Cardiopulmonary transit time: A novel PET imaging biomarker of in vivo physiology for risk stratification of heart transplant recipients.

BACKGROUND: Myocardial blood flow (MBF) can be quantified using dynamic PET studies. These studies also inherently contain tomographic images of early bolus displacement, which can provide cardiopulmonary transit times (CPTT) as measure of cardiopulmonary physiology. The aim of this study was to assess the incremental prognostic value of CPTT in heart transplant (OHT) recipients. METHODS: 94 patients (age 56 ± 16 years, 78% male) undergoing dynamic 13N-ammonia stress/rest studies were included, of which 68 underwent right-heart catherization. A recently validated cardiac allograft vasculopathy (CAV) score based on PET measures of regional perfusion, peak MBF and left-ventricular (LV) ejection fraction (LVEF) was used to identify patients with no, mild or moderate-severe CAV. Time-activity curves of the LV and right ventricular (RV) cavities were obtained and used to calculate the difference between the LV and RV bolus midpoint times, which represents the CPTT and is expressed in heartbeats. Patients were followed for a median of 2.5 years for the occurrence of major adverse cardiac events (MACE), including cardiovascular death, hospitalization for heart failure or acute coronary syndrome, or re-transplantation. RESULTS: CPTT was significantly correlated with cardiac filling pressures (r = .434, P = .0002 and r = .439, P = .0002 for right atrial and pulmonary wedge pressure), cardiac output (r = - .315, P = .01) and LVEF (r = - .513, P < .0001). CPTT was prolonged in patients with MACE (19.4 ± 6.0 vs 14.5 ± 3.0 heartbeats, P < .001, N = 15) with CPTT ≥ 17.75 beats showing optimal discriminatory value in ROC analysis. CPTT ≥ 17.75 heartbeats was associated with a 10.1-fold increased risk (P < .001) of MACE and a 7.3-fold increased risk (P < .001) after adjusting for PET-CAV, age, sex and time since transplant. CONCLUSION: Measurements of cardiopulmonary transit time provide incremental risk stratification in OHT recipients and enhance the value of multiparametric dynamic PET imaging, particularly in identifying high-risk patients.

Modeling the impact of bedaquiline treatment strategies on the multidrug-resistant tuberculosis burden in India.

SETTING: Bedaquiline (BDQ) has been approved in India for the treatment of multidrug-resistant tuberculosis (MDR-TB), but is currently recommended for MDR-TB patients who have failed initial treatment with standard regimens. While some have argued that such deferred BDQ use allows a second line of defense with a potent drug, this strategy may not be optimal. OBJECTIVE: To compare several distinct scenarios of BDQ access and use, and their potential impact on the MDR-TB disease burden and the associated net economic benefit in India. METHOD: We used a state-transition model to carry out this evaluation. The scenarios differed in the timing and breadth of BDQ access. RESULTS: The simulations showed that a strategy reliant on reserving the use of BDQ for those who have failed other MDR-TB regimens is likely to result in worse treatment outcomes for patients and in inferior public health outcomes for communities, leading to reduced net monetary benefit. CONCLUSION: Our study suggests that deferring patient access to new drugs such as BDQ until front-line regimens have failed, in order to 'save' these drugs for later use, could be detrimental to patients and to public health, and could reduce the economic benefit of treating MDR-TB.

Spinal cord ability ruler: an interval scale to measure volitional performance after spinal cord injury.

STUDY DESIGN: Retrospective statistical analysis of database. OBJECTIVE: Spinal cord injury (SCI) clinical trials are challenged to enroll participants, and early trial outcomes have often been equivocal. We hypothesized that a specifically designed novel true linear interval-scaled outcome measure targeted to simultaneously track a broad range of SCI will enable more inclusive enrollment of participants and valid comparisons of functional changes after SCI. METHODS: To define a single SCI measurement framework, we used items from existing measures. To evaluate linearity and validity of the measure, we used rigorous psychometric Rasch analysis on two data sets from over 2500 traumatic SCI participants (all levels and severities of SCI) within the EMSCI (European Multicenter study about SCI) database. RESULTS: Volitional performance was found to be the unidimensional construct that would detect and track a treatment effect from a central nervous system-directed therapeutic. Along with early evidence for voluntary neurological control of upper-extremity muscle contractions, volitional performance is best described by goal-directed activities of daily living that are increasingly difficult to re-acquire when activity within more caudal spinal segments is required. Validity of the Spinal Cord Ability Ruler (SCAR) as a linear interval construct was confirmed with Rasch analysis. All measurement items were properly ordered, as well as being precise and stable across clinically relevant groups. Only 5/24 items had some misfit. Targeting was excellent over time after SCI, with few gaps and only modest floor and ceiling effects (3% each). CONCLUSIONS: SCAR is a quantitative linear measure of volitional performance across an inclusive range of tetraplegic and paraplegic SCI.

In ovo carbohydrate supplementation modulates growth and immunity-related genes in broiler chickens.

A study was undertaken to investigate the role of in ovo administrated carbohydrates on the expression pattern of growth and immune-related genes. In ovo injections (n = 400) were carried out on the 14th day of incubation into the yolk sac/amnion of the broiler chicken embryos. Expression of growth-related genes: chicken growth hormone (cGH), insulin-like growth factor-I & II (IGF-I & II) and mucin were studied in hepatic and jejunum tissues of late-term embryo and early post-hatch chicks. Expression of candidate immune genes: Interleukin-2, 6, 10 and 12 (IL-2, IL-6, IL-10 and IL-12), Tumour necrosis factor-alpha (TNF-α) and Interferon gamma (IFN-γ) were studied in peripheral blood monocyte cells of in ovo-injected and control birds following antigenic stimulation with sheep RBC (SRBC) or mitogen concanavalin A (Con-A). Glucose injection significantly increased the expression of IGF-II gene during embryonic period and both cGH and IGF-II in early post-hatch period, while ribose-injected chicks had higher expression of IGF-II gene during embryonic stage. Enhanced mucin gene expression was also observed in fructose-injected chicks during embryonic age. Glucose-injected chicks had higher expression of IL-6 or IL-10, while those injected with fructose or ribose had higher expression of IL-2, IL-12 and IFN gamma. It is concluded that in ovo supplementation of carbohydrates might help in improving the growth of late-term embryos and chicks. In ovo glucose could modulate humoral-related immunity, while fructose or ribose might help in improving the cellular immunity in broiler chickens.

Assessment of tuberculosis burden in China using a dynamic disease simulation model.

SETTING: Although a preventable and treatable disease, tuberculosis (TB) is among the top 10 causes of death worldwide. A consequence of inadequately treated drug-susceptible TB (DS-TB) is multidrug-resistant TB (MDR-TB). OBJECTIVES: To improve our understanding of the primary drivers of incidence and prevalence of DS- and MDR-TB in China. METHODS: The Tuberculosis Disease Transmission Model (TBDTM) uses historical and current disease epidemiology and transmission trends and treatment effectiveness, and accounts for annual changes to these to estimate future DS-TB and MDR-TB burden. RESULTS: The model shows that in China, by 2050, incidence, prevalence and mortality of DS-TB will decrease by 32%, 50% and 41%, respectively, whereas MDR-TB will increase by respectively 60%, 48% and 35%. Reduction in DS-TB is a result of high treatment and cure rates leading to a decrease in the prevalence of latent tuberculous infection (LTBI), while the increase in MDR-TB is attributed to inappropriate treatment, leading to high transmission of infection and increased LTBI prevalence. CONCLUSIONS: These results demonstrate a reduction in DS-TB in China over the next 40 years, while MDR-TB will increase. Improvements in the diagnosis and treatment of MDR-TB are needed to counter this threat. The TBDTM tool has potential value in public health practice by demonstrating the impact of interventions and estimating their cost-effectiveness.

Clinical efficacy of various root canal obturating methods in primary teeth: a comparative study.

AIM: The purpose of this in vivo study was to evaluate and compare the efficacy of different obturating methods used in primary teeth, when obturated using a combination of zinc oxide and iodoform paste (Endoflas F.S.). MATERIALS AND METHODS: A group of 29 patients aged 3-9 years and a total of 64 teeth were selected. These 64 teeth (32 anterior teeth=32 canals, and 32 posterior teeth=80 canals) were randomly divided into 4 groups. Teeth were obturated with Lentulo spiral, pressure syringe, bi-directional spiral and Pastinject. Post-operative evaluation was done for: quality of canal obturation, (underfilled, optimally filled, overfilled) and presence of voids. RESULTS: Pastinject exhibited the highest number of optimally filled canals, while the highest number of underfilled canals were observed with bi-directional spiral, and the highest number of overfilled canals were observed with pressure syringe. A minimum number of voids was present in canals filled with the Pastinject technique and pressure syringe. CONCLUSION: These results suggest that Pastinject was the most effective technique for obturation of primary teeth.

Porcine brachial artery tortuosity for in vivo evaluation of neuroendovascular devices.

We report a novel model of arterial tortuosity in the porcine brachial artery for testing of endovascular devices in the flexed forelimb position. This provides an ideal vascular territory for an in vivo assessment of guidewires, microcatheters, and endovascular implants because it closely mimics the challenging curvature at the carotid siphon.

Inflammation and oxidative stress induced by cigarette smoke in Lewis rat brains.

Exposure to cigarette smoke has been associated with an increased risk of neurological diseases such as stroke, Alzheimer's disease and multiple sclerosis. In these studies, serum and brain sections from Lewis rats or those exposed to cigarette smoke and control rats were examined for evidence of increased inflammation and oxidative stress. Immunocytochemical staining of brain sections from CS-exposed rats showed increased expression of class II MHC and, in ELISA, levels of IFN-gamma and TNF-α were higher than for non-exposed rats. In polymerase chain reaction assays there was increased interferon-gamma, TNF-α, IL-1α, IL-1ß, IL-23, IL-6, IL-23, IL-17, IL-10, TGF-ß, T-bet and FoxP3 gene expression with CS exposure. There was also markedly elevated MIP-1α/CCL3, less prominent MCP-1/CCL2 and no elevation of SDF-1α gene expression. Analysis of samples from CS-exposed and control rats for anti-oxidant expression showed no significant difference in serum levels of glutathione and, in brain, similar levels of superoxide dismutase and decreased thioredoxin gene expression. In contrast, there was increased brain gene expression for the pro-oxidants iNOS and the NADPH components NOX4, dual oxidase 1 and p22(phox). Nrf2 expression, which is typically triggered as a secondary response to oxidative stress, was also increased in brains from CS-exposed rats with nuclear translocation of this protein from cytoplasm demonstrated in astrocytes in association with increased expression of the aryl hydrocarbon receptor gene, an Nrf2 target. These studies, therefore, demonstrate that CS exposure in these animals can trigger multiple immune and oxidative responses that may have important roles in the pathogenesis of CNS inflammatory neurological diseases.

Temporal evolution of susceptibility artifacts from coiled aneurysms on MR angiography: an in vivo canine study.

BACKGROUND AND PURPOSE: Intracranial aneurysms treated by coiling have a risk for recurrence, requiring surveillance imaging. MRA has emerged as an attractive technique for postcoiling aneurysm imaging. Previous research has evaluated MR imaging artifacts of the coil mass in vitro. Our aim in this study was to evaluate MR imaging artifacts of coiled aneurysms in vivo with time. MATERIALS AND METHODS: Four sidewall aneurysms were created in each of 4 dogs. Aneurysms were embolized receiving only 1 type of coils. After embolization, the animals were transferred to MR imaging, which included axial 3D TOF MRA (TEs, 3.5, 5, and 6.9 ms), phase-contrast MRA, and coronal CE-MRA. MR imaging studies were repeated at 1, 4, 6, 8, 14, and 28 weeks. We calculated an OEF: OEF = V(A)/V(CM), where the numerator represents the volume of the MR imaging artifacts and the denominator is the true volume of the coil mass measured by 3D RA. RESULTS: OEFs were largest immediately after embolization and showed a gradual decay until approximately 4 weeks, when there was stabilization of the size of the artifacts. By 4 weeks, there was mild coil compaction (average coil mass volume decrease of 7.8%); however, the OEFs decreased by 25% after 4 weeks (P < .001). CONCLUSIONS: MR imaging susceptibility artifacts change with time, being maximal in the postembolization setting and decaying until 4 weeks. The clinical implications of this study are that baseline MRA for comparison with future imaging should be acquired at a minimum of 1 week after the procedure.

Quantitative evaluation of C-arm CT cerebral blood volume in a canine model of ischemic stroke.

BACKGROUND AND PURPOSE: Previous studies have shown the feasibility of assessing qualitative CBV measurements in the angiography suite by using FPD-CBCT systems. We have investigated the correlation of FPD-CBCT CBV lesion volumes to the infarct volume. MATERIALS AND METHODS: Unilateral strokes were created in 7 adult dogs. MR imaging and FPD-CBCT data were obtained after MCA occlusion. FPD-CBCT CBV and ADC maps were generated for all subjects. The animals were sacrificed immediately following the last imaging study to measure infarct volume on histology. The reliability of FPD-CBCT-based lesion volume measurements was compared with those measured histologically by using regression and Bland-Altman analysis. RESULTS: The best correlation (R(2) = 0.72) between lesion volumes assessed with FPD-CBCT and histology was established with a threshold of mean healthy CBV - 2.5 × SD. These results were inferior to the correlation of lesion volumes measured with ADC and histology (R(2) = 0.99). Bland-Altman analysis showed that the agreement of ADC-derived lesion volumes with histology was superior to the agreement of FPD-CBCT-derived lesion volumes with histology. CONCLUSIONS: We correlated FPD-CBCT measurements of CBV and MR ADC lesion volumes with histologically assessed infarct volume. As expected, ADC is a very accurate and precise method for determining the extent of infarction. FPD-CBCT CBV lesion volumes are correlated to the size of the infarct. Improvement of FPD-CBCT image quality provides an opportunity to establish quantitative CBV measurement in the angiography suite.

Evaluation of a capillary blood collection system for screening for hemoglobinopathies in remote areas.

Accurate estimation of hemoglobin (Hbs) A, Hb A(2), Hb F and abnormal Hb is required for diagnosis of hemoglobinopathies and genetic counseling. High pressure liquid chromatography (HPLC) is the most suitable approach available. But for 70% of the rural Indian population, HPLC analysis facilities are not available and screening would require transportation of samples to laboratories in bigger cities. We thus evaluated the feasibility of using a kit designed for measuring Hb A(1c) using capillary blood for collection and preservation of samples over a period of 15 days at different temperatures for screening for hemoglobinopathies. Capillary blood (5 microl) of 90 individuals was collected in the capillary collection system and run on the Variant Hemoglobin Testing System on days 1, 3, 5, 8, 12 and 15 after incubation at 4, 22, 37, 42 and 50 degrees C. The stability of different Hbs varied at different temperatures. The stability was maintained for 12 to 15 days by most of the samples up to 37 degrees C. Hb E was stable for 3 days up to at 37 degrees C and Hb D and Hb Q for 3 days up to 42 degrees C. This capillary blood collection system would have tremendous potential for sample collection and transportation under adverse climatic conditions for screening of hemoglobinopathies in remote areas in different countries.

Pulmonary morbidity following esophagectomy is decreased after introduction of a multimodal anesthetic regimen.

Respiratory morbidity is the most frequent complication after esophagectomy, which can occur in 50% of the patients treated for esophageal cancer. We tested the hypothesis whether an anesthetic regimen, emphasizing intraoperative fluid restriction and early extubation could, positively influence postoperative morbidity, without affecting the gastric tube reconstruction. We introduced an anesthetic regimen, based on early extubation and a controlled intraoperative fluid management (net fluid balance < 4 L) in combination with the use of norepinephrine to maintain mean arterial blood pressure > 65 mmHg. Postoperative morbidity and mortality were compared with a similar group of patients operated one year before. From June 2005 till September 2006, 83 patients were treated according to the new regimen (NR) and compared to a similar number of patients from the same period in 2003-2005 (standard regimen: SR). Applying the NR resulted in significantly less fluid administration (balance of 3.5 +/- 0.2 L NR vs. 5.1 +/- 0.2 L SR, p < 0.05) resulting in fewer patients developing pneumonia (26% in the NR group vs. 42% in the SR group, p < 0.05). Similar per operative blood loss and urine output and occurrence of leakage or ischemia of the gastric tube anastomosis occurred in both groups. Respiratory morbidity is significantly reduced with the introduction of a new anesthetic regimen directed at intraoperative fluid restriction and early extubation, without increasing anastomotic leakage of the gastric tube reconstruction.

Heart retransplantation.

Retransplants comprise only a small minority (3-4%) of heart transplants, however outcome following retransplantation is compromised. Risk factors for a poor outcome following retransplantation include retransplantation early (<6 months) after primary transplant, retransplantation for acute rejection or early allograft failure, and retransplantation in an earlier era. The incidence of rejection and infection is similar following primary transplant and retransplantation. The compromised outcomes and risk factors for a poor outcome are similar in adult and pediatric heart retransplantation. However, due to the short half-life of the transplanted heart, it is an expectation that patients transplanted in childhood may require retransplantation. Based on the data available and the opinion of the working group, indications for heart retransplantation are (i) chronic severe cardiac allograft vasculopathy with symptoms of ischemia or heart failure (should be considered) or asymptomatic moderate or severe left ventricular dysfunction (may be considered) or (ii) chronic graft dysfunction with symptoms of progressive heart failure in the absence of active rejection. Patients with graft failure due to acute rejection with hemodynamic compromise, especially <6 months post-transplant, are inappropriate candidates for retransplantation. In addition, guidelines established for primary transplant candidacy should be strictly followed.

Contemporary concepts in prevention and treatment of cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV), is characterized by heterogeneous proliferative thickening of the vascular intima of the cardiac allograft vasculature. Since its presentation is commonly clinically silent, early diagnosis and preventative therapy are critical. Preventative therapy including optimization of immunosuppressive therapy and treatment of comorbidities associated with CAV progression must be initiated early since most of the intimal thickening occurs during the first year posttransplant. Long-term use of calcineurin inhibitors is associated with a high incidence of chronic renal disease and also contributes to hyperlipidemia and hypertension, all of which may exacerbate CAV. In addition, statins, antihypertensive agents and anti-CMV agents all have demonstrated benefits in reducing CAV. Once established, the limited treatment options include nonpharmacologic interventions such as retransplantation, percutaneous coronary interventions, coronary artery bypass grafting, transmyocardial laser revascularization and heparin-induced/mediated extracorporeal LDL plasmapheresis (HELP). As the use of new assessment tools increases our understanding of this disease, better preventative and treatment strategies are evolving.

Mycophenolate mofetil reduces intimal thickness by intravascular ultrasound after heart transplant: reanalysis of the multicenter trial.

UNLABELLED: The mycophenolate mofetil (MMF) trial involved 650 heart transplant patients from 28 centers who received MMF or azathioprine (AZA), both in combination with cyclosporine and corticosteroids. Baseline and 1-year intravascular ultrasound (IVUS) were performed in 196 patients (102 MMF and 94 AZA) with no differences between groups in IVUS results analyzed by morphometric analysis (average of 10 evenly spaced sites, without matching sites between studies). Baseline to first-year IVUS data can also be analyzed by site-to-site analysis (matching sites between studies), which has been reported to be more clinically relevant. Therefore, we used site-to-site analysis to reanalyze the multicenter MMF IVUS data. RESULTS: IVUS images were reviewed and interpretable in 190 patients (99 MMF and 91 AZA) from the multicenter randomized trial. The AZA group compared to the MMF group had a larger number of patients with first-year maximal intimal thickness (MIT)>or=0.3 mm (43% vs. 23%, p=0.005), a greater decrease in the mean lumen area (p=0.02) and a decrease in the mean vessel area (the area actually increased in the MMF group, p=0.03). CONCLUSION: MMF-treated heart transplant patients compared to AZA-treated patients, both concurrently on cyclosporine and corticosteroids, in this study have significantly less progression of first-year intimal thickening.