Initial characterization of an 18F-labeled myocardial perfusion tracer.

PET allows for quantitative, regional myocardial perfusion imaging. The short half-lives of the perfusion tracers currently in use limit their clinical applicability. Here, the biodistribution and imaging quality of a new 18F-labeled myocardial perfusion agent (18F-BMS-747158-02) in an animal model are described. METHODS: The biodistribution of 18F-BMS-747158-02 was determined at 10 and 60 min after injection. The first-pass extraction fraction of the tracer was measured in isolated rat hearts perfused with the Langendorff method. Small-animal PET imaging was used to study tracer retention. RESULTS: The biodistribution at 10 min after injection demonstrated high myocardial uptake (3.1 percentage injected dose per gram [%ID/g]) accompanied by little activity in the lungs (0.3 %ID/g) and liver (1.0 %ID/g). The tracer showed a high and flow-independent myocardial first-pass extraction fraction, averaging 0.94 (SD = 0.04). PET imaging provided excellent delineation of myocardial structures. The heart-to-lung activity ratio increased from 4.7 to 10.2 between 1 and 15 min after tracer injection (at rest). Adenosine infusion (140 microg/kg/min) led to a significant increase in myocardial tracer retention (from 1.68 [SD = 0.23]) s(-1) to 3.21 [SD = 0.92] s(-1); P = 0.03). CONCLUSION: The observation of a high and flow-independent first-pass extraction fraction promises linearity between tracer uptake and myocardial blood flow. Sustained myocardial tracer uptake, combined with high image contrast, will allow for imaging protocols with tracer injection at peak exercise followed by delayed imaging. Thus, 18F-BMS-747158-02 is a promising new tracer for the quantitative imaging of myocardial perfusion and can be distributed to imaging laboratories without a cyclotron.     

On Optimal Channel Configurations for SMR-based Brain–Computer Interfaces

One crucial question in the design of electroencephalogram (EEG)-based brain–computer interface (BCI) experiments is the selection of EEG channels. While a setup with few channels is more convenient and requires less preparation time, a dense placement of electrodes provides more detailed information and henceforth could lead to a better classification performance. Here, we investigate this question for a specific setting: a BCI that uses the popular CSP algorithm in order to classify voluntary modulations of sensorimotor rhythms (SMR). In a first approach 13 different fixed channel configurations are compared to the full one consisting of 119 channels. The configuration with 48 channels results to be the best one, while configurations with less channels, from 32 to 8, performed not significantly worse than the best configuration in cases where only few training trials are available. In a second approach an optimal channel configuration is obtained by an iterative procedure in the spirit of stepwise variable selection with nonparametric multiple comparisons. As a surprising result, in the second approach a setting with 22 channels centered over the motor areas was selected. Thanks to the acquisition of a large data set recorded from 80 novice participants using 119 EEG channels, the results of this study can be expected to have a high degree of generalizability.     

Role of cytokines in testicular function

Inflammatory disease has been established to affect male reproductive function and fertility. Relevant inflammatory diseases include general and chronic infectious diseases as well as localized acute or chronic infections of the male genitourinary tract. Male accessory gland infections account for almost 15% of all cases of male infertility seen in infertility clinics while fertility usually is not a clinical objective among patients with acute systemic infections such as Gramnegatives sepsis. Infections of the male accessory glands frequently are associated with increased counts of white blood cells in semen and elevated levels of proinflammatory cytokines in semen and the testis. There is a mounting body of evidence that demonstrates the importance of cytokines and chemokines in the regulation of testicular and glandular function during pathophysiological states as well as under normal physiological conditions when cytokines act as growth and differentiation factors. The purpose of this review is to examine the role of cytokines in the regulation of steroidogenesis and spermatogenesis in the testis under physiological and pathophysiological conditions and considers clinical investigations that help to improve the evaluation and treatment of male infertility.     

Specific immune tolerance during pregnancy after renal transplantation

Pregnancy is associated with specific immunological tolerance to fetal antigens suggesting that immunoregulatory processes during pregnancy can induce specific immunological unresponsiveness. We report a case of a female renal transplant recipient who stopped immunosuppressive therapy during first pregnancy. Despite histologically proven acute renal allograft rejection during the early course of transplantation, no immunological response was observed for 9 years after withdrawal of immunosuppression. Two further pregnancies within that time period did not evoke any renal complications, but were complicated by premature rupture of the amnion and by the development of preeclampsia. To our knowledge, there are no reports of such a long-term specific unresponsiveness to a renal allograft without immunosuppressive therapy. Natural and active immunoregulatory mechanism can be related for the development of specific immune tolerance to renal allograft in this case.     

Molecular Cytogenetic Analysis of RB-1 Deletions in Chronic B-Cell Leukemias

Deletions or translocations of 13q, most commonly involving band 13q14, belong to the most frequent structural chromosome abnormalities in B-cell chronic lymphocytic leukemia (B-CLL). In a combined metaphase and interphase cytogenetic study using conventional G-banding analysis and fluorescence in situ hybridization (ISH) we previously analysed the retinoblastoma susceptibility gene (RB-1) and its chromosomal locus 13q14 in 35 patients with chronic B-cell leukemias. We report here on the interphase cytogenetic analysis of 109 cases with chronic B-cell leukemias [B-CLL = 90; B-prolymphocytic leukemia (B-PLL) = 6, hairy cell leukemia (HCL) = 13]; a subset of 49 patients (B-CLL = 45; B-PLL = 4) was studied by conventional G-banding analysis. By G-banding, 5/45 (11%) patients with B-CLL had deletions or translocations affecting band 13q14; in contrast, ISH to interphase cells showed RB-1 deletion in 19/90 (21%) patients with B-CLL. No 13q14 abnormalities or RB-1 deletion were detected in patients with B-PLL and HCL. Our data confirm the high frequency of RB-I deletions in B-CLL and further emphasize the possible pathogenetic role of this genomic region.     

Bcl-2 Expression in Higher-grade Human Glioma: A Clinical and Experimental Study

Bcl-2 protein plays an important role in inhibiting apoptosis and protecting normal and neoplastic cells from toxicity. Bcl-2 overexpression in malignant tumors, on the other hand, may cause resistance against adjuvant treatment. Since there are subpopulations of patients with glioma that differ considerably in their treatment benefit, it is important to identify prognostic factors for outcome and to tailor adjuvant protocols in accordance with specific biological features of the respective tumor. The present study aimed at investigating the role of bcl-2 expression in higher-grade glioma (WHO grade III and IV). Bcl-2 expression was correlated with clinical and paraclinical parameters, and evaluated in univariate and multivariate statistical models. In addition, bcl-2-overexpressing human glioma cells in culture were used for modeling the in vivo findings and for investigating the importance of bcl-2 for tumor resistance against cytotoxic treatment.A group of 86 patients with higher-grade glioma were investigated. Anaplastic astrocytoma (AA; WHO G III, n=29) showed bcl-2 expression in 48% of the cases, and immunohistochemical positivity was associated with a significantly shorter survival time (p=0.0068). In glioblastoma patients (GBM; WHO G IV, n=57), 51% of tumors were bcl-2 positive, but bcl-2 expression did not correlate significantly with survival (p=0.39). In a Cox proportional hazards regression model, bcl-2 positivity was confirmed as a negative prognostic parameter in AA, but not in GBM.Bcl-2 overexpressing and control human glioma cell clones (T98MG line) were treated in culture with the cytotoxic drugs carmustine (BCNU), paclitaxel, vincristine, and doxorubicin. In addition, bcl-2-overexpressing and control cells were infected with a retrovirus carrying the herpes-simplex-virus thymidine kinase gene (HSV-tk), and then treated with ganciclovir (GCV). Bcl-2 overexpression significantly increased tumor cell resistance against all of the above cytotoxic drugs, and also against HSV-TK/GCV mediated gene therapy.     

Stimulating catheters for regional anesthesia: considerations in routine clinical use

The use of peripheral catheter techniques for regional anaesthesia and analgesia is quite common today. Although electrical nerve stimulation facilitates the correct placement of the insertion cannula, nobody knows where exactly the tip of the advanced catheter will be located after insertion. With the help of stimulation nerve catheters the stimulation of the target nerve via the tip of the catheter during insertion enables a placement nearby the nerve without additional devices. These new catheter systems require--in comparison to the conventional--a modified insertion technique. This article illustrates how to use these catheters in clinical practice and provides information about investigations to success rate and failure.     

Acquisition of basic fiberoptic intubation skills with a virtual reality airway simulator

STUDY OBJECTIVE: To test the hypothesis that a virtual reality (VR) airway simulator (the AccuTouch Virtual Reality Bronchsocopy Simulator; Immersion Medical, Gaithersburg, MD) can be used to teach residents basic fiberoptic intubation (FOI) skills effectively. DESIGN: Observational study. SETTING: University anesthesiology department. INTERVENTION: Supervised training was done using a VR airway simulator. MEASUREMENTS: Time to intubation before and after a 4-day training period using an adult VR FOI scenario and time to intubation using a fresh human cadaver two weeks after the training experience were measured. MAIN RESULTS: Residents were able to significantly improve time to intubation in the VR scenario (114 vs 75 seconds; P = 0.001). Novices differed from experienced attending anesthesiologists in time to intubation in the VR scenario, before but not after training (114 vs 79 seconds compared with 75 vs 72 seconds). Novices who had been trained with the simulator performed significantly faster in the cadaver than novices who had not (24 vs 86 seconds; P < 0.001). Furthermore, there was no difference in time to intubation in the cadaver between trained novices and experienced attending anesthesiologists (24 vs 23 seconds; P > 0.05). CONCLUSION: Use of a VR airway simulator enables anesthesia residents to acquire basic FOI skills comparable to those of experienced anesthesiologists in a human cadaver.     

Signalling and survival pathways in multiple myeloma

The main factors that govern the pathophysiology and malignant growth of multiple myeloma (MM) are genetic defects within the tumour and the interaction between myeloma cells and the bone marrow microenvironment (BMM). This interaction leads to the activation of signalling pathways that promote the expansion of the malignant clone and stimulate neoangiogenesis and osteoclastogenesis. For many years, the cytokine interleukin-6 (IL-6) was considered a central growth factor and was thus believed to play a pivitol role in the pathogenesis of MM. However, increasing numbers of cytokines, chemokines and cell-to-cell contacts provided by the BMM have since been found to support MM cells. It has consistently been demonstrated that oncogenic mutations as well as the BMM stimulate IL-6-independent signalling pathways that protect MM cells from apoptosis. Consequently, multiple targeting of a complex signalling network rather than inhibition of a single pathway or growth factor is required to effectively induce myeloma cell death. Because the tumour suppressor p53 is rarely mutated in MM, non-genotoxic activation of the p53-dependent death pathway could be another attractive therapeutic strategy for this disease. Even though a number of promising new drugs are currently being tested in MM, a comprehensive knowledge of the signalling and survival pathways should pinpoint additional molecular targets and lead to the development of novel and hopefully more effective treatment strategies.