Ultrasound-enhanced tissue plasminogen activator thrombolysis in an in vitro porcine clot model

INTRODUCTION: Thrombolytics such as recombinant tissue plasminogen activator (rt-PA) have advanced the treatment of ischemic stroke, myocardial infarction, deep vein thrombosis and pulmonary embolism. OBJECTIVE: To improve the efficacy of this thrombolytic therapy, the synergistic effect of rt-PA and 120 kHz or 1.0 MHz ultrasound was assessed in vitro using a porcine clot model. MATERIALS AND METHODS: Fully retracted whole blood clots prepared from fresh porcine blood were employed to compare rt-PA thrombolytic treatment with and without exposure to 120-kHz or 1-MHz ultrasound. For sham studies (without ultrasound), clot mass loss was measured as a function of rt-PA concentration from 0.003 to 0.107 mg/ml. For combined ultrasound and rt-PA treatments, peak-to-peak pressure amplitudes of 0.35, 0.70 or 1.0 MPa were employed. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was fixed at 1.7 KHz. RESULTS: For rt-PA alone, the mass loss increased monotonically as a function of rt-PA concentration up to approximately 0.050 mg/ml. With ultrasound and rt-PA exposure, clot mass loss increased by as much as 104% over rt-PA alone. Ultrasound without the presence of rt-PA did not significantly enhance thrombolysis compared to control treatment. The ultrasound-mediated clot mass loss enhancement increased with the square root of the overall treatment duration. CONCLUSIONS: Both 120-kHz and 1-MHz pulsed and CW ultrasound enhanced rt-PA thrombolysis in a porcine whole blood clot model in vitro. No clear dependence of the observed thrombolytic enhancement on ultrasound duty cycle was evident. The lack of duty cycle dependence suggests a more complex mechanism that could not be sustained by merely increasing the pulse duration.     

Precision medicine in chronic disease management: The multiple sclerosis BioScreen

We present a precision medicine application developed for multiple sclerosis (MS): the MS BioScreen. This new tool addresses the challenges of dynamic management of a complex chronic disease; the interaction of clinicians and patients with such a tool illustrates the extent to which translational digital medicine—that is, the application of information technology to medicine—has the potential to radically transform medical practice. We introduce 3 key evolutionary phases in displaying data to health care providers, patients, and researchers: visualization (accessing data), contextualization (understanding the data), and actionable interpretation (real‐time use of the data to assist decision making). Together, these form the stepping stones that are expected to accelerate standardization of data across platforms, promote evidence‐based medicine, support shared decision making, and ultimately lead to improved outcomes. Ann Neurol 2014;76:633–642     

Outcome analysis of 40 cases of vestibular schwannoma: A comparison of sitting and Park bench surgical position

The present study retrospectively reviews our experience in 40 cases of vestibular schwannoma, operated between the years 1995 and 2002. All the patients underwent tumour resection either in sitting or in the Park bench position via the suboccipital retromastoid route. The position of the patient was selected arbitrarily. Precordial Doppler echocardiography was used to monitor air embolism. Operative results, including the size of the tumour, completeness of resection, anatomical and functional preservation of the facial nerve, operative complications and mortality were analysed and compared in these two operative positions. There was no statistically significant difference in terms of surgical results between these two groups.      

Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters

Imaging of vesicular monoamine transporter 2 (VMAT2) in the brain with [(11)C]-dihydrotetrabenazine (DTBZ) in conjunction with positron emission tomography (PET) has demonstrated its usefulness in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's disease and Huntington's disease. We report on the development of (18)F analogs of DTBZ with a longer half-life (t=110 vs. 20 min for C-11) to increase the availability of VMAT2 imaging agents for routine clinical studies with PET. Racemic 9-fluoroethyl (FE) and 9-fluoropropyl (FP)-9-desmethyl-DTBZ and the corresponding hydroxyl derivatives were successfully prepared. No-carrier-added racemic (18)F-DTBZ derivatives were synthesized by an [(18)F]fluoride displacement of the corresponding mesylates with good yields (30-40%) and high specific activity (SA=1500-2000 Ci/mmol). Racemic (+/-)-FE-DTBZ (6a) and (+/-)-FP-DTBZ (6b) displayed excellent binding affinities (K(i)=0.76 and 0.56 nM, respectively) for VMAT2 binding sites in rat striatal homogenates, whereas the known compounds (+/-)-DTBZ and (+/-)-tetrabenazine (TBZ) showed K(i) values of 1.7+/-0.2 and 1.3+/-0.1 nM, respectively. Consistently, racemic [(18)F]6a and [(18)F]6b exhibited K(d) values of 0.52 and 0.48 nM, respectively (based on an SA of 2000 Ci/mmol), for VMAT2 binding sites using mouse striatal homogenates. Both agents showed comparable binding densities with those obtained with [(3)H](+/-)-TBZ. Results of in vitro autoradiography with [(18)F]6b showed a distinct binding in the caudate putamen region consistent with the localization of VMAT2 in the mouse brain, which was blocked by nonradioactive TBZ efficiently. Biodistribution studies on mice after an intravenous injection of the tracer exhibited excellent brain uptakes (4.66% and 7.08% ID/g at 2 min for racemic [(18)F]6a and [(18)F]6b, respectively). It was determined that [(18)F]6b displayed a faster brain washout than [(18)F]6a did. As a result, [(18)F]6b yielded a better target-to-background ratio (striatum/cerebellum=3.0 and 1.7 at 30 min after an intravenous injection for [(18)F]6b and [(18)F]6a, respectively). The blocking study with the nonradioactive (+/-)-DTBZ clearly confirmed the in vivo competition and specificity of [(18)F]6b binding for VMAT2 sites. In conclusion, these findings strongly suggest that the novel racemic [(18)F]6b is potentially useful as a molecular imaging agent for VMAT2 binding sites in the brain. Further studies are warranted to assess the utility of these (18)F-labeled DTBZ derivatives as PET tracers for the diagnosis of various neurodegenerative diseases.     

New approach to fully automated synthesis of sodium [18F]fluoroacetate -- a simple and fast method using a commercial synthesizer

A simple, rapid and fully automated preparation of sodium [(18)F]fluoroacetate has been developed by taking advantage of the similarities between the reaction pathways of [(18)F]fluoroacetate and [(18)F]-2-fluoro-deoxyglucose (FDG). The automated synthesis of sodium [(18)F]fluoroacetate was achieved with a commercial [(18)F]FDG synthesizer, the TRACERlab MX(FDG). The method produced the desired compound in a short synthesis time (32 min) and with a high and reproducible radiochemical yield (50.2 +/- 4.8%, decay corrected). The radiochemical purity of sodium [(18)F]fluoroacetate was greater than 99%.     

Comparing Cortical Plasticity Induced by Conventional and High-Definition 4 × 1 Ring tDCS: A Neurophysiological Study

BackgroundTranscranial direct current stimulation (tDCS) induces long-lasting NMDA receptor-dependent cortical plasticity via persistent subthreshold polarization of neuronal membranes. Conventional bipolar tDCS is applied with two large (35 cm²) rectangular electrodes, resulting in directional modulation of neuronal excitability. Recently a newly designed 4 × 1 high-definition (HD) tDCS protocol was proposed for more focal stimulation according to the results of computational modeling. HD tDCS utilizes small disc electrodes deployed in 4 × 1 ring configuration whereby the physiological effects of the induced electric field are thought to be grossly constrained to the cortical area circumscribed by the ring.ObjectiveWe aim to compare the physiological effects of both tDCS electrode arrangements on motor cortex excitability.MethodstDCS was applied with 2 mA for 10 min. Fourteen healthy subjects participated, and motor cortex excitability was monitored by transcranial magnetic stimulation (TMS) before and after tDCS.ResultsExcitability enhancement following anodal and a respective reduction after cathodal stimulation occurred in both, conventional and HD tDCS. However, the plastic changes showed a more delayed peak at 30 min and longer lasting after-effects for more than 2 h after HD tDCS for both polarities, as compared to conventional tDCS.ConclusionThe results show that this new electrode arrangement is efficient for the induction of neuroplasticity in the primary motor cortex. The pattern of aftereffects might be compatible with the concept of GABA-mediated surround inhibition, which should be explored in future studies directly.     

Outcome of Unicondylar Knee Arthroplasty vs Total Knee Arthroplasty for Early Medial Compartment Arthritis: A Randomized Study

Background

With increasing number of patients with early osteoarthritis of knee opting for total knee arthroplasty (TKA), there has been increase in patients dissatisfied with surgical outcomes. It is being presumed that offering unicondylar knee arthroplasty (UKA) to them would improve outcomes.

The position of the anal dimple in newborns and infants with anorectal malformations and its correlation with the normal anal position

Background/purpose

The anal position index (API) defines the normal anal position as the ratio of fourchette–anal distance to fourchette–coccyx distance for females and the scrotum–anal distance to scrotum‐coccyx distance for males. In this study, measurement of the API in newborns and infants with anorectal malformations (ARM), using the center of the midline anal dimple (AD) to represent the center of the proposed neoanus, was performed to assess whether or not the AD was located in a significantly abnormal position as correlated with the normal anal position.

Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats.

This is an extensive study in a defined initiation-promotion hepatocellular carcinoma model of hepatocarcinogenesis (in rats) in which many important marker enzymes and isoenzymes and 8-hydroxydeoxyguanosine formation have been studied together with two very important cellular proliferating genes, insulin-like growth factor II and c-raf.1, known for their role in hepatocellular cancer development. Experiments were carried out on hepatic tissues of male Sprague-Dawley rats. Variations in different enzyme/isoenzyme activities/contents/expression pattern and 8-hydroxydeoxyguanosine-positive cells were studied. Insulin-like growth factor II and c-raf.1 gene expressions were monitored. A direct shift with increase in size and numbers of lesions was found to occur in different experimental groups. In this study, glutathione peroxidase (1.14 and 1.46-fold) and reduced triphosphopyridine nucleotide (TPNH)-cytochrome-c-reductase (1.94 and 2.94-fold) activities, cytochrome b5 (1.57 and 3.28-fold) and P-450 contents (1.45 and 1.22-fold), glutathione content (1.27 and 1.45-fold) and superoxide dismutase and catalase (1.16 and 1.39-fold) activities in group A animals were found to be lower than those in initiation and promotion studies, respectively. 8-Hydroxydeoxyguanosine-positive nuclei count showed that oxidative damage of nuclear DNA enhanced with the progress of the disease. The insulin-like growth factor II expression was found to be predominant in hepatocellular carcinoma and in early preneoplastic lesions. Unlike insulin-like growth factor II, c-raf.1 expression was located in the late basophilic lesions associated with hepatocellular carcinoma. During the various stages of the development of hepatocellular carcinoma, the enzymes played a significant role in metabolizing carcinogens and thereby scavenging various toxic metabolites or free radicals produced. A sequence of cellular changes starting from the appearance of glycogen storage foci to basophilic foci leading to hepatocellular carcinoma via mixed cell foci varied the activity/content or expression pattern of the enzymes and isoenzymes and in 8-hydroxydeoxyguanosine formation. It has been established that c-raf.1-induced signaling pathways activated by insulin-like growth factor II is implicated in the late stage of development of cancer.