Impact of maintenance immunosuppressive regimens – balance between graft protective suppression of immune functions and a near physiological immune response

The Symphony study showed superior 1‐year kidney graft outcome in patients on immunosuppression with tacrolimus/mycophenolate mofetil (Tacr/MMF). To analyze whether differences in clinical outcome between maintenance regimens may be explained by their impact on clinically relevant immune parameters, we assessed CD4 helper activity, immunoglobulin‐secreting cell (ISC) formation, neopterin, sCD30, and intracellular cytokine production in a prospective study in 77 renal transplant recipients treated with cyclosporine A/azathioprine (CsA/Aza), CsA/MMF, Tacr/Aza or Tacr/MMF at 2 years post‐transplant. Tacr‐ compared with CsA‐based immunosuppression was independently associated with increased IL‐2 (P < 0.0001, CD4 cells; P = 0.014, CD8 cells) and CD4 cell IL‐4 responses (P = 0.046; stepwise logistic regression) resulting in physiological responses in Tacr/Aza patients as compared with 25 healthy controls. MMF versus Aza treatment was proven to be an independent variable associated with suppression of CD4 cell IL‐10 responses (P = 0.008), B‐cell IL‐6R expression (P < 0.0001) and ISC formation [P = 0.020, staphylococcus cowan strain I (SAC I); P = 0.021, pokeweed mitogen (PWM)]. Our data suggest that Tacr/MMF had the most effective impact on graft protective Th2 responses (enhanced CD4 cell IL‐4 by Tacr, decreased CD4 cell IL‐10 responses by MMF) and suppression of B‐cell functions (MMF), whereas Tacr/Aza was associated with physiological IL‐2 and IL‐4 and stronger humoral responses which may reduce the risk of infectious disease complications. (ClinicalTrials.gov number: NCT00150891).     

Development of aseptic osteonecrosis during the treatment of acute lymphoblastic leukemia: review of the literature and author's own data

We report a case of aceptic osteonecrosis (AON) of the left hymerus epiphysis in programmed treatment of a male patient with lymphoblastic lymphoma to illustrate clinical, laboratory, epidemiological, pathogenetic, diagnostic and therapeutic aspects of AON in programmed therapy of acute lymphoblastic leukemia (ALL). We believe that AON is a rather frequent but often missed for early diagnosis complication of ALL treatment. Even a weak pain in bones and joints under mechanical load in patients on long-term treatment with glucocorticosteroids is an alarming symptom which may indicate a risk of an osteodestructive process and relevant diagnostic and therapeutic measures may be needed.     

Visual and Cognitive Predictors of Performance on Brake Reaction Test: Salisbury Eye Evaluation Driving Study

Objectives: Concern for driving safety has prompted research into understanding factors related to performance. Brake reaction speed (BRS), the speed with which persons react to a sudden change in driving conditions, is a measure of performance. Our aim is to determine the visual, cognitive, and physical factors predicting BRS in a population sample of 1425 older drivers. Methods: The Maryland Department of Motor Vehicles roster of persons aged 67–87 and residing in Salisbury, MD, was used for recruitment of the study population. Procedures included the following: habitual, binocular visual acuity using ETDRS charts, contrast sensitivity using a Pelli-Robson chart, visual fields assessed with a 81-point screening Humphrey field at a single intensity threshold, and a questionnaire to ascertain medical conditions. Cognitive status was assessed using a standard battery of tests for attention, memory, visuo-spatial, and scanning. BRS was assessed using a computer-driven device that measured separately the initial reaction speed (IRS) (from light change to red until removing foot from accelerator) and physical response speed (PRS) (removing foot from accelerator to full brake depression). Five trial times were averaged, and time was converted to speed. Results: The median brake reaction time varied from 384 to 5688 milliseconds. Age, gender, and cognition predicted total BRS, a non-informative result as there are two distinct parts to the task. Once separated, decrease in IRS was associated with low scores on cognitive factors and missing points on the visual field. A decrease in PRS was associated with having three or more physical complaints related to legs and feet, and poorer vision search. Vision was not related to PRS. Conclusion: We have demonstrated the importance of segregating the speeds for the two tasks involved in brake reaction. Only the IRS depends on vision. Persons in good physical condition may perform poorly on brake reaction tests if their vision or cognition is compromised.     

Prediction of moderate or severe pulmonary hypertension by main pulmonary artery diameter and main pulmonary artery diameter/ascending aorta diameter in pulmonary embolism

We investigated the accuracy of computed tomographic measurements of main pulmonary artery diameter (MPAD) and of MPAD/ascending aorta diameter (AAD) in predicting moderate or severe pulmonary hypertension in 190 patients with acute pulmonary embolism. A pulmonary artery systolic pressure of > or = 50 mm Hg measured by Doppler echocardiography was considered moderate or severe pulmonary hypertension. A MPAD of > 28.6 mm and a MPAD/AAD ratio of > or = 1.00 measured by computed tomography were considered abnormal. A MPAD of > 28.6 mm had a 75% sensitivity and specificity, a 52% positive predictive value, a 89% negative predictive value, a 3.0 likelihood ratio for a positive test, and a 0.33 likelihood ratio for a negative test in predicting moderate or severe pulmonary hypertension. A MPAD/AAD ratio of > or = 1.00 had a 59% sensitivity, a 82% specificity, a 55% positive predictive value, a 84% negative predictive value, a 3.3 likelihood ratio for a positive test, and a 0.50 likelihood ratio for a negative test.     

Antifibrotic effect of captopril and enalapril on paraquat-induced lung fibrosis in rats

Although different treatment modalities have been implemented for pulmonary fibrosis, the results have not been promising and these conditions have been considered untreatable and irreversible. Thus, a plethora of new drugs has been tried for the control of this condition in recent years. This study examined the effects of two angiotensin-converting enzyme inhibitors, captopril and enalapril, on paraquat-induced pulmonary fibrosis in rats, through biochemical and histopathological parameters. Male albino Wistar rats were divided into eight groups (n = 4-5 each), including control, paraquat, captopril alone, captopril treatment and pre-treatment, enalapril alone, enalapril treatment and pre-treatment. After 21 days of treatment, the lungs were removed and the levels of hydroxyproline, glutathione and lipid peroxidation were determined. Angiotensin-converting enzyme inhibitors showed no effect on glutathione and lipid peroxidation. The results also demonstrated that captopril and enalapril improved pulmonary fibrosis as shown by histopathology, as well as a decreased content of hydroxyproline (P < 0.001) in the lung tissue. In conclusion, the present findings suggest that the antifibrotic effect of these drugs may be related to the inhibition of angiotensin-converting enzyme.     

Pilot study for a new bipolar radiofrequency ablation/aspirator device in the management of primary and secondary liver cancers

Background: In the US, the thermal ablation workload for cancer involving the liver is predicted to more than double in the next 5 years, emphasising the need to develop and improve the current technology. Study Design: A multicentre nonrandomised prospective clinical trial (NCT00514930) was undertaken, to assess the efficacy and safety of a new bipolar radiofrequency ablation/aspirator device, in the treatment of primary and secondary cancers of the liver. Results: A total of 34 lesions in 16 patients were ablated at laparotomy and followed up at 4 weeks. The mean diameter of lesion before ablation was 3.2±2.22 (range 1–10) cm, the mean volume aspirated during ablation was 9.25±7.3 (range 0–25) ml and the mean operative time was 145.95±40.7 (range 60–215) min. There was one major complication of a pleural effusion, which required drainage. The mean length of stay was 8±3.2 (range 3–14) days. In 11 patients, the ablated tumour was resected. On histological assessment, there was no evidence of viable cancer at the tumour edge. On follow‐up computed tomography, the ablation zone fully encompassed the targeted tumour and there were no local complications related to ablation. Conclusion: Initial analysis of the data from this small cohort, with only a short‐term follow‐up, shows this device to be safe and effective.     

Evaluation of PDTC for removing Ni(II) from human serum transferrin in vitro

Pyrrolidine dithiocarbamate (PDTC)can be an oral chelator with pKa=3.300+/-0.002. It behaves as a bidentate ligand at serum pH. The effect of pH on Ni2+-Tf indicated that the maximum adsorption was at pH=7.4. The effective Ni-PDTC binding constant was determined (logk=11.1+/-0.1) for the 1:2 Ni(PDTC)2 complex using UV-vis spectra. The isosbestic point at 298 indicated that the complexation reaction was done directly (without side reaction). Removal of Ni from transferrin (Tf) was investigated by reverse titration of PDTC at 25 masculineC and pH=7.4 using UV-vis spectra. PDTC is able to remove 25% of Ni from human serum transferrin.     

Arterio-venous gradients of free energy change for assessment of systemic and splanchnic perfusion in cardiac surgery patients

OBJECTIVE: Adequacy of organ perfusion depends on sufficient oxygen supply in relation to the metabolic needs. The aim of this study was to evaluate the relationship between gradients of free energy change, and the more commonly used parameter for the evaluation of the adequacy of organ perfusion, such as oxygen-extraction in patients undergoing valve replacement surgery using normothermic cardiopulmonary bypass (CPB). METHODS: In 43 cardiac patients, arterial, mixed venous, and hepato-venous blood samples were taken synchronously after induction of anaesthesia (preCPB), during CPB, and 2 and 7 h after admission to the intensive care unit (ICU+2, ICU+7). Blood gas analysis, cardiac output, and hepato-splanchnic blood flow were measured. Free energy change gradients between mixed venous and arterial (-deltadeltaG(v - a)) and hepato-venous and arterial (-deltadeltaG(hv - a)) compartments were calculated. MEASUREMENTS AND RESULTS: Cardiac index (CI) increased from 1.9 (0.7) to 2.8 (1.3) L/min/m (median, inter-quartile range) (p = 0.001), and hepato-splanchnic blood flow index (HBFI) from 0.6 (0.22) to 0.8 (0.53) L/min/m (p = 0.001). Despite increasing flow, systemic oxygen extraction increased after CPB from 24 (10)% to 35 (10)% at ICU+2 (p = 0.002), and splanchnic oxygen extraction increased during CPB from 37 (19)% to 52 (14)% (p = 0.001), and remained high thereafter. After CPB, high splanchnic and systemic gradients of free energy change gradients were associated with high splanchnic and systemic oxygen extraction, respectively (p = 0.001, 0.033, respectively). CONCLUSION: Gradients of free energy change may be helpful in characterising adequacy of perfusion in cardiac surgery patients independently from measurements or calculations of data from oxygen transport.     

Gadolinium neutron capture brachytherapy (GdNCB), a new treatment method for intravascular brachytherapy

Restenosis is a major problem after balloon angioplasty and stent implantation. The aim of this study is to introduce gadolinium neutron capture brachytherapy (GdNCB) as a suitable modality for treatment of stenosis. The utility of GdNCB in intravascular brachytherapy (IVBT) of stent stenosis is investigated by using the GEANT4 and MCNP4B Monte Carlo radiation transport codes. To study capture rate, Kerma, absorbed dose and absorbed dose rate around a Gd-containing stent activated with neutrons, a 30 mm long, 5 mm diameter gadolinium foil is chosen. The input data is a neutron spectrum used for clinical neutron capture therapy in Studsvik, Sweden. Thermal neutron capture in gadolinium yields a spectrum of high-energy gamma photons, which due to the build-up effect gives an almost flat dose delivery pattern to the first 4 mm around the stent. The absorbed dose rate is 1.33 Gy/min, 0.25 mm from the stent surface while the dose to normal tissue is in order of 0.22 Gy/min, i.e., a factor of 6 lower. To spare normal tissue further fractionation of the dose is also possible. The capture rate is relatively high at both ends of the foil. The dose distribution from gamma and charge particle radiation at the edges and inside the stent contributes to a nonuniform dose distribution. This will lead to higher doses to the surrounding tissue and may prevent stent edge and in-stent restenosis. The position of the stent can be verified and corrected by the treatment plan prior to activation. Activation of the stent by an external neutron field can be performed days after catherization when the target cells start to proliferate and can be expected to be more radiation sensitive. Another advantage of the nonradioactive gadolinium stent is the possibility to avoid radiation hazard to personnel.     

Calbindin D(9k) knockout mice are indistinguishable from wild-type mice in phenotype and serum calcium level

Since the discovery of calbindin D(9k), its role in intestinal calcium absorption has remained unsettled. Further, a wide distribution of calbindin D(9k) among tissues has argued for its biological importance. We discovered a frameshift deletion in the calbindin D(9k) gene in an ES cell line, E14.1, that originated from 129/OlaHsd mice. We produced mice with the mutant calbindin D(9k) gene by injecting the E14.1 ES cell subline into the C57BL/6 host blastocysts and proved that these mice lack calbindin D(9k) protein. Calbindin D(9k) knockout mice were indistinguishable from wild-type mice in phenotype, were able to reproduce, and had normal serum calcium levels. Thus, calbindin D(9k) is not required for viability, reproduction, or calcium homeostasis.