315I imatinib-resistant mutant forms of Bcr-Abl both in vitro and in vivo using a mouse xenograft model. AS602868 also affected the survival of LAMA84 cells and of an imatinib-resistant variant. Importantly, the IKK2 inhibitor strongly decreased in vitro survival and ability to form hematopoietic colonies of primary imatinib resistant CML cells including T315I cells. Our data strongly support the targeting of NF-,B as a promising new therapeutic opportunity for the treatment of imatinib resistant CML patients in particular in the case of T315I patients. The T315I mutation escapes all currently used Bcr-Abl inhibitors and is likely to become a major clinical problem as it is associated with a poor clinical outcome. © 2009 UICC [source] In Vivo RANK Signaling Blockade Using the Receptor Activator of NF-,B:Fc Effectively Prevents and Ameliorates Wear Debris-Induced Osteolysis via Osteoclast Depletion Without Inhibiting OsteogenesisJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2002Lisa M. Childs Abstract Prosthesis failure due to wear debris-induced osteolysis remains a major clinical problem and the greatest limitation for total joint arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of receptor activator of NF-,B (RANK) signaling in osteoclastogenesis and bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating titanium (Ti)-induced osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and bone resorption in response to Ti implanted locally. Complete inhibition occurred at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK,/, mice. We also evaluated the effects of a single injection of RANK:Fc on day 5 on established osteolysis and found that Ti-treated were still depleted for multinucleated tartrate-resistant acid phosphatase-positive (TRAP+) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced osteolysis without jeopardizing osteogenesis. [source] Effects of 5-HT2A receptor antagonist on blood flow in chronically compressed nerve rootsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 4 2004Miho Sekiguchi Abstract Neurogenic intermittent claudication (NIC) can be caused by compression of the cauda equina by spinal stenosis and is a major clinical problem. A reduction of blood flow is an important mechanism for inducing NIC and may be caused by a vasoconstrictive effect mediated by the serotonin 5-HT2A receptor in chronic cauda equina compression lesions. This study assessed the effects of the 5-HT2A receptor antagonist on nerve vasculature in chronically compressed nerve roots. A plastic balloon was placed under the lamina of L7 and inflated to 10 mmHg and left for 1 week in several cauda equina compression models. All experimental animals received an acute administration of serotonin. One group received sarpogrelate hydrochloride (5-HT2A receptor antagonist: 5-HTRA) before administration of serotonin, and another group was administered 5-HTRA after administration of serotonin. Diameters and blood flow in the vasculature of S2 or S3 nerve roots were measured after injection of serotonin. In animals without compression of the cauda equina (sham), blood vessels contracted and the blood flow was reduced after administration of serotonin. In sham and compression animals receiving both serotonin and 5-HTRA, blood vessel diameter was not reduced and was significantly larger than that in the compression group receiving only serotonin (p < 0.05). Likewise, the blood flow was not reduced in sham and compression animals receiving serotonin and 5-HTRA and was significantly greater in the compression group treated only with serotonin. 5-HTRA inhibited vasoconstriction and the reduction of blood flow in chronically compressed nerve roots challenged with serotonin. This fact suggests that 5-HTRA might be effective at improving blood flow in chronically compressed nerve roots in patients with spinal canal stenosis and changes in circulation levels of serotonin. [source] Platelet Recruitment in the Murine Hepatic Microvasculature During Experimental Sepsis: Role of NeutrophilsMICROCIRCULATION, Issue 2 2006GEORG SINGER ABSTRACT Objectives: Sepsis is a major clinical problem that often results in the dysfunction or failure of multiple organs, including the liver. While inflammatory cell activation has been implicated as an early critical event in sepsis-induced liver dysfunction, there is growing evidence for the involvement of activated platelets in this pathologic process. Methods: Intravital microscopy was used in this study to assess the magnitude and time course of platelet adhesion in the liver microcirculation during experimental sepsis and to determine whether the platelet accumulation is linked to leukocyte infiltration. The adhesion of platelets and leukocytes in terminal hepatic venules (THV) and sinusoids was quantified at 2, 4, and 6 h after abdominal sepsis induced by cecal ligation and puncture (CLP). Results: While the rolling and firm adhesion of platelets and leukocytes in THV were not altered in the first 2 h after CLP, platelet recruitment was observed at 4 h and further elevated at 6 h after CLP. Leukocyte adhesion in THV exhibited a similar time course. A similar accumulation of blood cells in sinusoids was noted after CLP. This was accompanied by an increased number of nonperfused sinusoids. CLP-induced leukocyte and platelet recruitment in THV and sinusoids was attenuated in mice rendered neutropenic with anti-neutrophil serum. Conclusion: These findings indicate that sepsis is associated with a neutrophil-dependent recruitment of platelets in the liver microcirculation that impairs sinusoidal perfusion and may contribute to the liver dysfunction associated with sepsis. [source] Neonatal Apnea: What's New?,PEDIATRIC PULMONOLOGY, Issue 10 2008Jalal M. Abu-Shaweesh MD Abstract Apnea of prematurity (AOP) remains a major clinical problem in present day neonatology that warrants frequent evaluations and imposes challenges in therapeutic strategies. Although the pathogenesis of AOP is poorly understood, it is probably a manifestation of physiologic immaturity of breathing control rather than a pathologic disorder. Immature breathing responses to hypoxia, hypercapnia and exaggerated inhibitory pulmonary reflexes in preterm infants might also contribute to the occurrence or severity of AOP. Recent data suggest a role for genetic predisposition. Although typically resolve with maturation, the role of bradycardia and desaturation episodes associated with AOP in the development of sleep disorder breathing and neurodevelopmental delay needs further clarification. Pharmacological treatment with methylxanthines and CPAP remain the mainstay for treatment of AOP. However, recent studies have implicated central inhibitory neuromodulators including prostaglandins, GABA and adenosine in its pathogenesis, the fact that might provide future specific targets for treatment. This review will summarize new insights involving these issues as well as others involving the pathogenesis, treatment strategies and consequences of apnea in premature infants. Pediatr Pulmonol. 2008; 43:937,944. © 2008 Wiley-Liss, Inc. [source] | |||||||||||||||||||