Background: Islets obtained from genetically‐engineered (GE) pigs with Gal‐knockout (GTKO) and high expression of hCD46 have shown long‐term function and successful correction of insulin ...independence in nonhuman primates (NHP). Two anti‐coagulant genes (hTFPI and hCD39), and an immunosuppressive gene (pCTLA4Ig) have been added to the GTKO/hCD46 background, using an islet‐specific expression system, for inhibition of thrombosis, inflammation, early islet loss, and rejection. Transplant outcomes are being tested in a diabetic monkey model using adult islets from these multi‐transgenic pigs.
Methods: Three individual vectors (CD39ins, TFPIins and CTLA4Igins), each under control of the rat insulin II promoter and mouse PDX‐1 enhancer, were transfected alone or in combination into GTKO/hCD46 pig fibroblast cells. GTKO/hCD46/CD39ins, GTKO/hCD46/TFPIins/CTLA4Igins, and GTKO/hCD46/CD39ins/TFPIins/CTLA4Igins cell lines were used for nuclear transfer (NT) to produce pregnancies. Cloned pigs were analyzed for transgene expression in pancreas, heart, and liver by IHC, Western, and real‐time PCR. Glucose metabolism in the various GE pigs was determined by measurement of blood glucose, c‐peptide, and via intravenous glucose tolerance tests (ivGTT) or arginine stimulation test. GE islets from adult pigs were transplanted intraportally into STZ‐diabetic monkeys using an ATG/MMF/anti‐CD154 immunosuppression regimen.
Results: Viable multi‐transgenic pigs with three, four, or five different genetic modifications were produced. Three different pig lines were established: (i) GTKO/hCD46/CD39ins, (ii) GTKO/hCD46/TFPIins/CTLA4Igins, and (iii) GTKO/hCD46/CD39ins/TFPIins/CTLA4Igins. IHC revealed robust islet‐specific expression of CD39, TFPI and CTLA4Ig in pancreas, with only background expression in heart and liver. Western analysis showed strong pCTLA4Ig expression only in the pancreas. Blood glucose metabolism was normal in all GE pigs tested. Islets from GE pigs containing the TFPI transgene, when mixed with human blood, showed prolonged clotting times. Early islet loss (IBMIR) was reduced 5–7 fold in NHP transplants using islets from 4‐GE and 5‐GE pigs vs. 2‐GE pig islets.
Conclusions: (i) Healthy multi‐transgenic pigs with islet‐specific expression of hCD39, hTFPI, and pCTLA4Ig were produced. (ii) Glucose metabolism was normal in these GE pigs. (iii) GE islets showed anti‐coagulation activity in vitro, and protection from IBMIR in vivo in NHP transplants. (iv) GE islets transplanted into diabetic monkeys demonstrated prolonged survival, function, and complete normalization of blood glucose levels for up to 1 year.
Summary Background: The aim of the study was to determine if concurrent use of short‐acting sedatives would decrease the incidence of emergence agitation associated with desflurane while preserving ...rapid recovery.
Methods: Sixty‐nine children, aged 2–9 years, who were undergoing adenotonsillectomy, were randomly assigned to three groups: (i) intravenous midazolam 0.1 mg·kg–1; (ii) propofol 2 mg·kg–1; and (iii) control. An observer blind to anaesthetic technique assessed emergence times and behaviour. Data were compared using chi‐squared and ANOVA.
Results: Midazolam initially decreased the incidence of emergence agitation but, in the postanaesthesia care unit, significant agitation was seen in all three groups. Emergence and complete recovery were delayed in groups 1 and 2.
Conlusions: The concurrent use of midazolam or propofol did not reduce the incidence of emergence agitation but did delay emergence and recovery. These agents are not recommended for reducing emergence agitation in children receiving desflurane.
No studies have analyzed quality of life (QOL) from before to after heart transplantation in patients with a left ventricular assist device (LVAD). Therefore, the purpose of this longitudinal, ...multi-site study was to compare QOL outcomes of patients listed for heart transplantation who required a left ventricular assist device (LVAD) at 3 months after implantation of an LVAD vs 3 months after heart transplantation.
A non-random sample of 40 patients (predominantly middle-aged, married, white men), who had paired data at both 3 months after LVAD implantation and 3 months after heart transplantation, were investigated. Patients completed self-report questionnaires (with acceptable reliability and validity) at both time periods, including the Quality of Life Index, Rating Question Form, Heart Failure Symptom Checklist, Sickness Impact Profile, LVAD Stressor Scale (completed only after LVAD implant), Heart Transplant Stressor Scale (completed only after heart transplant) and Jalowiec Coping Scale. Descriptive analyses and comparative analyses using paired
t-tests were performed with statistical significance set at 0.01.
Patients were significantly more satisfied with their lives overall and with their health and functioning at 3 months after heart transplantation as compared with 3 months after LVAD implantation. Mobility, self-care ability, physical ability and overall functional ability improved from 3 months after LVAD implant to 3 months after heart transplant. There was significantly less symptom distress after LVAD implant as compared with after heart transplant for the neurologic, dermatologic and physical sub-scales. Work/school/financial stress was significantly lower after heart transplant vs after LVAD implant. In contrast, 2 other areas of stress were significantly lower after LVAD implant vs after heart transplant: self-care stress and hospital/clinic-related stress.
Differences were found in QOL outcomes at 3 months after LVAD implant as compared with 3 months after heart transplant. Our findings point out specific areas of concern with respect to QOL after LVAD implant and post-transplant, some of which are amenable to health-care provider interventions.
To determine exposure to a variety of infectious diseases potentially important for native ungulates, livestock, and humans, serum samples from 114 (94 adults, 20 fawns) female white-tailed deer ...(Odocoileus virginianus) were collected during January 2000–03 from multiple locations in southeast (SE) and southwest (SW) Minnesota. Antibody prevalence was determined for the following pathogens: Mycobacterium avium subsp. paratuberculosis, Leptospira interrogans (six serovars), Anaplasma marginale, Borrelia burgdorferi, Brucella abortus, epizootic hemorrhagic disease virus, and bovine viral diarrhea virus (BVDV) types 1 and 2. Samples collected in 2001 were screened for antibodies against Anaplasma phagocytophilum, and whole blood was submitted for polymerase chain reaction (PCR) testing for A. phagocytophilum and B. burgdorferi. In addition, serum selenium concentrations were evaluated for samples collected during 2001– 03. Antibody prevalence and selenium concentration were compared by age-class and geographic region. Antibodies to all of the infectious agents except A. marginale and B. abortus were detected; when detected, antibody prevalence was highest in adults. Deer collected from SE Minnesota had a higher antibody prevalence to B. burgdorferi than SW deer. Blood culture and PCR results for A. phagocytophilum and B. burgdorferi were negative. Antibodies against BVDV (combined types 1 and 2) were more prevalent (χ2=3.617, P≤0.029) in deer collected in SW (41%) than in SE (25%) Minnesota. No statistically significant differences in serum selenium concentrations were detected when data were analyzed by age-class or by geographic location.
Most clinical PET scans involve radiotracers labeled with 18 F. A number of radiotracers labeled with nuclides other than 18 F have been introduced, including 68 Ga-labeled PSMA, 68 Ga- and 64 ...Cu-DOTATATE, and 89 Zr-labeled antibodies or minibodies. These "non-standard" radionuclides have complex decay properties that are challenging for quantitative PET imaging (e.g., low signal due to low positron fraction and/or long half-life that limits injected activity, cascade gammas). The high sensitivity of a long axial field-of-view (AFOV) system can mitigate the low signal, but the wide axial angle coupled with the additional gammas can lead to more scatter and random events that pose a challenge for conventional corrections. In this work we imaged uniform cylindrical phantoms filled with non-standard radionuclides ( 52 Mn, 55 Co, 64 Cu, 68 Ga, 86 Y, 89 Zr) on the PennPET Explorer (112-cm AFOV) to assess quantitative accuracy and image uniformity in comparison to 18 F. Lowering the upper energy threshold (E max ) was studied to reduce contributions from higher energy gammas. Data were reconstructed using the time-of-flight list-mode ordered subsets expectation maximization algorithm with standard corrections for scatter and random coincidences. Uptake recovery was 5-10% of the true activity for radionuclides without prompt gammas, whereas inaccurate activity estimates and significant image non-uniformities were observed for 52 Mn, 55 Co and 86 Y. Lowering E max and adding a DC offset to the scatter estimate to compensate for the cascade gammas led to improved accuracy and uniformity, but further refinements of the corrections are needed. This work will pave the way for quantitative human studies with these non-standard radionuclides.
Hyperamylasemia (HA) is often reported in patients with acute liver failure (ALF). Direct toxic effects of acetaminophen on the pancreas have been postulated, but the occurrence of HA in other ...etiologies raises the question of whether multiorgan failure is part of the pathogenesis of HA in this setting. Our main aim was to describe and analyze the incidence, clinical characteristics, and outcomes of HA in ALF of different etiologies.
Patients enrolled in the Acute Liver Failure Study Group registry with an admission amylase value available were included. For the purpose of this analysis, HA was defined as > or =3x upper limits of normal. Patients were classified as having acetaminophen (APAP)- or non-APAP-induced ALF, and by amylase group: normal (<115), mildly elevated (115-345), or HA (>345). Significant variables identified by univariate analysis were added to a multiple linear regression model. The primary outcome was overall survival.
In total, 622 eligible patients were identified in the database, including 287 (46%) with APAP-induced ALF; 76 (12%) patients met the criteria for HA. Among patients with HA, 7 (9%) had documented clinical pancreatitis. The incidence of HA was similar among APAP (13%) and non-APAP (12%) patients. Although HA was associated with renal failure and greater Model for End-stage Liver Disease scores for both groups, HA was not an independent predictor of mortality in multivariate analysis.
Although not an independent predictor of mortality, HA in ALF was present in all etiologies and was associated with diminished overall survival. HA appeared to be related to renal dysfunction in both groups and multiorgan failure in non-APAP ALF.
To attract students to the risk management and insurance profession, strategies need to be developed to overcome biases in their perceptions of the profession. This study attempts to determine some ...of those perceptions of students—specifically a group of business career high school students and a group of college students enrolled in an introduction to business course—about the personality traits of insurance professionals. A Personality Factor Questionnaire previously used extensively in other research was used to measure differences in student perceptions of personality profiles of different professions. We also measured how student characteristics such as age, sex, and expected college major influence student perceptions of these traits. The overall general conclusion was that perceptions of the profession are not as negative as many imagine, but do require some substantive work to improve, even among students seeking business careers.
The successful use of left ventricular assist devices (LVADs) as a bridge to heart transplantation has prompted our examination of quality of life (QOL) outcomes. The purposes of this study are to ...describe QOL in patients 1 to 2 weeks after LVAD implantation and to compare QOL in a smaller cohort of patients from before to 1 to 2 weeks after surgery.
Data were collected from a convenience sample of 81 patients who completed booklets of questionnaires that measure domains of QOL 1 to 2 weeks after LVAD insertion and from 30 of 81 patients who completed booklets at both the pre-implantation and post-implantation periods. Patients completed booklets of 6 to 8 self-reporting instruments, with acceptable reliability and validity. Data were analyzed using descriptive and comparative statistics (chi-square, Mann-Whitney
U and Wilcoxon signed ranks tests) with
p = 0.01 considered statistically significant.
One to 2 weeks after LVAD implantation, patients were quite satisfied with their lives, experienced moderately low amounts of stress, coped well, and perceived themselves as having good health and QOL, low symptom distress, and moderately low functional disability. Patients reported significantly better QOL, more satisfaction with health and functioning, and were significantly less distressed by symptoms from immediately pre-operatively to post-operatively. However, patients reported significantly more self-care disability and more dissatisfaction with socioeconomic areas of life from before to immediately after surgery. Psychological distress was low and did not change with time.
Given that QOL improved from before to after LVAD implantation, our findings provide a springboard for investigation of the impact of LVADs on long-term QOL outcomes.
Hypothesis: Intravenous magnesium sulfate improves objective measures of expiratory flow in patients with acute severe exacerbations of asthma.
Design: Randomized, double-blind, placebo-controlled ...trial.
Setting: Urban emergency department.
Participants: Forty-eight asthmatic patients aged 18 to 60 years with initial peak expiratory flow rate (PEFR) <200 L/min who failed to double their initial PEFR after two standardized albuterol treatments.
Interventions: Subjects were randomized to three groups: a loading dose of magnesium sulfate, 2 g IV over 20 min followed by 2 g/h over 4 h (infusion), magnesium sulfate, 2 g over 20 min followed by placebo infusion (bolus), or placebo loading dose and infusion (placebo). All subjects received standardized aminophylline and steroid therapy.
Measurements: The PEFR and FEV1 were measured at the start of the loading dose, and 20, 50, 80, 140, 200, and 260 min later using a water-displacement spirometer. Changes from baseline were compared by one-way analysis of variance for repeated measures.
Results: Magnesium sulfate administration did not at any time significantly improve either FEV1 (F=0.036, p=0.96) or PEFR (F=0.51, p=0.61). This study had the power to detect a PEFR difference of 26 L/min and a FEV1 difference of 0.19 L between groups (β=0.20, α=0.05 two-tailed significance).
Conclusion: Use of IV magnesium sulfate in addition to standard therapy does not provide clinically meaningful improvement of objective measures of expiratory flow in patients with moderate to severe asthma exacerbations.
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