Showing papers by "Jewish Hospital published in 2002"

Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin

Abstract: BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS), would safely reduce the rate of first trimester spontaneous abortion (SAB) and increase the number of live births without teratogenicity. METHODS: Seventytwo oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were prospectively assessed in an outpatient clinical research centre. Outcome measures included number of first trimester SAB, live births, normal ongoing pregnancies ≥13 weeks, gestational diabetes (GD), congenital defects (CD), birthweight and height, as well as weight, height, and motor and social development during the first 6 months of life. RESULTS: Of the 84 fetuses, to date there have been 63 normal live births without CD (75%), 14 first trimester SAB (17%), and seven ongoing pregnancies ≥13 weeks with normal sonograms without CD (8%). Previously, without metformin, 40 of the 72 women had 100 pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47 fetuses), there have been 33 live births (70%), two pregnancies ongoing ≥13 weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis, and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 µU/ml rise in insulin), 95% CI 1.09– 1.60 (P 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous pregnancies without metformin, P 0.025. There have been no major CD in the 63 live births or CD by sonography in the seven fetuses ≤13 weeks. In the 63 live births, neither weight nor height differed from the normal neonatal population. At 6 month follow-up, height was greater (P 0.008) and weight did not differ from the normal paediatric population; motor and social development were normal. CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely associated with reduction in SAB and in GD, was not teratogenic, and did not adversely affect birthweight or height, or height, weight, and motor and social development at 3 and 6 months of life.

Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning

Abstract: More than 10 years after its discovery, the function of cyclooxygenase-2 (COX-2) in the cardiovascular system remains largely an enigma. Many scholars have assumed that the allegedly detrimental effects of COX-2 in other systems (e.g. proinflammatory actions and tumorigenesis) signify a detrimental role of this protein in cardiovascular homeostasis as well. This view, however, is ill-founded. Recent studies have demonstrated that ischemic preconditioning (PC) upregulates the expression and activity of COX-2 in the heart, and that this increase in COX-2 activity mediates the protective effects of the late phase of PC against both myocardial stunning and myocardial infarction. An obligatory role of COX-2 has been observed in the setting of late PC induced not only by ischemia but also by delta-opioid agonists and physical exercise, supporting the view that the recruitment of this protein is a central mechanism whereby the heart protects itself from ischemia. The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE(2) and/or PGI(2). Since inhibition of iNOS in preconditioned myocardium blocks COX-2 activity whereas inhibition of COX-2 does not affect iNOS activity, COX-2 appears to be downstream of iNOS in the protective pathway of late PC. The results of these studies challenge the widely accepted paradigm that views COX-2 activity as detrimental. The discovery that COX-2 plays an indispensable role in the anti-stunning and anti-infarct effects of late PC demonstrates that the recruitment of this protein is a fundamental mechanism whereby the heart adapts to stress, thereby revealing a novel, hitherto unappreciated cardioprotective function of COX-2. From a practical standpoint, the recognition that COX-2 is an obligatory co-mediator (together with iNOS) of the protection afforded by late PC has implications for the clinical use of COX-2 selective inhibitors as well as nonselective COX inhibitors. For example, the possibility that inhibition of COX-2 activity may augment myocardial cell death by obliterating the innate defensive response of the heart against ischemia/reperfusion injury needs to be considered and is the object of much current debate. Furthermore, the concept that the COX-2 byproducts, PGE(2) and/or PGI(2), play a necessary role in late PC provides a basis for novel therapeutic strategies designed to enhance the biosynthesis of these cytoprotective prostanoids in the ischemic myocardium. From a conceptual standpoint, the COX-2 hypothesis of late PC expands our understanding of the function of this enzyme in the cardiovascular system and impels a critical reassessment of current thinking regarding the biologic significance of COX-2.

Metallothionein protection against alcoholic liver injury through inhibition of oxidative stress.

Abstract: Antioxidants are likely potential pharmaceutical agents for the treatment of alcoholic liver disease. Metallothionein (MT) is a cysteine-rich protein and functions as an antioxidant. This study was designed to determine whether MT confers resistance to acute alcohol-induced hepatotoxicity and to explore the mechanistic link between oxidative stress and alcoholic liver injury. MT-overexpressing transgenic and wild-type mice were administrated three gastric doses of alcohol at 5 g/kg. Liver injury, oxidative stress, and ethanol metabolism-associated changes were determined. Acute ethanol administration in the wild-type mice caused prominent microvesicular steatosis, along with necrosis and elevation of serum alanine aminotransferase. Ultrastructural changes of the hepatocytes include glycogen and fat accumulation, organelle abnormality, and focal cytoplasmic degeneration. This acute alcohol hepatotoxicity was significantly inhibited in the MT-transgenic mice. Furthermore, ethanol treatment decreased hepatic-reduced glutathione, but increased oxidized glutathione along with lipid peroxidation, protein oxidation, and superoxide generation in the wild-type mice. This hepatic oxidative stress was significantly suppressed in the MT-transgenic mice. However, MT did not affect the ethanol metabolism-associated decrease in NAD(+)/NADH ratio or increase in cytochrome P450 2E1. In conclusion, MT is an effective agent in cytoprotection against alcohol-induced liver injury, and hepatic protection by MT is likely through inhibition of alcohol-induced oxidative stress.

Multicenter Evaluation of an Automated Assay for Troponin I

Abstract: Background: Cardiac troponin I (cTnI) is a powerful tool to aid in the diagnosis of myocardial infarction and cardiac muscle damage. We describe an assay that overcomes problems of early assays that were often affected by cTnI degradation, assay interference, poor sensitivity, and imprecision. Methods: The analytical performance of the Access® AccuTnITM assay (Beckman Coulter) was evaluated at five institutions. Controls, zero calibrator, and diluted patient samples were used to determine precision, detection limit, functional sensitivity, and linearity. The 97.5 and 99 percentiles of a reference population were determined. Common interferents and heterophilic patient samples were tested. Equimolarity was determined by assaying samples with various ratios of free and complexed cTnI. Matched samples drawn into serum, EDTA, lithium heparin, and sodium heparin sample tubes were compared. Results: Total imprecision (CVs) was 4.0–8.8% between 0.40 and 31 μg/L cTnI. The detection limit was 60 μg/L and not affected by common assay interferents. An equimolar response was observed with free, complexed, phosphorylated, and dephosphorylated forms of cTnI. Results were 4% lower in serum and 14% lower in EDTA plasma than in lithium heparin plasma ( P <0.01), independent of cTnI concentration. Conclusion: AccuTnI is a sensitive and precise assay for the measurement of cTnI.

Metallothionein-Independent Zinc Protection from Alcoholic Liver Injury

Abstract: Previous studies using metallothionein (MT)-overexpressing transgenic mice have demonstrated that MT protects the liver from oxidative injury induced by alcohol. The mechanism of action of MT is unknown. Because MT primarily binds to zinc under physiological conditions and releases zinc under oxidative stress and zinc is an antioxidant element, it is likely that zinc mediates the protective action of MT. The present study was undertaken to determine the distinct role of zinc in hepatic protection from alcoholic injury. MT I/II-knockout (MT-KO) mice along with their wild-type controls were treated with three gastric doses of ethanol at 5 g/kg at 12-hour intervals. Zinc sulfate was injected intraperitoneally in a dosage of 5 mg/kg/day for 3 days before ethanol treatment. MT concentrations in MT-KO mice were very low and zinc concentrations in MT-KO mice were lower than in wild-type mice. Zinc treatment significantly elevated hepatic MT concentrations only in wild-type mice and increased zinc concentrations in both MT-KO and wild-type mice. Ethanol treatment caused degenerative morphological changes and necrotic appearance in the livers of MT-KO mice. Microvesicular steatosis was the only ethanol-induced change in the liver of wild-type mice. Ethanol treatment decreased hepatic glutathione concentrations and increased hepatic lipid peroxidation, and the concentrations of lipid peroxide products in the wild-type mice were lower than in the MT-KO mice. All of these alcohol-induced toxic responses were significantly suppressed by zinc treatment in both MT-KO and wild-type mouse livers. These results demonstrate that zinc, independent of MT, plays an important role in protection from alcoholic liver injury. However, MT is required to maintain high levels of zinc in the liver, suggesting that the protective action of MT in the liver is likely mediated by zinc.

A position statement in support of hand transplantation.

Abstract: The scientific basis for human trials of hand transplantation was both experimental and clinical. Prolonged survival of limb transplants was achieved in small and large animals by using novel immunosuppressive drugs. Further, all tissue components of the hand (skin, muscle, tendon, nerve, bone, and joint) were individually transplanted with success in humans. After appropriate institutional review of the ethics, experimental data, treatment protocol, and informed consent, clinical trials were approved. Thirteen hands have been transplanted onto 10 recipients, with resultant low morbidity and no mortality. With the exception of one recipient who requested amputation after the second year, results of hand transplantation have been highly successful. Functional return mirrored that seen after hand replantation. The limbs were progressively integrated into activities of daily living and professional tasks. The hand and patient survival rate exceeds the initial results of any previously transplanted organ. This success strongly supports continuation of these human trials.

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome

Abstract: Women with polycystic ovary syndrome (PCOS) characteristically are obese and have insulin resistance and hyperinsulinemia-all risk factors for gestational diabetes. Conversely women who develop gestational diabetes are likely to have polycystic ovaries. The investigators evaluated treatment with metformin, a safe and effective insulin-sensitizing drug, in forestalling the development of gestational diabetes in 72 women with established PCOS. All were nondiabetic before their pregnancies and had had at least one live birth. Thirty-three women conceived while taking metformin in a dose of 2.55 gm daily, and were studied prospectively. All but five of these women took the drug throughout pregnancy, and there were 34 live births. The remaining 39 women with PCOS were studied retrospectively. They had a total of 64 live births, for 60 of which information on gestational diabetes was available. Women in the prospective group were placed on a high-protein, low-carbohydrate diet with 30% calories as fat. Women were screened for gestational diabetes with a 100-gm glucose challenge at 26 to 28 weeks' gestation. Both groups of women were insulin-resistant with high fasting insulin levels and had elevated insulin secretion. Only one woman in the prospective series (3% of pregnancies) developed gestational diabetes, contrasting with 67% of their previous pregnancies in the absence of metformin therapy. Gestational diabetes developed in 23% of pregnancies in the retrospective group. The overall incidence in all live births without metformin therapy was 31%. The odds ratio of gestational diabetes in pregnancies of metformin-treated women compared to those not receiving metformin was 0.115 (95% CI, 0.014-0.938). Women taking metformin throughout their pregnancies had decreases in body weight and body mass index. At the same time, insulin levels and insulin resistance both declined and did not change significantly during the rest of pregnancy. No woman taking metformin developed lactic acidosis. Intermittent diarrhea or gastritis was common in the first 3 weeks of treatment, but subsequently resolved spontaneously. None of 34 live-born infants were hypoglycemic or had major malformations. A substantial reduction in risk of gestational diabetes is observed when women with PCOS take metformin throughout pregnancy. The drop in insulin resistance and insulin secretion decreases the secretory demands placed on the pancreatic beta cells.

Realist Activity Theory for Digital Library Evaluation: Conceptual Framework and Case Study

Abstract: A critical yet largely unexamined facet of digital library design and use is how library content is assembled and vetted, which in turn has profound implications for ongoing digital library usefulness and usability. This article presents a social realist evaluation framework for an activity theoretic case study of the Flora of North America digital library. Social realist evaluation is a relatively new evaluation paradigm, positing that outcomes follow from mechanisms acting in contingently configured contexts. Because this study focuses on the digital library content vetting process, a significant part of the present analysis concerns the publication subsystem of the Flora of North America digital library – Collaborative Publishing Services – and how problems related to its design and use facilitates our ability to explain the Flora of North America not only as a functioning digital library project, but as a contradiction-driven organizational form in expansive development. Activity theory is a philosophical and cross-disciplinary framework for studying different forms of human practices in a multi-level, stratified manner, developmentally in time and through space. This intensive case study of the Flora of North America digital library illustrates that while social realism, itself content-neutral mechanics of explanation, provides a i>real foundation for activity theoretic analyses of work and technology, activity theory supplies a conceptually and substantively rich vocabulary for explanatory reasoning about technologically mediated social practices, such as digital library assemblage and use.

Serial 1H-MRS in relapsing-remitting multiple sclerosis: effects of interferon-β therapy on absolute metabolite concentrations

Abstract: To assess the applicability of magnetic resonance spectroscopy (MRS) for long-term follow-up of neurological diseases a longitudinal 1H-MRS study at 3 T was carried out on ten patients having relapsing-remitting multiple sclerosis (MS) who, after baseline examination, received interferon-β (IFN) lb. At 8–20 examinations within up to 34 months absolute concentrations ofN-acetylaspartate (NAA), total creatine (tG), and choline-containing compounds (tCho) were determined in a large non-enhancing lesion and contralateral normal appearing white matter (NAWM). MR spectra were analyzed using a novel time domain-frequency domain method including non-parametric background characterization. For comparison at baseline, ten healthy controls were examined. The concentrations of tCho and tCr were found to be higher in MS brain than in control brain. Besides a non-significantly lower NAA concentration in lesions there were no concentration differences between lesions and NAWM. Over the follow-up period the measured metabolite concentrations exhibited a high variability. Most concentrations remained within this scatter, and statistical tests revealed significant fluctuations in the levels of metabolites in one case only. This stability of the metabolite concentrations over time might result from IFN therapy as for the spontaneous course of relapsing-remitting MS decreasing metabolite (NAA/tCr) ratios have been reported. The results further suggest that future treatment trials intending to use metabolite concentrations as a secondary outcome indicator use even longer observation periods and, besides group analysis of large cohorts, investigate the time behavior of selected single cases. The biochemical abnormalities found in NAWM emphasize the importance of analyzing both lesion and NAWM.

Both paracetamol and ibuprofen are equally effective in managing flu-like symptoms in relapsing-remitting multiple sclerosis patients during interferon beta-1a (AVONEX) therapy

Abstract: Interferon beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS) Adverse effects in the first weeks of treatment are common This open-label, multicenter, randomized, prospective study compared treatment of flu-like symptoms (FLS) with paracetamol versus ibuprofen administered 48 h within interferon injection The percentage of patients with FLS was comparable between both treatment groups and improved during the course of the study (baseline: paracetamol 92%, ibuprofen 90%; week 12: paracetamol 60%, ibuprofen 57%) More than 75% of patients receiving either paracetamol or ibuprofen reported no or only mild impairment of daily activities There was no significant difference in general satisfaction or incidence of additional symptoms (weakness, nausea, headache; paracetamol 846% patients, ibuprofen 860% patients) between the two groups A significant overall improvement from baseline to week 12 was observed for all parameters studied (paracetamol and ibuprofen groups were pooled) These results indicate that neither the paracetamol nor the ibuprofen treatment regimen is better

Myocardial toxicity of arsenic trioxide in a mouse model.

Abstract: Arsenic trioxide is highly effective in the treatment of acute promyelocytic leukemia (APL) In September 2000, the Trisenox brand of arsenic trioxide for the treatment of relapsed and refractory APL was approved in the United States A recent clinical report has shown a serious ventricular tachycardia at the therapeutic doses of arsenic trioxide in APL patients The present study was undertaken to investigate the cardiotoxic effect of arsenic trioxide using a mouse model Animals were injected intraperitoneally with arsenic trioxide 5 mg/ kg/d for 30 d, a dose regiment that has been shown to produce plasma concentrations of arsenic within the range of those present in arsenic-treated APL patients Analysis of myocardial function revealed that arsenic caused a significant decrease in the maximum rate of rise in intraventricular pressure during ventricular contraction (MAX dP/dt), and significant increases in the end diastolic pressure and ventricle minimum diastolic pressure In response to B-adrenergic stimulation by isoproterenol, the arsenic-treated heart did not show increase in MAX dP/dt, which was observed as a stress response in the saline-treated controls The functional alterations were accompanied by cardiomyopathy, as revealed by histopathological and ultrastructural examination Furthermore, arsenic caused myocardial apoptosis, as determined by a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, which was confirmed by caspase-3 activation detected by enzymatic assay Our study thus demonstrates that arsenic trioxide, in a dose that could produce clinically comparable serum concentrations to those observed in humans, causes cardiotoxicity

Elevation of serum endothelins and cardiotoxicity induced by particulate matter (PM2.5) in rats with acute myocardial infarction.

Abstract: Epidemiological studies have defined a significant positive association of acute exposure to ambient concentrations of particulate matter (PM) with increased daily mortality and hospital admission for cardiovascular diseases. Experimental studies have shown that animals with pre-existing cardiovascular diseases are more susceptible to the cardiac effect of PM exposure. The present study was undertaken to investigate possible involvement of upregulation of the endothelin system in PM exposure-induced cardiotoxicity in rats with acute myocardial infarction (MI). Adult male Sprague-Dawley rats were subjected to occlusion of the left coronary artery and displayed myocardial infarction 12 h after the surgery. The heart rate significantly decreased and premature ventricular complexes of the electrocardiogram occurred in the myocardial infarct animals. Exposure to PM2.5 via intratracheal instillation with 2.0 mg in 0.3 mL normal saline significantly worsened the ventricular arrhythmia along with a further decrease in heart rate. The same PM exposure only caused slight cardiac changes in the sham-operated animals. Serum total endothelin concentrations were significantly elevated in both myocardial infarct rats and sham-operated controls in response to PM exposure. However, increased numbers of the endothelin receptor type A on the cardiomyocytes were observed only in the infarct myocardium. This study thus suggests that upregulation of the endothelin system in rats with MI is likely involved in the PM exposure-induced cardiotoxicity.

The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin.

Abstract: Gestational diabetes (GD) develops because pregnancy increases requirements for insulin secretion while increasing insulin resistance. Women with GD often have impaired pancreatic β-cell compensation for insulin resistance. The nature of GD is currently contentious, with debate about its existence, diagnosis and ramifications for both mother and offspring from pregnancy into later life. Also contentious are the outcomes of intervention with diet, insulin, glyburide (Glynase™, Pharmacia Upjohn) and metformin (Glucophage™, Bristol-Myers Squibb). There is consensus that women with unequivocal GD have a significant risk of adverse perinatal outcomes and increased risk of later type 2 diabetes mellitus. Foetuses from pregnancies with GD have a higher risk of macrosomia (associated with higher rate of birth injuries), asphyxia, and neonatal hypoglycaemia and hyperinsulinaemia. Uncontrolled GD predisposes foetuses to accelerated, excessive fat accumulation, insulin resistance, pancreatic exhaustion secondary to ...

Rigid ureteroscopy for diagnosis and treatment of ureteral calculi during pregnancy.

Abstract: OBJECTIVE To evaluate ureteroscopy as a treatment option for women presenting ureteral calculi during pregnancy. MATERIALS AND METHODS Eighteen pregnant patients presenting renal colic and indication of surgical treatment for ureteral calculi were analyzed. Patients were 20 to 34 years old (medium = 28), and the gestation period ranged from 12 to 34 weeks (medium = 18). Lumbar pain was present in 14 patients, and 4 had diffuse abdominal pain. Four patients were febrile in the occasion of the examination. Thirteen patients presented microscopic hematuria, 8 leucocituria, and 4 positive urine culture. The stone was detected by ultrasonography (US) in 12 patients. Magnetic resonance imaging (MRI) was performed in 2 cases, and did not demonstrate calculi. The stone location was: 1 in the superior ureter (pregnancy of 15 weeks), 4 in the medium ureter (pregnancy of 12, 15, 18 and 20 weeks), 12 in the inferior ureter, and 1 was not determined. The surgical indication was difficult pain control, fever, and presence of uterine contractions. RESULTS Double-J insertion, as single treatment, was possible in 4 patients and it was kept in place for up to 2 weeks after delivery. Among the patients submitted to ureteroscopy, the calculi retrieval was always possible, except in 1 case where the calculus was not located by US, MRI or ureteroscopy. In 2 patients, the ultrasonic lithotriptor was used and in 11 the stone was removed intact with a basket. There were no complications due to the procedure and all pregnancies were carried to full term. CONCLUSION Rigid ureteroscopy for extraction of ureteral calculi during pregnancy is efficient and safe.

Provider-patient roles in chronic disease management.

Abstract: Health care provider-patient role relationships can influence patient satisfaction, adherence to treatment, and health outcomes positively. Existing models of role relationships reflect one of three approaches to clinical management--paternalism, consumerism, or shared decision making. These models may or may not reflect the reality of chronic disease management in clinical practice. To characterize the nature of chronic disease management from the perspectives of primary care providers, we asked four nurse practitioners and four internists to describe the roles they saw for themselves and for their patients. A qualitative approach using a descriptive mode supported the formulation of a narrative description of these roles. The roles reflected a paternalistic approach to chronic disease management. The shared decision making approach supported in the literature was not evident. This finding is important for health professional education and practice.

Initial experience with a novel heat-exchanging catheter in neurosurgical patients.

Abstract: Even mild hypothermia provides marked protection against cerebral ischemia in animal models. Hypothermia may be of therapeutic value during neurosurgical procedures. However, current cooling systems often fail to induce sufficient hypothermia before the dura is opened. Furthermore, they usually fail to restore normothermia by the end of surgery, thus delaying extubation. We evaluated a new internal heat-exchanging catheter. Eight ASA physical status II–IV patients (29 –72 yr) undergoing craniotomy were enrolled. After the induction of general anesthesia, we introduced the SetPoint ® catheter into the inferior vena cava via a femoral vein. The target core body temperature was 34°C– 34.5°C. After reaching the target, core temperature was maintained until the dura was closed. Target core temperature was then set to 37.0°C, and the patient was rewarmed as quickly as possible. Seven patients had a tumor resection, and one had an aneurysm clipped. The core-cooling rate was 3.9°C 1.6°C/h, and the rewarming rate was 2.0°C 0.5°C/h; core temperature was 35.9°C 0.2°C by the end of surgery. Patients were subsequently kept normothermic for 3 h before the catheter was removed. No thrombus or other particulate material was identified on the extracted catheters. None of the patients suffered any complications that could be attributed to the SetPoint ® system or thermal

Monitored impact loading of the hip: initial testing of a home-use device.

Abstract: Many studies have been done involving exercise, impact loading, and the effect on BMD. In some of these studies, particularly those involving outpatient activity, compliance and the specific parameters of an individual's impact loading have been difficult to monitor effectively. In this study, an individual, home-use platform was used to record daily, specific, and reproducible impact forces generated during a heel drop exercise. At three centers over 24 months, we conducted a randomized, prospective study of 157 osteoporotic and osteopenic women, aged 60-85 years. A total of 99 patients used the home Osteocare® device (OrthoGenesis Incorporated, Northborough, Massachusetts USA) to generate a reproducible and specific daily impact program (active group). Controls (32) performed a similar motion on the unit but without trying to trigger an impact force (sham group), and 26 patients did no prescribed heel drop exercise (control group). All groups had the same calcium and vitamin D supplementation. Hip DXA was performed at baseline and every 6 months during the entire study duration. Compliance with the 3-5 min routine was high, and patients were able to consistently achieve the specific targeted impact range. Pooled BMD results showed no significant differences between groups in overall BMD measurements. However, a classification model that looked at individual site-specific BMD changes showed that more than 75% of the active group responded (versus 62% for both the sham and the control groups) by maintaining or increasing site-specific hip BMD over the 2-year trial. In fact, at the end of the study, 45% of the actives were gainers versus 12% and 22% in the sham and control groups, respectively. This study suggests that hip BMD may be maintained through a brief, safe, at-home, monitored impact loading program.

Low-dose immunosuppression in a rat hind-limb transplantation model.

Abstract: Composite tissue allografts (CTAs) offer an alternative to conventional reconstructive methods. However, the toxicity of the drugs that are required to prevent rejection has prevented its widespread clinical application. The purpose of this study was to determine whether a low-dose, corticosteroid-free combination regimen of tacrolimus and mycophenolate mofetil (MMF) would prevent rejection in a rat hind-limb model, with minimal toxic side effects. Three groups were used in this study. In group I, Wistar Furth (WF) rats received a syngeneic WF hind-limb. In groups II and III, WF rats received an ACI hind-limb. The latter were treated with tacrolimus-MMF. Assessment for rejection, flow cytometry, and mixed lymphocyte reactions was performed. Biopsies were taken regularly and at the time of killing. Combination therapy with low-dose tacrolimus-MMF effectively prolonged CTA survival indefinitely, with minimal side effects. Toxicity associated with immunosuppressive drugs can be avoided in a low-dose combination corticosteroid-free regimen.

Prior increase in metallothionein levels is required to prevent doxorubicin cardiotoxicity.

Abstract: Many studies have shown that metallothionein (MT) can be increased significantly by different oxidative insults in multiple organ systems. However, the increase in MT production often fails to protect against oxidative tissue injury. On the other hand, recent studies using a cardiac-specific, MT-overexpressing, transgenic mouse model have shown that MT protects against oxidative heart injury. Thus, the present study was undertaken to test the hypothesis that prior increase in MT levels is required to prevent oxidative injury. Oxidative heart injury was induced by doxorubicin (DOX), an important anticancer drug that causes severe cardiotoxicity through oxidative stress. Cardiac-specific, MT-overexpressing, transgenic mice and wild-type (WT) FVB mice were treated with DOX at 20 mg/kg. Four days after the treatment, MT concentrations were markedly elevated in the WT mouse heart. The elevated MT concentrations were comparable with those found in the transgenic mouse heart, which did not show further MT elevation in response to DOX challenge. Severe oxidative injury occurred in the heart of WT mice, including myocardial lipid peroxidation, morphological changes as examined by electron microscopy, high levels of serum creatine kinase activity, and decreased total glutathione concentrations in the heart. However, all of these pathological changes were significantly inhibited in the MT-transgenic mice. Therefore, this study demonstrates that there is a correlation between MT induction and oxidative stress in the DOX-treated mouse heart. However, MT can protect the heart from oxidative injury only if it is present prior to induction of oxidative stress.

Inhibition of tumor necrosis factor-alpha-dependent cardiomyocyte apoptosis by metallothionein.

Abstract: Myocardial cell death is an important cellular event of heart failure. Tumor necrosis factor-α (TNF) accumulates in the failing heart and causes myocyte apoptosis, but the mechanism of this action is unclear. This study was undertaken to examine the relationship between TNF-induced cardiomyocyte apoptosis and activation of p38 mitogen-activated protein kinase (MAPK) through oxidative stress. Primary cultures of neonatal cardiomyocytes isolated from transgenic mouse hearts that overexpress metallothionein (MT) as well as cardiomyocytes isolated from wild-type mice were used. The treatment of wild-type cardiomyocytes with TNF at 10 ng/mL induced apoptosis, as detected by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and confirmed by Annexin V-fluorescein isothiocyanate binding. The apoptotic effect of TNF was significantly inhibited in the MT-overexpressing cardiomyocytes. Corresponding to the apoptotic effect, TNF at 10 ng/mL caused rapid phosphorylation of p38 MAPK in wild-type cardiomyocytes. The activation of p38 MAPK was further confirmed by an in vivo experiment treating the mice with TNF and measuring p38 MAPK activity using an immune complex kinase assay. The activation of p38 MAPK was not observed in the MT-overexpressing cardiomyocytes either in vitro or in vivo. Importantly, TNF-induced accumulation of reactive oxygen species was dramatically reduced in the MT-overex-pressing cardiomyocytes as determined by a carboxy-H2-DCFDA staining method. This study thus suggests that p38 MAPK activation is likely involved in TNF-induced cardiomyocyte apoptosis, which is also related to reactive oxygen species accumulation.

Cellular compositions which facilitate engraftment of hematopoietic stem cells while minimizing the risk of gvhd

Abstract: The present invention provides for cellular compositions which facilitate engraftment of hematopoietic stem cells from a syngeneic, allogeneic or xenogeneic donor. The cellular compositions of the invention facilitate engraftment while minimizing the risk of graft versus host disease in the graft recipient. According to a preferred embodiment of the invention, a cell composition is provided, which cell composition comprises hematopoietic stem cells, such as CD34+ cells and/or facilitating cells, in combination with αβ TCR+ T cells. The invention also relates to methods of using the cellular compositions of the invention to induce donor specific tolerance in a recipient, thus allowing the transplantation of donor organs, cells and tissues. Also disclosed are methods of treating leukemia and cancer as well as infectious diseases caused by viruses.

Estrogen replacement therapy, thrombophilia, and atherothrombosis.

Abstract: In a consecutive case series, cross-sectional study of 401 women referred for hyperlipidemia therapy, (110 [27%] on estrogen replacement therapy [ERT]), we assessed whether ERT-mediated thrombophilia and heritable thrombophilia (20210 G[rarr ]A prothrombin gene [PTG], Factor V Leiden gene mutation [FV]) interacted as risk factors for atherothrombotic cardiovascular disease (ATCVD). Thirty-eight percent of women (152/401) had [ge ] 1 ATCVD event, 57 (14%) had [ge ] 2 ATCVD events. Fifteen women (3.7%) were PTG heterozygotes, 24 (6.0%) were FV heterozygotes, (there was 1 double heterozygote [0.25%]); 363 (91%) were wild-type normal for both genes. Of the 152 women with [ge ] 1 ATCVD event, 21 (14%) had [ge ] 1 thrombophilic gene mutation, versus 17/249 (7%) without events (X2 = 5.4, P = .02). In women on ERT and with both genes wild-type normal, 23 of 96 (24%) had [ge ] 1 ATCVD event versus 8 of 14 (57%) on ERT and with [ge ] 1 thrombophilic mutation, X2 = 6.6, P = .01. By stepwise logistic regression, in 401 women (152 with [ge ] 1 ATCVD event, 249 no events), positive explanatory variables for ATCVD included FV and/or PTG (risk odds ratio, 2.59, 95% confidence interval [CI] 1.26 to 5.36, P = .01) and a PTG*ERT interaction term (risk odds ratio, 2.27, 95% CI 1.36 to 3.79, P = .0017). After deleting 23 FV heterozygotes and 14 PTG heterozygotes and 1 double heterozygote from the 401 women, ERT was protective against ATCVD events, with a risk odds ratio of 0.50 and 95% CI of 0.29 to 0.87 P = .014. PTG and FV may increase risk for ATCVD, particularly in the presence of ERT, whereas ERT may be protective against ATCVD when PTG and FV are absent.

Waiting for lung transplantation: family experiences of relocation.

Abstract: The waiting period for pediatric lung transplantation begins when it is determined that a child's only choice, other than transplantation, is death within 1 year. Children who are on the waiting list must always be within beeper range of the transplant center. Six parents who temporarily relocated with their children to be closer to the transplant center shared their perceptions of the experience. Data analysis led to the formulation of a descriptive category, experiencing relocation, and six related themes--putting life on hold, experiencing diminished emotional support, establishing new sources of support, undergoing role change, worrying about money, and making the best of the situation. Recognizing the unique needs of parents who must relocate for a child's transplant supports the delivery of individualized nursing care and the effective allocation of program resources.

Development of coagulation regulatory proteins in the fetal and neonatal lamb.

Abstract: To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein.