Vascular imaging of solid tumors in rats with a radioactive arsenic-labeled antibody that binds exposed phosphatidylserine.

PURPOSE: We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats. EXPERIMENTAL DESIGN: Bavituximab was labeled with (74)As (beta(+), T(1/2) 17.8 days) or (77)As (beta(-), T(1/2) 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1 tumors in rats. RESULTS: Clear images of the tumors were obtained using planar gamma-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium. CONCLUSIONS: These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors.     

Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression.

Deep brain stimulation (DBS) to different sites allows interfering with dysfunctional network function implicated in major depression. Because a prominent clinical feature of depression is anhedonia--the inability to experience pleasure from previously pleasurable activities--and because there is clear evidence of dysfunctions of the reward system in depression, DBS to the nucleus accumbens might offer a new possibility to target depressive symptomatology in otherwise treatment-resistant depression. Three patients suffering from extremely resistant forms of depression, who did not respond to pharmacotherapy, psychotherapy, and electroconvulsive therapy, were implanted with bilateral DBS electrodes in the nucleus accumbens. Stimulation parameters were modified in a double-blind manner, and clinical ratings were assessed at each modification. Additionally, brain metabolism was assessed 1 week before and 1 week after stimulation onset. Clinical ratings improved in all three patients when the stimulator was on, and worsened in all three patients when the stimulator was turned off. Effects were observable immediately, and no side effects occurred in any of the patients. Using FDG-PET, significant changes in brain metabolism as a function of the stimulation in fronto-striatal networks were observed. No unwanted effects of DBS other than those directly related to the surgical procedure (eg pain at sites of implantation) were observed. Dysfunctions of the reward system--in which the nucleus accumbens is a key structure--are implicated in the neurobiology of major depression and might be responsible for impaired reward processing, as evidenced by the symptom of anhedonia. These preliminary findings suggest that DBS to the nucleus accumbens might be a hypothesis-guided approach for refractory major depression.     

Synthesis,self‐association and chiroselectivity of isotopically labeled trianglamine macrocycles in the ion trap mass spectrometer

The synthesis and self‐association of chiral isotopically labeled trianglamine macrocycles under electrospray mass spectrometer conditions in an ion trap are described. A moderate diastereoselectivity in the self‐association process was observed providing a synthetic model system for the investigation of chiral self‐association in the gas phase. The first non‐covalently bound dimer exclusively bonded through aromatic–aromatic interactions was observed in the gas phase. Evidence for self‐association in solution was observed by diffusion nuclear magnetic resonance spectroscopy. Copyright © 2007 John Wiley & Sons, Ltd.     

Direct quantification of ethyl glucuronide in clinical urine samples by liquid chromatography-mass spectrometry

Ethyl glucuronide is a minor metabolite of ethanol, and its presence in urine can be used as a laboratory test to detect recent alcohol intake, even for some time after the ethanol is no longer measurable. A simple analytical procedure was developed based on direct injection of urine diluted with a deuterated internal standard into an electrospray liquid chromatographic-mass spectrometric (LC-MS) system. A novel LC system using a porous graphite column (Hypercarb) enabled an isocratic elution with retention times of 5-6 minutes. The intra- and inter-assay coefficients of variation were 2-12%, and the measuring range was 0.1-1,500 mg/L (0.45-6,750 micromol/L). Ethyl glucuronide was found to be stable in urine for more than 4 days at room temperature, and no artifactual formation was observed on storage of urine samples fortified with 1% ethanol. Ethyl glucuronide was not detected in urine samples collected after abstinence from alcohol. Intake of a very low amount (7 g) of ethanol produced ethyl glucuronide values up to 8.4 mg/L after 4 hours and was still detectable at 6 hours. When the method was applied for routine screening of 252 clinical urine samples (range, 0-1,240 mg/L), it fulfilled the need for a simple and reliable assay to be used in the evaluation of urinary ethyl glucuronide as a routine test of recent alcohol intake.     

Apoptotic neutrophils in the circulation of patients with glycogen storage disease type 1b (GSD1b)

Glycogen storage disease type 1b (GSD1b) is a rare autosomal recessive disorder characterized by hypoglycemia, hepatomegaly, and growth retardation, and associated-for unknown reasons- with neutropenia and neutrophil dysfunction. In 5 GSD1b patients in whom nicotin-amide adenine dinucleotide phosphate-oxidase activity and chemotaxis were defective, we found that the majority of circulating granulocytes bound Annexin-V. The neutrophils showed signs of apoptosis with increased caspase activity, condensed nuclei, and perinuclear clustering of mitochondria to which the proapoptotic Bcl-2 member Bax had translocated already. Granulocyte colony-stimulating factor (G-CSF) addition to in vitro cultures did not rescue the GSD1b neutrophils from apoptosis as occurs with G-CSF-treated control neutrophils. Moreover, the 2 GSD1b patients on G-CSF treatment did not show significantly lower levels of apoptotic neutrophils in the bloodstream. Current understanding of neutrophil apoptosis and the accompanying functional demise suggests that GSD1b granulocytes are dysfunctional because they are apoptotic.     

Spike sequences and mean firing rate in rat neocortical neurons in vitro

Properties of neuronal discharges and their interrelationship with mean evoked firing rate (MF) were investigated in detail in the rat somatosensory cortex in vitro. Firing was evoked by 1-min depolarizing current injection (0.1-1.0 nA) into pyramidal neurons (n=93) of layers II/III and V. Spike sequence patterns (SSPs) with consecutive increasing or decreasing interspike intervals were analyzed. SSP rate (change of pattern, 2-50 min(-1)) and the deviations of afterhyperpolarizing potentials (up to 1.5 mV) associated with the SSPs were significantly correlated with MF. The number of transitions in spike frequency was dependent on the MF and showed a biphasic interrelation with a reversible point at 5-8 Hz. All neurons analysed were subdivided into two groups: with depolarizing potential after single spike and without such afterdepolarizing potential. It was found that despite significant differences in electrophysiological properties of the cells from these groups, similar dependency in patterns of their discharges upon MF was observed. A possible role of spike sequence patterns in neocortical rhythmical processes is discussed.     

A cost minimization analysis of implant treatment in mandibular edentulous patients

PURPOSE: This study aimed to determine if implant-supported overdentures are a long-term economically efficacious therapy for edentulous patients when compared to fixed osseointegrated prostheses. MATERIALS AND METHODS: Clinical records of 25 patients from two long-term studies (fixed and overdenture) were included in this analysis. A cost minimization analysis from the patient perspective was employed. Direct clinical and time costs incurred over the 9-year period were deflated to 1995 Canadian dollars using the Consumer Price Index. National salary rates by occupation and gender were used to value patients' time, and a sensitivity analysis was carried out to assess the robustness of the results when an equal mean salary rate across treatment groups was assumed. RESULTS: The mean total, clinical, and time costs were significantly higher (Ps .05) for the fixed restoration group (dollars CAD10,748, dollars CAD10,094, and dollars CAD654, respectively) when compared to the overdenture group (dollars CAD3,665, dollars CAD3,343, and dollars CAD322, respectively). The initial, maintenance, and clinical visit costs were also significantly higher (P < or = .05) in the fixed restoration group (dollars CAD7,567, dollars CAD2,527, dollars CAD542, respectively) than in the overdenture group (dollars CAD2,505, dollars CAD830, dollars CAD292, respectively). The sensitivity analysis demonstrated that the time cost for the fixed prosthodontic group (dollars CAD488 vs dollars CAD322) was still significantly higher (P = .002), even after an equal mean salary rate was assumed. CONCLUSION: Overdenture therapy for edentulous patients is a more cost-effective treatment compared to fixed prosthodontic treatment.     

Decremental Pulmonary Venous Pulse Propagation: Impact for Catheter Ablation in Focal Atrial Fibrillation

Background: Electrical isolation of pulmonary veins (PV's) is crucial to achieve success in catheter ablation for trigger elimination in focal atrial fibrillation (AF). To guide ostial PV radiofrequency (RF) delivery, it is necessary to identify the electrical breakthrough (EBT) between PV and left atrium. For this purpose, coronary sinus (CS) fixed rate pacing is commonly used. This study evaluated, whether CS extrastimulus pacing is superior in identifying the EBT area as compared to fixed rate pacing. Methods: In 9 patients (51 ± 10 years) undergoing a left sided electrophysiological study for AF ablation, 25 PV's (10 right and 15 left-sided PV's) were mapped using a 4 French fixed-wire catheter with eight 6 mm coiled Platinum electrodes in a distal looped configuration (Revelation Helix, Cardima Inc.). For mapping and ablation the electrode loop was positioned in the PV ostium rectangular to the longitudinal PV axis. EBT area was identified as those electrodes indicating the earliest PV signals during CS pacing. We measured number of EBT electrodes and time between EBT and the latest activated bipoles at the electrode loop during fixed rate and extrastimulus pacing. The reduction of two or more EBT electrodes was defined as a significant benefit in EBT identification. Results: In 22 of 25 PV's mapped PV potentials could be observed. Performing fixed rate pacing the EBT area was identified in a mean of 4.2 ± 1 electrodes, whereas using extrastimulus pacing, EBT area could be significantly reduced to 2.3 ± 0.8 electrodes. The time between EBT and latest electrode activated increased from 14 ± 7 ms to 22 ± 10 ms indicating an intrapulmonary conduction delay during extrastimulus pacing. In 13 of 22 PV's mapped (59%), extrastimulus pacing was beneficial in the identification of the EBT, as the primary target for RF delivery. Conclusions: CS extrastimulus pacing induces intra-PV decremental conduction properties allowing one to identify a more localised and smaller EBT area as the primary target for RF delivery. Performing PV ablation to treat focal AF, extrastimulus maneouvers allow to unmask the true EBT and thus may help to limit intrapulmonary RF delivery.