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Therapeutic Implications (therapeutic + implication)
Kinds of Therapeutic Implications Selected AbstractsRenin-Angiotensin System Blockade: Therapeutic Implications Beyond Blood Pressure ControlJOURNAL OF CLINICAL HYPERTENSION, Issue 2007Norman M. Kaplan MD No abstract is available for this article. [source] Distributions of Cervical Lymph Node Metastases in Oropharyngeal Carcinoma: Therapeutic Implications for the N0 NeckTHE LARYNGOSCOPE, Issue 7 2006Young Chang Lim MD Abstract Objectives: This study sought to investigate the patterns and distributions of lymph node metastases in oropharyngeal squamous cell carcinoma (SCC) and improve the rationale for elective treatment of N0 neck. Materials and Methods: One hundred four patients with oropharyngeal SCC who underwent neck dissection between 1992 and 2003 were analyzed retrospectively. All patients had curative surgery as their initial treatment for the primary tumor and neck. A total of 161 neck dissections on both sides of the neck were performed. Therapeutic dissections were done in 71 and 5 necks and elective neck dissection was done on 33 and 52 necks on the ipsilateral and contralateral sides, respectively. Surgical treatment was followed by postoperative radiotherapy for 78 patients. The follow-up period ranged from 1 to 96 months (mean, 30 months). Results: Of the 161 neck dissection specimens evaluated, 90 (56%) necks were found to have lymph node metastases found by pathologic examination. These consisted of 76 (73% of 104 necks) of the ipsilateral side and 14 (25% of 57 necks) of the contralateral side dissections. The occult metastatic rate was 24% (8 of 33) of ipsilateral neck samples and 21% (11 of 52) of contralateral neck samples. Of the 68 patients who had a therapeutic dissection on the ipsilateral side and had lymphatic metastasis, the incidence rate of level IV and level I metastasis was 37% (25 of 68) and 10% (7 of 68), respectively. Isolated metastasis to level IV occurred on the ipsilateral side in three patients. There were no cases of isolated ipsilateral level I pathologic involvement in an N-positive neck or occult metastasis to this group. The incidence rate of level IV metastasis in patients with ipsilateral nodal metastasis was significantly higher in base of tongue cancer (86% [6 of 7]) compared with tonsillar cancer (34% [20 of 59]) (P = .013). Patients with level IV metastasis had significantly worse 5-year disease-free survival rates than patients with metastasis to other neck levels (54% versus 71%; P = .04). Conclusion: These results suggest that elective N0 neck treatment in patients with oropharyngeal SCC, especially base of tongue cancer, should include neck levels II, III, and IV instead of levels I, II, and III. [source] Localized transmeningeal muscimol prevents neocortical seizures in rats and nonhuman primates: Therapeutic implicationsEPILEPSIA, Issue 4 2009Nandor Ludvig Summary Purpose:, To determine whether muscimol delivered epidurally or into the subarachnoid space can prevent and/or terminate acetylcholine (Ach),induced focal neocortical seizures at concentrations not affecting behavior and background electroencephalography (EEG) activity. Methods:, Rats (n = 12) and squirrel monkeys (n = 3) were chronically implanted with an epidural or subarachnoid drug delivery device, respectively, over the right frontal/parietal cortex, with adjacent EEG electrodes. Recordings were performed in behaving rats and chaired monkeys. Via the implants, either a control solution (artificial cerebrospinal fluid, ACSF) or muscimol (0.25,12.5 mm) was delivered locally as a "pretreatment," followed by the similar delivery of a seizure-inducing concentration of Ach. In five additional rats, the quantities of food-pellets consumed during epidural ACSF and muscimol (2.5 mm) exposures were measured. In a last group of four rats, muscimol (0.8,2.5 mm) was delivered epidurally during the ongoing, Ach-induced EEG seizure. Results:, In contrast to ACSF pretreatments, epidural muscimol pretreatment in rats completely prevented the seizures at and above 2.5 mm. In the monkeys, subarachnoid muscimol pretreatments at 2.5 mm completely prevented the focal-seizure,inducing effect of Ach, whereas similar deliveries of ACSF did not affect the seizures. Furthermore, 2.5 mm epidural muscimol left the eating behavior of rats intact and caused only slight changes in the EEG power spectra. Finally, muscimol delivery during Ach-induced EEG seizures terminated the seizure activity within 1,3 min. Conclusions:, The results of this study suggest that muscimol is a viable candidate for the transmeningeal pharmacotherapy of intractable focal epilepsy. [source] The distribution of lymph node metastases in supraglottic squamous cell carcinoma: Therapeutic implicationsHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2002Luca O. Redaelli de Zinis MD Abstract Background. The treatment of the neck in cancer of the upper aerodigestive tract is still a matter of controversy, even though nowadays there is a trend in the literature toward elective surgery in the N0 neck when the probability of occult lymph node metastasis is greater than 20%. In the elective setup, every effort is made for preservation of uninvolved nonlymphatic structures in positive neck. The aim of this study is to analyze in a large cohort of patients treated for supraglottic carcinoma the prevalence of lymph node metastases and their distribution through various neck levels to redefine our policy of neck treatment. Methods. A retrospective review of 402 consecutive patients, who underwent surgery in the Department of Otolaryngology of the University of Brescia (Italy) for supraglottic squamous cell carcinoma in a 14-year period, has been performed. The prevalence of neck metastases was assessed by pT category and site (marginal vs vestibular) of the primary tumor. The side(s) of neck disease was related to the side of the primary tumor, whether lateral or central. The distribution of involved lymph nodes through the neck levels was determined. Results. Overall lymph node metastases accounted for 40%; their prevalence rate increased with pT category from 10% to 57% (p = .0001). Occult metastases were found in 26% of N0 patients from 0% in pT1 to 40% in pT4 (p = .02). There was no difference in metastases rate between marginal vs vestibular, and central vs lateral neoplasms, whereas bilateral metastases were more frequent in central tumors (20% vs 5%; p < .0001). Level IV was involved only in association with level II and/or level III. Levels I and V were rarely involved when overt metastases were present and never by occult metastases. Conclusions. Elective lateral neck dissection (levels II,IV) is recommended in T2,T4 N0 supraglottic cancers; clearance of both sides of the neck is indicated whenever the lesion is not strictly lateral. We still perform a selective neck dissection including levels II,V whenever there is clinical, radiologic, or intraoperative evidence of metastases at any level. © 2002 Wiley Periodicals, Inc. Head Neck 24: 000,000, 2002 [source] Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: Therapeutic implications for Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2002Kwok-Keung Tai Abstract It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO4 or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease. © 2002 Wiley-Liss, Inc. [source] Therapeutic implications of the MDR-1 geneJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2004K. L. Mealey Drug transporters significantly influence drug pharmacokinetics and pharmacodynamics. P-glycoprotein (P-gp), the product of the MDR1 (ABCB1) gene, is among the most well-characterized drug transporters, particularly in veterinary medicine. A number of clinically relevant, structurally and functionally unrelated drugs are substrates for P-gp. P-gp is expressed by a variety of normal tissues including the intestines, renal tubular cells, brain capillary endothelial cells, biliary canalicular cells, and others, where it functions to actively extrude substrate drugs. In this capacity, P-gp limits oral absorption and central nervous system entry of many substrate drugs. A number of MDR1 polymorphisms have been described in human patients, some of which result in altered drug pharmacokinetics and susceptibility to diseases such as Parkinson's disease, inflammatory bowel disease, refractory seizures, and others. An MDR1 polymorphism in herding breed dogs, including collies and Australian shepherds, has been demonstrated to be the cause of ivermectin sensitivity in these breeds. Recent evidence suggests that this polymorphism, a 4-bp deletion mutation, results in increased susceptibility to the toxicity of several drugs in addition to ivermectin. Furthermore, data in rodent models suggest that P-gp may play an important role in regulating the hypothalamic,pituitary,adrenal axis. [source] Late onset Wilson's disease: Therapeutic implicationsMOVEMENT DISORDERS, Issue 6 2008Anna Cz, onkowska MD Abstract The clinical symptoms of Wilson's disease (WD) usually develop between 3 and 40 years of age and include signs of liver and/or neurologic and psychiatric disease. We report on an 84-year-old woman with WD. Despite the absence of treatment, the only symptom she presented with, until the age of 74 years, was Kayser-Fleisher rings. At the age of 74, she developed slightly abnormal liver function. This case raises the following issues: (a) Should WD be considered in all patients of all ages who manifest signs related to the disease? (b) Are ATP7B mutations fully penetrant? (c) Should all patients diagnosed presymptomatically receive anticopper therapy? © 2008 Movement Disorder Society [source] Research Review: Cholinergic mechanisms, early brain development, and risk for schizophreniaTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 5 2010Randal G. Ross The onset of diagnostic symptomology for neuropsychiatric diseases is often the end result of a decades-long process of aberrant brain development. Identification of novel treatment strategies aimed at normalizing early brain development and preventing mental illness should be a major therapeutic goal. However, there are few models for how this goal might be achieved. This review uses the development of a psychophysiological correlate of attentional deficits in schizophrenia to propose a developmental model with translational primary prevention implications. Review of genetic and neurobiological studies suggests that an early interaction between ,7 nicotinic receptor density and choline availability may contribute to the development of schizophrenia-associated attentional deficits. Therapeutic implications, including perinatal dietary choline supplementation, are discussed. [source] Multicenter clinical experience with flow cytometric method for fetomaternal hemorrhage detectionCYTOMETRY, Issue 6 2002Jenn C. Chen Abstract BACKGROUND Enumeration of fetal red blood cells (RBCs) is important in the management of fetomaternal hemorrhage (FMH), particularly in situations of Rh incompatibility. METHODS We evaluated results from three institutions using the flow cytometric method (FCM) to detect fetal RBCs based on the anti-hemoglobin F (HbF) monoclonal antibody method. RESULTS During 1997,2001, 69 of 1,248 patients (5.5%) had measurable fetal erythrocytes (RBCs) in maternal blood. Only 21 patients (1.7%) had more than 30 mL of fetal blood detected in maternal blood. Of the 11 patients with large FMH and clinical follow-up, 7 had fetal demise (64%). In positive samples, significant differences were found in the fluorescence intensity (FI) of anti-HbF antibody staining between HbF-negative erythrocytes (HbF-) and adult HbF containing erythrocytes (F cells; 4 ± 0 versus 57 ± 9 linear mean channels [LMC]; P < 0.001) and between HbF-cells and fetal RBCs (4 ± 0 versus 433 ± 136 LMC; P < 0.001). In addition, significant differences were observed in forward light scatter intensity between HbF-cells and fetal RBCs (298 ± 15 versus 355 ± 68 LMC, P = 0.03). The transportability of the test is also addressed by comparing results from two other laboratories. The experience of our three laboratories, as well as the results from the recently reinitiated College of American Pathologists survey, which compares FCM and manual methods, clearly documents the superiority of the FCM test over the manual Kleihauer-Betke (KB) test. CONCLUSIONS The FCM is a simpler, more objective, and more precise alternative to the KB method in clinical testing. The high mortality rate associated with large FMH and therapeutic implications of these results should give laboratories motivation to abandon the KB method with more robust FCM to detect FMH. Cytometry (Clin. Cytometry) 50:285,290, 2002. © 2002 Wiley-Liss, Inc. [source] Interactions between microvascular and macrovascular disease in diabetes: pathophysiology and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2007Andrew J. Krentz Convention partitions the complications of diabetes into two main subtypes. First are the diabetes-specific microvascular complications of retinopathy, nephropathy and neuropathy; second are the atherothrombotic macrovascular complications that account for the majority of premature deaths. Pathological interactions between microvascular and macrovascular complications, for example, nephropathy and macrovascular disease, are common. Similar mechanisms and shared risk factors drive the development and progression of both small and large vessel disease. This concept has therapeutic implications. Mounting evidence points to the need for multifactorial strategies to prevent vascular complications in subjects with diabetes and/or the metabolic syndrome. We advocate a combined therapeutic approach that addresses small and large vessel disease. Preferential use should be made of drug regimens that (i) maximize vascular protection, (ii) reduce the risk of iatrogenic vascular damage and (iii) minimize the increasing problem of polypharmacy. [source] AMP-activated protein kinase: role in metabolism and therapeutic implicationsDIABETES OBESITY & METABOLISM, Issue 6 2006Greg Schimmack AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge which becomes activated in situations of energy consumption. AMPK functions to restore cellular ATP levels by modifying diverse metabolic and cellular pathways. In the skeletal muscle, AMPK is activated during exercise and is involved in contraction-stimulated glucose transport and fatty acid oxidation. In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. In the liver, AMPK inhibits the production of glucose, cholesterol and triglycerides and stimulates fatty acid oxidation. Recent studies have shown that AMPK is involved in the mechanism of action of metformin and thiazolidinediones, and the adipocytokines leptin and adiponectin. These data, along with evidence that pharmacological activation of AMPK in vivo improves blood glucose homeostasis, cholesterol concentrations and blood pressure in insulin-resistant rodents, make this enzyme an attractive pharmacological target for the treatment of type 2 diabetes, ischaemic heart disease and other metabolic diseases. [source] Role of histone and transcription factor acetylation in diabetes pathogenesisDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 5 2005Steven G. Gray Abstract Globally, diabetes (and, in particular, type 2 diabetes) represents a major challenge to world health. Currently in the United States, the costs of treating diabetes and its associated complications exceed $100 billion annually, and this figure is expected to soar in the near future. Despite decades of intense research efforts, the genetic basis of the events involved in the pathogenesis of diabetes is still poorly understood. Diabetes is a complex multigenic syndrome primarily due to beta-cell dysfunction associated with a variable degree of insulin resistance. Recent advances have led to exciting new developments with regard to our understanding of the mechanisms that regulate insulin transcription. These include data that implicate chromatin as a critical regulator of this event. The ,Histone Code' is a widely accepted hypothesis, whereby sequential modifications to the histones in chromatin lead to regulated transcription of genes. One of the modifications used in the histone code is acetylation. This is probably the best characterized modification of histones, which is carried out under the control of histone acetyltransferases (HATs) and histone deacetylases (HDACs). These enzymes also regulate the activity of a number of transcription factors through acetylation. Increasing evidence links possible dysregulation of these mechanisms in the pathogenesis of diabetes, with important therapeutic implications. Copyright © 2005 John Wiley & Sons, Ltd. [source] Epithelioid cell granulomas in urine cytology smears: Same cause, different implicationsDIAGNOSTIC CYTOPATHOLOGY, Issue 10 2010Sandeep Kumar Arora M.D. Abstract Tuberculosis of the urinary tract is usually secondary to tuberculosis of the kidney. Multinucleated giant cell histiocytes, often with peripheral nuclei (Langhans' cells), may be identified. Acid-fast bacilli on smear or positive urine cultures confirm the diagnosis. Similar findings can also be seen in patients treated with Bacillus Calmette Guérin (BCG) for transitional cell carcinoma or after bladder surgery. Here, we present two cases showing epithelioid cell granulomas and multinucleated giant cells on urine cytology, and discuss the differentiating features on cytomorphology and their therapeutic implications. Diagn. Cytopathol. 2010;38:765,767. © 2010 Wiley-Liss, Inc. [source] Comparison of four groups of substance-abusing in-patients with different psychiatric comorbidityACTA PSYCHIATRICA SCANDINAVICA, Issue 1 2001J. Hättenschwiler Objective: ,Comparisons of different groups of dual patients are rare, yet potential differences could have therapeutic implications. In this study, four groups of psychiatric in-patients with substance use disorder were compared to each other: patients with no psychiatric comorbidity, patients with comorbid schizophrenia and patients with affective and personality disorder. Method: ,Apart from sociodemographic, therapy-related variables and a detailed survey of their substance use, all subjects were assessed with BPRS and SCL-90-R. Results: ,No differences were found in the patients' demography, psychosocial adjustment and substance consumption career. Significant differences were found in regard to some therapy variables reflecting adherence to treatment and global outcome and to the level of psychopathology. Conclusion: ,Both substance use and comorbid psychiatric disorder have a variable impact on distinct areas of patients' general condition and functioning. The group with comorbid affective disorder appeared to be the most difficult to treat and the therapeutic approach to this disorder deserves reconsideration. [source] Bench to Bedside: Pharmacogenomics, Adverse Drug Interactions, and the Cytochrome P450 SystemACADEMIC EMERGENCY MEDICINE, Issue 12 2005Rishi Sikka MD As physicians attempt to improve the quality of health care, one area of particular concern has been preventable medical errors from adverse drug interactions. The cytochrome P450 family of enzymes has been implicated in a large number of these preventable, adverse drug interactions. This report reviews the basic biochemistry and pharmacogenomics underlying the reactions catalyzed by the cytochrome P450 family of enzymes. An emphasis is placed on the phenotypic variations within a population and the resulting clinical effects. In addition, six members of the cytochrome P450 superfamily that are responsible for the metabolism of the majority of pharmaceutical agents are profiled in detail. These enzymes, CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2, are reviewed with regard to their phenotypic variation in the population and the resulting clinical and therapeutic implications. [source] Subtypes of major depression in substance dependenceADDICTION, Issue 10 2009Mark J. Niciu ABSTRACT Aims This study evaluated features that differentiate subtypes of major depressive episode (MDE) in the context of substance dependence (SD). Design Secondary data analysis using pooled data from family-based and case,control genetic studies of SD. Setting Community recruitment through academic medical centers. Participants A total of 1929 unrelated subjects with alcohol and/or drug dependence. Measurements Demographics, diagnostic criteria for psychiatric and substance use disorders and related clinical features were obtained using the Semi-Structured Assessment for Drug Dependence and Alcoholism. We compared four groups: no life-time MDE (no MDE), independent MDE only (I-MDE), substance-induced MDE only (SI-MDE) and both types of MDE. Findings Psychiatric measures were better predictors of MDE subtype than substance-related or socio-demographic ones. Subjects with both types of MDE reported more life-time depressive symptoms and comorbid anxiety disorders and were more likely to have attempted suicide than subjects with I-MDE or SI-MDE. Subjects with both types of MDE, like those with I-MDE, were also more likely than subjects with SI-MDE to be alcohol-dependent only than either drug-dependent only or both alcohol- and drug-dependent. Conclusions SD individuals with both types of MDE have greater psychiatric severity than those with I-MDE only or SI-MDE only. These and other features that distinguish among the MDE subtypes have important diagnostic and potential therapeutic implications. [source] Lectin-aided separation of circulating tumor cells and assay of their response to an anticancer drug in an integrated microfluidic deviceELECTROPHORESIS, Issue 18 2010Li Li Abstract Metastasis caused by the entry of circulating tumor cells (CTCs) into the bloodstream or lymphatic vessels is a major factor contributing to death in cancer patients. Separation of CTCs and studies on CTC,drug interactions are very important for prognostic and therapeutic implications of metastatic cancer. In this study, an integrated microfluidic device for CTC separation through the combination of lectin and microstructure is presented. This microfluidic device and lectin concanavalin A were utilized for the separation of K562 cells in whole blood samples. The results showed that the separation efficiency can reach 84%, which is much higher than that of an experiment without concanavalin A treatment. To further demonstrate the feasibility of this microfluidic device application in sequential studies after target cells were separated, the interactions of K562 cells and an anticancer drug, cytarabine, were also examined. After 6,h on-chip treatment with cytarabine, the viabilities of K562 cells were 85.29, 77.05, and 40% for drug concentration levels of 0.25, 0.5, and 1.0,g/L, respectively. This system can facilitate the rapid and efficient in vitro investigation of CTC separation and CTC-related studies. [source] DNA interstrand crosslinks: Repair, cell signaling, and therapeutic implicationsENVIRONMENTAL AND MOLECULAR MUTAGENESIS, Issue 6 2010Karen M. Vasquez No abstract is available for this article. [source] Ready, willing and able to change: motivational aspects of the assessment and treatment of eating disordersEUROPEAN EATING DISORDERS REVIEW, Issue 1 2001Janet Treasure This paper focuses on motivational aspects in the assessment and treatment of eating disorders. Measurement issues and therapeutic implications are reviewed as will be the limitations of the motivational model. Copyright © 2001 John Wiley & Sons, Ltd and Eating Disorders Association. [source] Insulin, blood pressure and elevated Na+/H+ exchange activity , novel therapeutic implicationsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001M. Tepel No abstract is available for this article. [source] Cardiological diagnostic work-up in stroke patients , a comprehensive study of test results and therapeutic implicationsEUROPEAN JOURNAL OF NEUROLOGY, Issue 2 2009B. Schaer Background and purpose:, In some Western countries, many stroke patients undergo routine tests including ECG, echocardiography, carotid ultrasound and Holter monitoring, even though they have been shown to express limited value in unselected patients. Comprehensive data on yield of tests, especially on consequences taken from positive test results, are scanty. Methods:, Consecutive stroke patients with evidence of ischaemic lesions by imaging techniques were included. Aetiology was determined using TOAST-classifications. Rates of positive test results and their impact on drug therapy, especially anticoagulation were evaluated. Results:, Two hundred and forty-one consecutive patients, age 69 ± 13 years were included. Positive test results were documented in 19% with 12-lead ECG, 24% with carotid ultrasound, 24% with echocardiography and never with Holter monitoring. Overall, in 41% positive test results were present. Apart from echocardiography (37%), a change of therapy resulted in 51,56% of patients with a positive test result. Conclusions:, Even though 12-lead ECG, carotid ultrasound and echocardiography only had relatively low incidences of positive findings, their impact on management in case of positive test results was quite high. Nevertheless, future studies to select patients more appropriately are needed. In contrast, Holter monitoring had no impact and should not be used in routine evaluation of stroke patients. [source] Attachment, Social Rank, and Affect Regulation: Speculations on an Ethological Approach to Family Interaction,FAMILY PROCESS, Issue 3 2002F.R.C.P. (C), L.R.C.P., Leon Sloman M.R.C.P. The attachment and social rank systems are biological-evolutionary systems that can serve as models for conceptualizing family interaction. By exploring both their unique and interrelated impact on affect regulation, we can differentiate between processes that foster healthy growth and those leading to individual psychopathology. This perspective facilitates the integration of biological and psychological models, and has therapeutic implications. It also integrates well with other family therapy models. [source] Endothelial cell-specific molecule 2 (ECSM2) modulates actin remodeling and epidermal growth factor receptor signalingGENES TO CELLS, Issue 3 2009Fanxin Ma Endothelial cell-specific molecules (ECSMs) play a pivotal role in the pathogenesis of many angiogenesis-related diseases. Since its initial discovery, the exact function of human ECSM2 has not been defined. In this study, by database mining, we identified a number of hypothetical proteins across species exhibiting substantial sequence homology to the human ECSM2. We showed that ECSM2 is preferentially expressed in endothelial cells and blood vessels. Their characteristic structures and unique expression patterns suggest that ECSM2 is an evolutionarily conserved gene and may have important functions. We further explored the potential roles of human ECSM2 at the molecular and cellular level. Using a reconstitution mammalian cell system, we demonstrated that ECSM2 mainly resides at the cell membrane, is critically involved in cell-shape changes and actin cytoskeletal rearrangement, and suppresses tyrosine phosphorylation signaling. More importantly, we uncovered that ECSM2 can cross-talk with epidermal growth factor receptor (EGFR) to attenuate the EGF-induced cell migration, possibly via inhibiting the Shc-Ras-ERK (MAP kinase) pathway. Given the importance of growth factor and receptor tyrosine kinase-mediated signaling and cell migration in angiogenesis-related diseases, our findings regarding the inhibitory effects of ECSM2 on EGF-mediated signaling and cell motility may have important therapeutic implications. [source] Different roles of proteolipids and 70-kDa subunits of V-ATPase in growth and death of cultured human cellsGENES TO CELLS, Issue 6 2003Hong Zhan Background: The vacuolar-type proton-translocating adenosine triphosphatase (V-ATPase) plays important roles in cell growth and tumour progression. V-ATPase is composed of two distinct structures, a hydrophilic catalytic cytosolic sector (V1) and a hydrophobic transmembrane sector (V0). The V1 sector is composed of 5,8 different subunits with the structure A3B3C1D1E1F1G1H1. The V0 sector is composed of 5 different subunits with the structure 1161381191166. The over-expression of 16-kDa proteolipid subunit of V-ATPase in the perinuclear region of the human adventitial fibroblasts promotes phenotypic modulation that contributes to neointimal formation and medial thickening. A relationship between oncogenicity and the expression of the 16-kDa proteolipid has also been suggested in human pancreatic carcinoma tissue. Results: We found that the mRNA levels of the 16-kDa proteolipid but not of the 70-kDa subunit of V-ATPase in human myofibroblasts were more abundant in serum-containing medium (MF(+) cells) than serum-free medium (MF(,) cells). In HeLa cells, the levels of mRNA and protein of the 16-kDa, 21-kDa or 70-kDa were clearly suppressed when the corresponding anti-sense oligonucleotides were administered to the culture medium. The growth rate and viability (mostly due to necrosis) of HeLa cells were reduced markedly by the 16-kDa and 21-kDa anti-sense, but little by the 70-kDa anti-sense, and not at all by any sense oligonucleotides. The localization of 16-kDa/21-kDa proteolipid subunits was different from that of the 70-kDa subunit in HeLa cells. Conclusion: These results suggest that the 16-kDa and 21-kDa proteolipid subunits of the V0 sector play crucial roles in growth and death of cultured human cells. Our results may provide new insights into the mechanism and therapeutic implications for vessel wall hyperplasia and tumorigenesis. [source] Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action,GLIA, Issue 1 2009You-Joung Kim Abstract Parkinson's disease (PD) is a common, progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra (SN). Numerous studies have provided evidence suggesting that neuroinflammation plays an important role in the pathogenesis of PD. In this study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether human mesenchymal stem cells (hMSCs) have a protective effect on the dopaminergic system through anti-inflammatory mechanisms. The hMSC treatment significantly decreased LPS-induced microglial activation, tumor necrosis factor (TNF)-,, inducible nitric oxide synthase (iNOS) mRNA expression, and production of NO and TNF-, compared with the LPS-only treatment group. In co-cultures of microglia and mesencephalic dopaminergic neurons, hMSC treatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells. The hMSC treatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the SN was considerably decreased and was clearly accompanied by a decrease in activation of microglia, as well as TNF-, and iNOS mRNA expression and production of TNF-,. These data suggest that hMSCs have a neuroprotective effect on dopaminergic neurons through anti-inflammatory actions mediated by the modulation of microglial activation. Along with various trophic effects and trans-differentiational potency, the anti-inflammatory properties of MSCs could have major therapeutic implications in the treatment of PD. © 2008 Wiley-Liss, Inc. [source] Intramitochondrial crystalline inclusions in nonalcoholic steatohepatitis,HEPATOLOGY, Issue 6 2009Stephen H. Caldwell Mitochondrial dysfunction is an important element in the pathogenesis of nonalcoholic steatohepatitis (NASH). Intramitochondrial crystals (IMCs) are a well-documented morphological abnormality seen on transmission electron microscopy in this disease. It has been suggested that IMCs consist of phospholipids, but their exact composition remain uncertain many years after their discovery. Micellar phase transitions of phospholipid bilayers is a well-known but little-studied phenomenon in living systems. Its presence in the mitochondria of NASH would offer significant insight into the disease with possible therapeutic implications. We postulated that intramitochondrial disturbances in NASH are sufficient to produce such transitions and that their detection in fresh biopsies would therefore be a dynamic process. To test this, we performed a blinded, prospective analysis of fresh liver biopsy samples immediately fixed under different conditions. Quantitative transmission electron microscopy morphometry, performed by systematically counting total mitochondria and IMCs within areas of uniform dimension, showed a stepwise decline in IMCs with cooler fixation temperature in each subject studied. Randomization testing (Monte Carlo resampling) confirmed that the detection of IMCs was strongly dependent on fixation temperature (P < 0.0001). Conclusion: These results indicate that the intramitochondrial crystals characteristic of NASH are highly dynamic and unstable structures. The findings offer the strongest support yet for their origin in micellar phase transitions. We speculate that such transitions result from microenvironmental changes within the mitochondria and carry therapeutic implications, especially in regard to dietary manipulations of mitochondrial lipid composition. (HEPATOLOGY 2009.) [source] Risk factors of fibrosis in alcohol-induced liver diseaseHEPATOLOGY, Issue 3 2002Bruno Raynard In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P = .001), BMI (P = .002), female sex (P < .05), Perls grade (P < .05), and blood glucose level (P < .05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients. [source] Highly sensitive detection of the MGB1 transcript (mammaglobin) in the peripheral blood of breast cancer patientsINTERNATIONAL JOURNAL OF CANCER, Issue 4 2004Nuno Cerveira Abstract We describe a new one-step RT-PCR assay for the detection of the mammaglobin (MGB1) gene transcript in the peripheral blood of breast cancer patients. With this approach, the MGB1 transcript could be detected in the peripheral blood of 22 of 54 (41%) breast cancer patients prior to any therapy. This method, using specific primers for cDNA synthesis, proved to be more sensitive (10,6 to 10,11, usually 10,7) than previously reported methodologies. This increased sensitivity was achieved without compromising specificity, as the MGB1 transcript was not detected in 38 blood samples of healthy donors and in only 1 of 18 blood samples of patients presenting with hematologic malignancies. A positive correlation was seen between MGB1 positivity and breast cancer stage: 0/3 (0%) in stage 0, 3/13 (23%) in stage I, 6/17 (35%) in stage II, 5/10 (50%) in stage III, 8/11 (73%) in stage IV (p = 0.003). The prognostic and therapeutic implications of MGB1 positivity by one-step RT-PCR in the peripheral blood of breast cancer patients, especially in clinically localized disease (stages I and II), should be evaluated after long-term clinical follow-up of these patients. © 2003 Wiley-Liss, Inc. [source] Heterogeneity of violence in schizophrenia and implications for long-term treatmentINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 8 2008J. Volavka Summary Aims:, Most patients with schizophrenia are not violent. However, persistent violent behaviour in a minority of patients presents a therapeutic challenge. Published treatment guidelines and most pharmacological and epidemiological literature on violence in schizophrenia treat overt physical aggression as a homogeneous phenomenon. The aim of this review is to address the subtyping of violent behaviour in schizophrenia, and to relate the subtypes to treatment. Method:, Literature describing subtypes of violence in schizophrenia and the treatment of this problem was reviewed. ,Schizophrenia', ,violence', ,aggression', ,hostility' and ,personality disorders' were the principal search terms describing behaviours. Generic names of individual atypical antipsychotics and mood stabilisers were used in treatment searches. Results:, There are at least three aetiological subtypes of violence in schizophrenia (i) that related directly to positive psychotic symptoms, (ii) impulsive violence and (iii) violence stemming from comorbidity with personality disorders, particularly psychopathy. Current treatment of violence in schizophrenia relies on antipsychotics and mood stabilisers. The evidence of effectiveness is relatively strong for clozapine, but inconsistent for other treatments. No systematic recommendations relating the treatment to aetiological subtypes of violence were found. Discussion:, The inconsistent effectiveness of the current treatments of violent behaviour in schizophrenia is due, at least in part, to the aetiological heterogeneity of that behaviour. We should not expect that any given pharmacological treatment will be equally effective in reducing violent behaviour caused by psychosis, impaired impulse control or personality disorder. Conclusion:, Violence in schizophrenia is aetiologically heterogeneous. This heterogeneity has therapeutic implications that impact clinical practice today and should be further explored in future studies. [source] Cutaneous vascular patterns in psoriasisINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 3 2010Giuseppe Micali MD Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in its pathogenesis. Investigational studies have shown that activated keratinocytes in lesional skin undergo an accelerated epidermal cell turnover and are a major source of pro-angiogenic cytokines, like as VEGF, ESAF, PDECGE/TP, TNF-,, TGF-, and PDGF, suggesting that the epidermis is capable of inducing vascular proliferation. On the other hand, microvascular alterations are essential for the development and persistence of the psoriatic lesions as they provide cellular and tissue nutrition to hyperplastic keratinocytes and promote inflammatory cell migration. Also, dilated and slightly tortuous blood vessels within dermal papillae represent one of the earliest detectable histological changes for all stages of lesional development. Videodermatoscopy is a new non invasive imaging technique able to identify modifications of microvascular architecture in vivo and such evaluation will be useful for the dermatologist both for diagnostic and prognostic evaluation, as well as for post-therapeutic follow-up. In this review, the role of microvascular abnormalities in the pathogenesis of psoriasis as well as the mechanisms underlying vascular changes and their primary therapeutic implications will be reviewed and discussed. [source] | ||||||||||||||||||||||||||||||||||||||||||||||