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Organ Function (organ + function)
Selected AbstractsTherapy with Cell Encapsulation for Substitution of Organ Function and Tumor Treatment (Adv. Eng.ADVANCED ENGINEERING MATERIALS, Issue 8 2009Mater. The cover shows life and dead assay demonstrating living cells within a cellulose sulfate capsule. More information can be found in the article by J. M. Lohr et al. on page B129. [source] Therapy with Cell Encapsulation for Substitution of Organ Function and Tumor Treatment,ADVANCED ENGINEERING MATERIALS, Issue 8 2009J. Matthias Löhr Cell encapsulation represents an innovative technique. However, clinical applications are sparse. Most experiments and clinical studies have been performed with either alginate or cellulose sulfate capsules, containing several cell lines and a broad variety of applications, ranging all the way from substitution for impaired organ function and release of cytokines or growth factors to gene-directed enzyme prodrug therapy. A few clinical studies have been conducted and/or are under way. [source] Laryngeal presentation of systemic apolipoprotein A-I,derived amyloidosis,THE LARYNGOSCOPE, Issue 3 2009Aldert J. C. Hazenberg MD Abstract Objective: To study the clinical and pathological characteristics of two patients with laryngeal apolipoprotein A-I (apoA-I)-derived (AApoAI) amyloidosis with the apolipoprotein A-I variants Leu174Ser and Leu178Pro, respectively. The latter variant has not been associated with amyloid before. Study Design: Descriptive report of two patients who presented with laryngeal amyloid presumed to be of localized AL type, but in who further assessments demonstrated systemic amyloidosis. Methods: The larynx was examined by videolaryngostroboscopy. The voice was analyzed with the GRBAS system, phonation times, and phonetography. Laryngeal biopsies were stained with Congo red and analyzed immunohistochemically. Organ function was assessed and tissue involvement by amyloid further determined by rectal biopsy, abdominal fat tissue aspirate, and serum amyloid P component scintigraphy. Results: The appearance of the laryngeal amyloid was unusual in both patients, occurring as small, irregular floppy proliferations affecting the borders of both vocal folds. Amyloid was stained with antibodies to apoA-I and not with antibodies to immunoglobulin light chains. The 45-year-old woman with the previously described amyloidogenic apoA-I Leu174Ser variant had possible involvement by amyloid in joints, peripheral nerves, and heart. Whereas in the 67-year-old man with apoA-I Leu178Pro there was a clinical suggestion of autonomic and cardiac amyloid and histological corroboration of systemic amyloidosis in abdominal fat. Conclusions: Laryngeal symptoms may be the presenting feature of hereditary systemic AApoAI amyloidosis, and comprehensive investigations including apoA-I genotyping are warranted in patients who present with apparently localized laryngeal amyloidosis. The distinctive appearance of the amyloidotic vocal folds described here may further signal the possibility of hereditary AApoAI type. Laryngoscope, 119:608,615, 2009 [source] Extended Mechanical Circulatory Support With a Continuous-Flow Rotary Left Ventricular Assist DeviceCONGESTIVE HEART FAILURE, Issue 2 2010Scott Harris DO Background LVAD therapy is an established treatment modality for patients with advanced heart failure. Pulsatile LVADs have limitations in design precluding their use for extended support. Continuous-flow rotary LVADs represent an innovative design with potential for small size and greater reliability by simplification of the pumping mechanism. Methods In a prospective multicenter study, 281 patients urgently listed (United Network for Organ Sharing status 1A or 1B) for heart transplant underwent implant of a continuous-flow LVAD. Survival and transplant rates were assessed at 18 months. Patients were assessed for adverse events throughout the study and for quality of life, functional status, and organ function for 6 months. Results Of 281 patients, 222 (79%) underwent transplant or LVAD removal for cardiac recovery or had ongoing LVAD support at 18-month follow-up. Actuarial survival on support was 72% (95% confidence interval, 65%,79%) at 18 months. At 6 months, there were significant improvements in functional status and 6-minute walk test results (from 0% to 83% of patients in New York Heart Association functional class I or II and from 13% to 89% of patients completing a 6-minute walk test) and in quality of life (mean values improved 41% with Minnesota Living With Heart Failure and 75% with Kansas City Cardiomyopathy questionnaires). Major adverse events included bleeding, stroke, right heart failure, and percutaneous lead infection. Pump thrombosis occurred in 4 patients. Conclusions A continuous-flow LVAD provides effective hemodynamic support for at least 18 months in patients awaiting transplant, with improved functional status and quality of life. [source] Therapy with Cell Encapsulation for Substitution of Organ Function and Tumor Treatment,ADVANCED ENGINEERING MATERIALS, Issue 8 2009J. Matthias Löhr Cell encapsulation represents an innovative technique. However, clinical applications are sparse. Most experiments and clinical studies have been performed with either alginate or cellulose sulfate capsules, containing several cell lines and a broad variety of applications, ranging all the way from substitution for impaired organ function and release of cytokines or growth factors to gene-directed enzyme prodrug therapy. A few clinical studies have been conducted and/or are under way. [source] Salvage surgery after radical accelerated radiotherapy with concomitant boost technique for head and neck carcinomasHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 3 2005Daniel Taussky MD Abstract Background. Definitive radiotherapy (RT) for head and neck cancer is increasingly used to preserve organ function, whereas surgery is reserved for treatment failure. However, data are sparse regarding the feasibility of salvage surgery, particularly for unselected patients after accelerated RT. Methods. From 1991 to 2001, 297 patients, most with stage III to IV cancer (Union Internationale Contre le Cancer) were treated with concomitant boost RT (median dose, 69.9 Gy in 41 fractions) with or without chemotherapy (in 33%, usually cisplatin with or without 5-fluorouracil). The 75 patients seen with local and/or regional failure were studied. We analyzed the factors influencing the decision to attempt surgical salvage, the oncologic outcome, and the associated complications. Results. Seventeen (23%) of the 75 patients had a salvage operation. This included all five patients with laryngeal cancers but only 16% to 20% of patients with tumors in other locations. Most patients could not be operated on because of disease extension (40%) and poor general condition/advanced age (30%). Patients with low initial primary T and N classification were more likely to undergo surgery (p = .002 and .014, respectively). Median post-recurrence survival was significantly better for patients who had salvage operations than for those without surgical salvage treatment (44 vs 11 months, p = .0001). Thirteen patients were initially seen with postoperative complications (mostly delayed wound healing and fistula formation). Conclusions. After definitive accelerated RT with the concomitant boost technique, only a minority of patients with local or regional recurrence underwent salvage surgery. Disease stage, tumor location, and patient's general condition at the initial diagnosis seemed to be the main factors influencing the decision to attempt surgical salvage. For patients with initially resectable disease who undergo radical nonsurgical treatment, more effective follow-up is needed to favor early detection of treatment failure, which may lead to a timely and effective salvage surgery. © 2004 Wiley Periodicals, Inc. Head Neck27: 182,186, 2005 [source] Inflammation-associated remodelling and fibrosis in the lung , a process and an end pointINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2007William A.H. Wallace Summary Fibrosis by common usage in the pathological and clinical literature is the end result of a healing process and synonymous with scarring. We would argue that its use to describe a dynamic series of events which may be reversible is unhelpful and that the term ,lung remodelling' is a better description for this process as it reflects changes in tissue organization that may or may not progress to ,fibrosis' as a final fixed point. Resolution, through reversal of active lung remodelling, by therapeutic intervention is possible providing the alveolar architecture remains intact. If the lung architecture is lost then healing by permanent fibrosis with loss of organ function is inevitable. [source] Oral features and dental health in Hurler Syndrome following hematopoietic stem cell transplantationINTERNATIONAL JOURNAL OF PAEDIATRIC DENTISTRY, Issue 5 2010ELEANOR McGOVERN International Journal of Paediatric Dentistry 2010; 20: 322,329 Background., Hurler Syndrome is associated with a deficiency of a specific lysosomal enzyme involved in the degradation of glycosaminoglycans. Hematopoietic stem cell transplantation (HSCT) in early infancy is undertaken to help prevent the accumulation of glycosaminoglycans and improve organ function. Aim., To investigate the oral features and dental health of patients with Hurler Syndrome who have undergone successful HSCT. Materials and methods., Twenty-five patients (median age 8.6 years) post-HSCT (mean age 9.4 months) underwent oral assessment (mean of 7.5 years post-HSCT). Results., Dental development was delayed. Numerous occlusal anomalies were noted including: open-bite, class III skeletal base, dental spacing, primary molar infra-occlusion and ectopic tooth eruption. Dental anomalies included hypodontia, microdontia, enamel defects, thin tapering canine crowns, pointed molar cusps, bulbous molar crowns and molar taurodontism. Tooth roots were usually short/blunted/spindle-like in permanent molars. The prevalence of dental caries was low in the permanent dentition (mean DMFT 0.7) but high in the primary dentition (mean dmft 2.4). Oral hygiene instruction with plaque and or calculus removal was indicated in 71% of those that were dentate. Conclusion., Patients with Hurler Syndrome post-HSCT are likely to have delayed dental development, a malocclusion, and dental anomalies, particularly hypodontia and microdontia. [source] Cellular senescence in pretransplant renal biopsies predicts postoperative organ functionAGING CELL, Issue 1 2009Liane M. McGlynn Summary Older and marginal donors have been used to meet the shortfall in available organs for renal transplantation. Post-transplant renal function and outcome from these donors are often poorer than chronologically younger donors. Some organs, however, function adequately for many years. We have hypothesized that such organs are biologically younger than poorer performing counterparts. We have tested this hypothesis in a cohort of pre-implantation human renal allograft biopsies (n = 75) that have been assayed by real-time polymerase chain reaction for the expression of known markers of cellular damage and biological aging, including CDKN2A, CDKN1A, SIRT2 and POT1. These have been investigated for any associations with traditional factors affecting transplant outcome (donor age, cold ischaemic time) and organ function post-transplant (serum creatinine levels). Linear regression analyses indicated a strong association for serum creatinine with pre-transplant CDKN2A levels (p = 0.001) and donor age (p = 0.004) at 6 months post-transplant. Both these markers correlated significantly with urinary protein to creatinine ratios (p = 0.002 and p = 0.005 respectively), an informative marker for subsequent graft dysfunction. POT1 expression also showed a significant association with this parameter (p = 0.05). Multiple linear regression analyses for CDKN2A and donor age accounted for 24.6% (p = 0.001) of observed variability in serum creatinine levels at 6 months and 23.7% (p = 0.001) at 1 year post-transplant. Thus, these data indicate that allograft biological age is an important novel prognostic determinant for renal transplant outcome. [source] Systemic inflammation in the brain-dead organ donorACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2009A. BARKLIN Brain death itself impairs organ function in the potential donor, thereby limiting the number of suitable organs for transplantation. In addition, graft survival of kidneys obtained from brain-dead (BD) donors is inferior to that of kidneys obtained from living donors. Experimental studies confirm an inferior graft survival for the heart, liver and lungs from BD compared with living donors. The mechanism underlying the deteriorating effect of brain death on the organs has not yet been fully established. We know that brain death triggers massive circulatory, hormonal and metabolic changes. Moreover, the past 10 years have produced evidence that brain death is associated with a systemic inflammatory response. However, it remains uncertain whether the inflammation is induced by brain death itself or by events before and after becoming BD. The purpose of this study is to discuss the risk factors associated with brain death in general and the inflammatory response in the organs in particular. Special attention will be paid to the heart, lung, liver and kidney and evidence will be presented from clinical and experimental studies. [source] Evodia rutaecarpa protects against circulation failure and organ dysfunction in endotoxaemic rats through modulating nitric oxide releaseJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2002Wen Fei Chiou Using a rat model of septic shock we studied the effects of Evodia rutaecarpa, a Chinese herbal medicine with antimicrobial and anti-inflammatory activity, on haemodynamic parameters, biochemical markers of organ function and nitric oxide (NO) production. Anaesthetized rats challenged with a high dosage of endotoxin (Escherichia coli lipopolysaccharide; LPS; 50 mg kg,1, i.v.) for 6 h showed a severe decrease in mean arterial pressure. This was accompanied by delayed bradycardia, vascular hyporeactivity to phenylephrine and increase in plasma levels of lactate dehydrogenase, aspartate aminotransferase, bilirubin and creatinine, as well as NOx (NO,2 plus NO,3). Pretreatment with ethanol extract of E. rutaecarpa (25,50 and 100 mg kg,1, i.v.), 1 h before LPS, dose-dependently prevented the circulation failure, vascular hyporeactivity to phenylephrine, prevented liver dysfunction and reduced the NOx over-production in plasma in endotoxaemic rats. A selective inducible NO-synthase (iNOS) inhibitor, aminoguanidine (15 mg kg,1, i.v.), also effectively ameliorated the above pathophysiological phenomenon associated with endotoxaemia so that the normal condition was approached. Endotoxaemia for 6 h resulted in a significant increase in iNOS activity in the liver homogenate, which was attenuated significantly by E. rutaecarpa pretreatment. In summary, E. rutaecarpa, at the dosages used, exerted these beneficial effects probably through inhibition of iNOS activity and subsequent modulation of the release of NO. These significant results may offer E. rutaecarpa as a candidate for the treatment of this model of endotoxaemia. [source] Development of renal failure during the initial 24 h of intensive care unit stay correlates with hospital mortality in trauma patientsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2006T. Ala-Kokko Background:, Although multiple organ failure is the leading late cause of death, there is controversy about the impact of acute organ dysfunction and failure on trauma survival. Methods:, Consecutive adult trauma admissions between January 2000 and June 2003, excluding isolated head traumas and burns, were analysed for parameters of organ function during the first 24 h following intensive care unit (ICU) admission using the Sequential Organ Failure Assessment (SOFA) scoring system. A national prospectively collected ICU data registry was used for analysis, including data from 22 ICUs in university and central hospitals in Finland. Results:, The study population consisted of 1044 eligible trauma admissions; 32% of the cases were treated at university hospital level, the rest being secondary referral central hospital admissions. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score was 15 (SD8), ICU mortality was 5.6% and a further 1.6% of patients died during their post-ICU hospital stay. Forty-five per cent of the patients were categorized as having multiple traumas. In univariate analysis, APACHE II , 25 [odds ratio (OR), 35; 95% confidence interval (CI), 18,66] and renal failure (OR, 29.5; 95% CI, 14,63) produced the highest ORs for ICU mortality. In the APACHE II-, sex- and age-adjusted logistic regression model, renal failure was a significant risk factor for both ICU and hospital mortality (OR, 11.8; 95% CI, 3.9,35.4; OR, 8.2; 95% CI, 2.9,23.2, respectively). Conclusion:, The development of renal failure during the initial 24 h of ICU stay remained an independent risk factor for mortality in trauma patients requiring intensive care treatment even after adjusting for the APACHE II score, age and sex. [source] Small-volume resuscitation: from experimental evidence to clinical routine.ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2002Advantages, disadvantages of hypertonic solutions Background: The concept of small-volume resuscitatioin (SVR) using hypertonic solutions encompasses the rapid infusion of a small dose (4 ml per kg body weight, i.e. approximately 250 ml in an adult patient) of 7.2,7.5% NaCl/colloid solution. Originally, SVR was aimed for initial therapy of severe hypovolemia and shock associated with trauma. Methods: The present review focusses on the findings concerning the working mechanisms responsible for the rapid onset of the circulatory effect, the impact of the colloid component on microcirculatory resuscitation, and describes the indications for its application in the preclinical scenario as well as perioperatively and in intensive care medicine. Results: With respect to the actual data base of clinical trials SVR seems to be superior to conventional volume therapy with regard to faster normalization of microvascular perfusion during shock phases and early resumption of organ function. Particularly patients with head trauma in association with systemic hypotension appear to benefit. Besides, potential indications for this concept include cardiac and cardiovascular surgery (attenuation of reperfusion injury during declamping phase) and burn injury. The review also describes disadvantaages and potential adverse effects of SVR: Conclusion: Small-volume resuscitation by means of hypertonic NaCl/colloid solutions stands for one of the most innovative concepts for primary resuscitation from trauma and shock established in the past decade. Today the spectrum of potential indications envolves not only prehospital trauma care, but also perioperative and intensive care therapy. [source] Problems and advantages of continuous renal replacement therapy,NEPHROLOGY, Issue 3 2002Merlin C THOMAS SUMMARY: The continuous replacement of renal function must facilitate fluid and solute homeostasis, nutrition and vital organ function, and, where possible, hasten the recovery of renal function. Difficulties with anticoagulation, biocompatibility, mobility and cost remain obstacles to be overcome. the use of continuous renal replacement therapy (CRRT) to remove systemic inflammatory mediators is yet to be confirmed. Although survival benefits of CRRT over intermittent dialysis remain controversial, the slow continuous removal of fluid, acid and solute has a number of advantages, especially where patients are haemodynamically unstable. [source] Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anaesthesia: A prospective study in methadone, heroin, codeine and morphine addictsACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2000M. Hensel Background: In the present study a method of rapid opiate detoxification under general anaesthesia has been evaluated regarding the safety, the efficacy in preventing withdrawal symptoms, and the long-term results. In addition, it was investigated whether the profile and severity of withdrawal symptoms depend on the type of opiate abused (methadone, heroin, codeine, morphine). Methods: Seventy-two opiate addicts were detoxified in an intensive care unit (ICU). Anaesthesia was induced and maintained using propofol infusion. Patients were endotracheally intubated. The opiate receptor antagonist naltrexon was administered into the stomach via a nasogastric tube. Withdrawal symptoms before and after the detoxification treatment were assessed using an objective and a subjective opiate withdrawal scale (OOWS, SOWS). After detoxification patients entered a long-term naltrexone maintenance programme as well as a supportive psychotherapy programme. Vital organ function was monitored using haemodynamic and respiratory parameters as well as body temperature. Results: Organ function parameters were stable during the whole treatment in all patients and no anaesthetic complications were registered. Minor side effects such as bradycardia or hypotension were observed in 20 patients. Compared to patients with pre-existing heroin, codeine, or morphine abuse respectively, patients from the methadone maintenance programme had significantly higher (P<0.01) OOWS as well as SOWS values after the treatment. Twelve months after the detoxification 49 patients (68%) were abstinent from opiates whereas 17 patients had relapsed during the period of follow-up. Six patients were lost during follow-up. Conclusions: Rapid opiate detoxification under general anaesthesia is a safe and efficient method to suppress withdrawal symptoms. This treatment may be of benefit in patients who particularly suffer from severe withdrawal symptoms during detoxification and who have failed repeatedly to complete conventional withdrawal. Methadone patients have more withdrawal symptoms than other opiate addicts. [source] Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or after hematopoietic stem cell transplantation: Single-center analysis and validation of the Seattle, French, and Strasbourg prognostic indexes,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2009Rocio Parody In this retrospective monocenter study, we analyzed the outcomes of 130 adult hematological patients who developed a proven (n = 23), probable (n = 71), and possible (n = 36) invasive aspergillosis (IA) in a 13-year period. Forty-nine patients (38%) were recipients of an allogeneic hematopoietic stem cell transplantation (AlloHSCT). The main goal of the study was the identification of prognostic factors for 4-month aspergillosis free survival (AFS) and overall survival (OS). IA was identified as the main cause of death in 27/49 recipients of an AlloHSCT (55%) and 28/81 nontransplanted patients (35%). Diagnosis of IA at or before 2000 had a negative impact in both 4-month AFS and 4-month OS in the entire group. In multivariate analysis performed separately for nontransplanted and allo-HSCT patients, five variables (excluding the year of diagnosis) decreased 4-month AFS: (i) impairment of one organ function (OF), (ii) impairment of two or more OFs (two points), (iii) disseminated IA, (iv) neutropenia lasting more than 10 days (non-AlloHSCT group only) or monocytopenia (<0.1 × 109/l) [AlloHSCT group only], and (v) high-dose steroids (non-AlloHSCT group only) or an alternative donor (AlloHSCT group only). According to the number of adverse risk factors, three prognostic subgroups were defined in non-transplanted and alloHSCT patients with good (97% and 78% AFS), intermediate (73% and 32% AFS) and poor prognosis (20% and 11% AFS) of IA [P < 0.01]. In addition, we validated the French and Seattle prognostic indexes for allo-HSCT recipients and the Strasbourg model for all hematological patients with IA. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Reproduction in male rats is vulnerable to treatment with the flavonoid-rich seed extracts of Vitex negundoPHYTOTHERAPY RESEARCH, Issue 1 2004Suwagmani Das Abstract A partially puri,ed ,avonoid-rich extract was prepared from the seed of Vitex negundo. The effect of this extract on the reproductive system of male rats was investigated at four different concentrations. All the major accessory sex organs shed weight when the preparation was administered at doses of ,15 mg/rat/day after 15 days of treatment. The drop in weight was also re,ected in disturbed tissue biochemistry. Secretory products such as citric acid in the prostate, fructose in seminal vesicles and epididymal , -glucosidase activity, indices of accessory sex organ function in males, diminished. Microscopic examination of the sperm derived from the cauda epididymides of treated animals showed only a marginal change in vitality. However, sperm numbers dwindled and slackness in their motility was observed, factors that may impede fertility. Toxicity testing in blood did not point to distress in any of the vital organs. Taken together, it is inferred that the seed extracts of V. negundo interfere with male reproductive function without producing adverse toxicity in other vital organs. Copyright © 2004 John Wiley & Sons, Ltd. [source] Carcinoma of the Tongue Base Treated by Transoral Laser Microsurgery, Part Two: Persistent, Recurrent and Second Primary TumorsTHE LARYNGOSCOPE, Issue 12 2006David G. Grant MD Abstract Objectives: To report the oncologic and functional outcomes of transoral laser microsurgery (TLM) in the treatment of persistent, recurrent, and second primary squamous cell carcinoma of the tongue base. Study Design: A two-center prospective case series analysis. Methods: Twenty-five patients with persistent, recurrent, or second primary squamous cell carcinoma of the tongue base were treated with TLM between 1997 and 2005. Four (16%) patients with persistent disease at the primary site were considered TX. Eleven (44%) patients with recurrent disease were pathologically staged rT1 3/11, rT2 2/11, rT3 4/11, T4 1/11, and TX 1/11. Ten (40%) patients with second primary tumors were staged pT1, 4/10; pT2, 3/10; pT3, 2/10; and pT4, 1/10. Eight (32%) patients underwent neck dissection. Three (12%) patients received adjuvant radiotherapy. Pre- and post-treatment organ function was assessed using a clinical Functional Outcome Swallowing Scale (FOSS) and Communication Scale. Results: The mean follow-up period was 26 months. The 2-year Kaplan-Meier local control and locoregional control estimate was 69%. For those patients presenting with persistent/recurrent or second primary disease, the 2 year local control estimates were 75% and 68%, respectively. For all patients, the respective 2 and 5 year overall survival estimates were 54% and 26%. Two (8%) patients suffered postoperative hemorrhage. The average duration of hospitalization was 3.6 days. The median pretreatment and posttreatment FOSS stage was stage 2 and stage 3, respectively. Conclusions: Transoral laser surgery is a rational and effective treatment in appropriately selected patients with persistent, recurrent, or second primary tongue base cancer. The low morbidity and mortality and shortened duration of hospitalization associated with TLM make it an attractive therapeutic alternative. [source] An Integrated View of Molecular Changes, Histopathology and Outcomes in Kidney TransplantsAMERICAN JOURNAL OF TRANSPLANTATION, Issue 10 2010P. F. Halloran Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury,repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell-mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury,repair response, including de-differentiation, cell cycling and apoptosis. The active injury,repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease. [source] Brain Death Activates Donor Organs and Is Associated with a Worse I/R Injury After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2007S. Weiss The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation. Hepatic tissues from brain dead (n = 32) and living donors (n = 26) were collected at the time of donor laparotomy. Additional biopsies were performed before organ preservation, at the time of transplantation and one hour after reperfusion. Cytokines were assessed by real-time reverse transcriptase,polymerase chain reaction (RT,PCR) and cytometric bead array. Additionally, immunohistological analysis of tissue specimens was performed. Inflammatory cytokines including IL-6, IL-10, TNF-,, TGF-, and MIP-1, were significantly higher in brain dead donors immediately after laparotomy compared to living donors. Cellular infiltrates significantly increased in parallel to the soluble cytokines IL-6 and IL-10. Enhanced immune activation in brain dead donors was reflected by a deteriorated I/R injury proven by elevated alanin-amino-transferase (ALT), aspartat-amino-transferase (AST) and bilirubin levels, increased rates of acute rejection and primary nonfunction. Based on our clinical data, we demonstrate that brain death and the events that precede it are associated with a significant upregulation of inflammatory cytokines and lead to a worse ischemia/reperfusion injury after transplantation. [source] Analysis of Baroreflex Sensitivity During Undulation Pump Ventricular Assist Device SupportARTIFICIAL ORGANS, Issue 7 2009Hongjian Liu Abstract The aim of this study was to examine the baroreflex sensitivity (BRS), which involves the autonomic nervous system, in a goat with a chronically implanted undulation pump ventricular assist device (UPVAD). The UPVAD involved transforming the rotation of a brushless DC motor into an undulating motion by a disc attached via a special linking mechanism, and a jellyfish valve in the outflow cannula to prevent diastolic backflow. The pump was implanted into the thoracic cavity of a goat by a left thoracotomy, and the inflow and outflow cannulae were sutured to the apex of the left ventricle and to the descending aorta, respectively. The driving cable was wired percutaneously to an external controller. Electrocardiogram and hemodynamic waveforms were recorded at a sampling frequency of 1 kHz. BRS was determined when awake by the slope of the linear regression of R-R interval against mean arterial pressure changes, which were induced by the administration of methoxamine hydrochloride, both with continuous driving of the UPVAD as well as without assistance. BRS values during the UPVAD support and without assistance were 1.60 ± 0.30 msec/mm Hg and 0.98 ± 0.22 msec/mm Hg (n = 5, P < 0.05), respectively. BRS was significantly improved during left ventricular assistance. Therefore, UPVAD support might decrease sympathetic nerve activity and increase parasympathetic nerve activity to improve both microcirculation and organ function. [source] The Complementarity of the Technical Tools of Tissue Engineering and the Concepts of Artificial Organs for the Design of Functional Bioartificial TissuesARTIFICIAL ORGANS, Issue 9 2008Petros Lenas Abstract:, Although tissue engineering uses powerful biological tools, it still has a weak conceptual foundation, which is restricted at the cell level. The design criteria at the cell level are not directly related with the tissue functions, and consequently, such functions cannot be implemented in bioartificial tissues with the currently used methods. On the contrary, the field of artificial organs focuses on the function of the artificial organs that are treated in the design as integral entities, instead of the optimization of the artificial organ components. The field of artificial organs has already developed and tested methodologies that are based on system concepts and mathematical-computational methods that connect the component properties with the desired global organ function. Such methodologies are needed in tissue engineering for the design of bioartificial tissues with tissue functions. Under the framework of biomedical engineering, artificial organs and tissue engineering do not present competitive approaches, but are rather complementary and should therefore design a common future for the benefit of patients. [source] Development of the Baylor Gyro Permanently Implantable Centrifugal Blood Pump as a Biventricular Assist DeviceARTIFICIAL ORGANS, Issue 9 2001Kenji Nonaka Abstract: The Baylor Gyro permanently implantable centrifugal blood pump (Gyro PI pump) has been under development since 1995 at Baylor College of Medicine. Excellent results were achieved as a left ventricular assist device (LVAD) with survival up to 284 days. Based on these results, we are now focusing on the development of a biventricular assist device (BVAD) system, which requires 2 pumps to be implanted simultaneously in the preperitoneal space. Our hypothesis was that the Gyro PI pump would be an appropriate device for an implantable BVAD system. The Gyro PI 700 pump is fabricated from titanium alloy and has a 25 ml priming volume, pump weight of 204 g, height of 45 mm, and pump diameter of 65 mm. This pump can provide 5 L/min against 100 mm Hg at 2,000 rpm. In this study, 6 half-Dexter healthy calves have been used as the experimental model. The right pump was applied between the infundibular of the right ventricle and the main pulmonary artery. The left pump was applied between the apex of the left ventricle and the thoracic descending aorta. As for anticoagulation, heparin was administered at the first postoperative week and then converted to warfarin sodium from the second week after surgery. Both pump flow rates were controlled maintaining a pulmonary arterial flow of less than 160 ml/kg/min for the sake of avoidance of pulmonary congestion. Blood sampling was done to assess visceral organ function, and the data regarding pump performance were collected. After encountering the endpoint, which the study could not keep for any reasons, necropsy and histopathological examinations were performed. The first 2 cases were terminated within 1 week. Deterioration of the pump flow due to suction phenomenon was recognized in both cases. To avoid the suction phenomenon, a flexible conduit attached on the inlet conduit was designed and implanted. After using the flexible inflow conduit, the required power and the rotational speed were reduced. Furthermore, the suction phenomenon was not observed except for 1 case. There was no deterioration regarding visceral organ function, and pulmonary function was maintained within normal range except for 1 case. Even though the experimental animal survived up to 45 days with the flexible inflow conduit, an increase in power consumption due to thrombus formation behind the impeller became a problem. Lower rotational speed, which was probably produced by the effectiveness of the flexible inflow conduit, was speculated to be one of the reasons. And the minimum range of rotational speed was 1,950 rpm in these 6 BVAD cases and the previous 3 cases of LVAD. In conclusion, 6 cases of BVAD implantation were performed as in vivo animal studies and were observed up to 45 days. The flexible inflow conduit was applied in 4 of 6 cases, and it was effective in avoiding a suction phenomenon. The proper rotational speed of the Gyro PI 700 pump was detected from the viewpoint of antithrombogenicity, which is more than 1,950 rpm. [source] A morphometric analysis of bulbar urethral stricturesBJU INTERNATIONAL, Issue 2 2007Andre G. Cavalcanti In a beautifully descriptive paper, authors from Rio de Janeiro and San Francisco report a quantitative and qualitative histological analysis of spongiosal tissue in patients with bulbar urethral strictures. They found that stricture formation was characterised by major alterations in extracellular matrix features. OBJECTIVE To report a quantitative and qualitative histological analysis of spongiosum tissue in patients with bulbar urethral strictures. MATERIALS AND METHODS Urethral specimens from 15 patients who had end-to-end anastomotic urethroplasty were evaluated; the control group comprised five bulbar urethras from cadavers. The collagen content, elastic fibres, smooth muscle and vessels were analysed using stereological methods. RESULTS There was complete loss of the relationship between smooth muscle, extracellular matrix and sinusoids in the peri-luminal area (PLA), with collagen replacement. The extension of the fibrotic area was greater in those with a traumatic than in those with an atraumatic stricture. The content of smooth muscle and collagen in the peripheral spongiosum (PS) area was similar for the stricture and control groups, and results were comparable for traumatic and atraumatic groups and those with suprapubic cystostomy diversion or not before surgery. There was a remarkably lower vascular density in the traumatic than in the atraumatic group. There was an increase in type III collagen in the PLA and in type I collagen in the PS; collagen type III in the PLA was greater in the group with no suprapubic cystostomy diversion before surgery. There were fewer elastic fibres in both stricture areas (PLA and PS) than in the control group. CONCLUSIONS Urethral stricture formation is characterized by marked changes in extracellular matrix features, with consequent changes in organ function. [source] Using gene chips to identify organ-specific, smooth muscle responses to experimental diabetes: potential applications to urological diseasesBJU INTERNATIONAL, Issue 2 2007Jason D. Hipp OBJECTIVE To identify early diabetes-related alterations in gene expression in bladder and erectile tissue that would provide novel diagnostic and therapeutic treatment targets to prevent, delay or ameliorate the ensuing bladder and erectile dysfunction. MATERIALS AND METHODS The RG-U34A rat GeneChip® (Affymetrix Inc., Sunnyvale, CA, USA) oligonucleotide microarray (containing ,8799 genes) was used to evaluate gene expression in corporal and male bladder tissue excised from rats 1 week after confirmation of a diabetic state, but before demonstrable changes in organ function in vivo. A conservative analytical approach was used to detect alterations in gene expression, and gene ontology (GO) classifications were used to identify biological themes/pathways involved in the aetiology of the organ dysfunction. RESULTS In all, 320 and 313 genes were differentially expressed in bladder and corporal tissue, respectively. GO analysis in bladder tissue showed prominent increases in biological pathways involved in cell proliferation, metabolism, actin cytoskeleton and myosin, as well as decreases in cell motility, and regulation of muscle contraction. GO analysis in corpora showed increases in pathways related to ion channel transport and ion channel activity, while there were decreases in collagen I and actin genes. CONCLUSIONS The changes in gene expression in these initial experiments are consistent with the pathophysiological characteristics of the bladder and erectile dysfunction seen later in the diabetic disease process. Thus, the observed changes in gene expression might be harbingers or biomarkers of impending organ dysfunction, and could provide useful diagnostic and therapeutic targets for a variety of progressive urological diseases/conditions (i.e. lower urinary tract symptoms related to benign prostatic hyperplasia, erectile dysfunction, etc.). [source] Electrolytic liver ablation is not associated with evidence of a systemic inflammatory response syndromeBRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 2 2004B. D. Teague Background Local ablation has been proposed for treatment of liver tumours. Cryoshock, a variant of the systemic inflammatory response syndrome (SIRS), is a potentially fatal complication of cryoablation caused by systemic release of necrotic breakdown products from ablated liver. The proinflammatory cytokines tissue necrosis factor (TNF) , and interleukin (IL) 1 are important mediators of this response. This study assessed the risk of SIRS complicating electrolytic liver ablation by measuring circulating levels of inflammatory cytokines, other inflammatory markers and clinical markers of organ function. Methods Electrolytic liver ablation was performed in 16 pigs and four pigs served as controls. Platelet count, and serum levels of urea, creatinine, liver enzymes, C-reactive protein (CRP), TNF-, and IL-1, were measured before treatment and for 72 h after the procedure. Results There were significant dose-related increases in CRP and alanine aminotransferase levels with liver electrolysis. There was no significant derangement in renal function or platelet count following ablation. A rise in serum TNF-, and IL-1, levels was not associated with liver electrolysis. Conclusion There was no evidence of organ failure or significantly raised levels of proinflammatory cytokines as a result of liver electrolysis, suggesting that this is a safe procedure for liver ablation. Copyright © 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source] Phase 2 trial of combination thalidomide plus temozolomide in patients with metastatic malignant melanoma: Southwest Oncology Group S0508,CANCER, Issue 2 2010Joseph I. Clark MD Abstract BACKGROUND: In limited institution phase 2 studies, thalidomide and temozolomide has yielded response rates (RRs) up to 32% for advanced melanoma, leading to the use of this combination as "standard" by some. We conducted a multicenter phase 2 trial to better define the clinical efficacy of thalidomide and temozolomide and the immune modulatory effects of thalidomide, when combined with temozolomide, in patients with metastatic melanoma. METHODS: Patients must have had stage IV cutaneous melanoma, no active brain metastases, Zubrod PS 0-1, up to 1 prior systemic therapy excluding thalidomide, temozolomide, or dacarbazine, adequate organ function, and given informed consent. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), RR, toxicities, and assessment of relationships between biomarkers and clinical outcomes. Patients received thalidomide (200 mg/d escalated to 400 mg/d for patients <70, or 100 mg/d escalated to 250 mg/d for patients ,70) plus temozolomide (75 mg/m2/d × 6 weeks, and then 2 weeks rest). RESULTS: Sixty-four patients were enrolled; 2 refused treatment. The 6-month PFS was 15% (95% confidence interval [CI], 6%-23%), the 1-year OS was 35% (95% CI, 24%-47%), and the RR was 13% (95% CI, 5%-25%), all partial. One treatment-related death occurred from myocardial infarction; 3 other grade 4 events occurred, including pulmonary embolism, neutropenia, and central nervous system (CNS) ischemia. There was no significant correlation between biomarkers and PFS or OS. CONCLUSIONS: This combination of thalidomide and temozolomide does not appear to have a clinical benefit that exceeds dacarbazine alone. We would not recommend it further for phase 3 trials or for standard community use. Cancer 2010. © 2010 American Cancer Society. [source] An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated, advanced gastric or gastroesophageal cancer : The GC4 studyCANCER, Issue 9 2006Jaffer A. Ajani M.D. Abstract BACKGROUND Gastrin hormone is trophic to in vitro gastric cancer, and the antigastrin antibodies (AGAs) are antiproliferative and antimetastatic. Human gastric cancers overexpress gastrin genes and receptors that react to gastrin's trophic effects. Immunogen G17DT elicits a specific and high-affinity AGA. The authors evaluated G17DT vaccination given with cisplatin plus 5-fluorouracil for the treatment gastric adenocarcinoma. METHODS In this multicenter, Phase II study, patients received G17DT vaccination intramuscularly on Weeks 1, 5, 9 and 25 and cisplatin plus 5-fluorouracil every 28 days. Eligible patients had untreated, metastatic, or unresectable gastric or gastroesophageal adenocarcinoma with near-normal organ function. The primary endpoint of the study was the over response rate (ORR), and secondary endpoints included overall survival (OS), safety, and the impact of successful vaccination on patient outcome. RESULTS In total, 103 patients were enrolled in 5 countries. Seven patients who were overdosed inadvertently with 5-fluorouracil (a major protocol violation) were removed from the analysis. The confirmed ORR was 30% in 79 patients who were evaluated for response. The median time-to-progression (TTP) was 5.4 months, and the median survival (MS) was 9.0 months (n = 96 patients). Sixty-five of 94 patients who were vaccinated (69%) had 2 consecutive AGA titers of ,1 units (successfully vaccinated patients or immune-responders). The TTP was longer in immune-responders than in immune-nonresponders (P = .0005). Similarly, the MS was longer in immune-responders than in immune-nonresponders (10.3 months vs. 3.8 months; P ,.0001). In a multivariate analysis, successful vaccination was an independent OS prognosticator (P = .0001). G17DT did not have an adverse effect on safety. CONCLUSIONS The results demonstrated that successful G17DT vaccination was correlated with longer TTP and MS. AGA response was an independent OS prognosticator. A Phase III evaluation of G17DT in gastric cancer is warranted. Cancer 2006. © 2006 American Cancer Society. [source] Phase I study of TZT-1027, a novel synthetic dolastatin 10 derivative and inhibitor of tubulin polymerization, given weekly to advanced solid tumor patients for 3 weeksCANCER SCIENCE, Issue 2 2009Nobuyuki Yamamoto TZT-1027 is a novel synthetic dolastatin 10 derivative that inhibits tubulin polymerization. A phase I study was conducted to determine the maximum tolerated dose (MTD) of TZT-1027, and to assess its pharmacokinetic profile in Japanese patients with advanced solid tumors following administration of the drug weekly for 3 weeks. Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and met the following criteria: performance status ,2 and acceptable organ function. The MTD was defined as the highest dose at which more than two-thirds of the patients experienced grade 4 hematological toxicity or grade 3/4 non-hematological toxicity during weekly TZT-1027 administration for 3 weeks. Forty patients were enrolled in the present study. Twelve doses between 0.3 and 2.1 mg/m2 were evaluated. Grade 4 neutropenia was the principal dose-limiting toxicity (DLT). At a dose of 2.1 mg/m2, two patients developed DLT: one patient developed grade 4 neutropenia, grade 3 myalgia, and grade 4 constipation, and the other one developed grade 4 neutropenia and grade 3 constipation. At a dose level of 1.8 mg/m2, toxicity was acceptable and no DLT was observed. The area under the curve and maximum concentration of TZT-1027 tended to increase linearly with the dose. The DLT observed were neutropenia, myalgia, and constipation, and the MTD was 2.1 mg/m2. The recommended dose for a phase II study was determined to be 1.8 mg/m2 for the drug administered weekly for 3 weeks. (Cancer Sci 2009; 100: 316,321) [source] Vitamin D and calcium deficits predispose for multiple chronic diseasesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2005M. Peterlik Abstract There is evidence from both observational studies and clinical trials that calcium malnutrition and hypovitaminosis D are predisposing conditions for various common chronic diseases. In addition to skeletal disorders, calcium and vitamin D deficits increase the risk of malignancies, particularly of colon, breast and prostate gland, of chronic inflammatory and autoimmune diseases (e.g. insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis), as well as of metabolic disorders (metabolic syndrome, hypertension). The aim of the present review was to provide improved understanding of the molecular and cellular processes by which deficits in calcium and vitamin D cause specific changes in cell and organ functions and thereby increase the risk for chronic diseases of different aetiology. 1,25-dihydroxyvitamin D3 and extracellular Ca++ are both key regulators of proliferation, differentiation and function at the cellular level. However, the efficiency of vitamin D receptor-mediated intracellular signalling is limited by the negative effects of hypovitaminosis D on extrarenal 25-hydroxyvitamin D-1,-hydroxylase activity and thus on the production of 1,25-dihydroxyvitamin D3. Calcium malnutrition eventually causes a decrease in calcium concentration in extracellular fluid compartments, resulting in organ-specific modulation of calcium-sensing receptor activity. Hence, attenuation of signal transduction from the ligand-activated vitamin D receptor and calcium-sensing receptor seems to be the prime mechanism by which calcium and vitamin D insufficiencies cause perturbation of cellular functions in bone, kidney, intestine, mammary and prostate glands, endocrine pancreas, vascular endothelium, and, importantly, in the immune system. The wide range of diseases associated with deficits in calcium and vitamin D in combination with the high prevalence of these conditions represents a special challenge for preventive medicine. [source] | |||||||||||||||||||||||||