Digital Gangrene is a Rare Presentation of Takayasu's Arteritis.

Takayasu's arteritis is a chronic large vessel vasculitis that mainly affects the aorta and its major branches such as brachiocephalic, carotid, subclavian, vertebral, renal, coronary and pulmonary arteries. It most commonly occurs in female at child bearing age and female to male ratio is 8:2. Initial presentations of Takayasu's arteritis may be nonspecific like fever, malaise, weakness, fatigue, arthralgia, myalgia and weight loss but in advanced stage there may be features of vascular inflammation like segmental stenosis, occlusion, dilatation and/or aneurysm. It is a sub acute process over months to years and usually with good collateral formation. So, critical limb ischemia due to acute onset of vascular stenosis is very rare. Here we are reporting a case of a 50-year- old male patient who presented with digital gangrene due to critical limb ischemia. Though the age of onset was at 50 years and the patient lacks clinical features like constitutional symptoms, bruit, claudication, asymmetrical blood pressure, the patient was diagnosed as a case of Takayasus's arteritis. The patient dramatically improved with oral glucocorticoid treatment. Although rare, takayasu's arteritis can presents only with digital gangrene without having other clinical features. The physicians should be aware of this unusual but limb threatening presentation and more studies are needed to find out the exact mechanism of this presentation.

Kinetic Analysis of Drug Release from Compounded Slow-release Capsules of Liothyronine Sodium (T3).

The purpose of this study was to formulate extemporaneously compounded Liothyronine Sodium (T3) slow-release capsules and to evaluate their in vitro drug release performance. Twenty-one formulations containing T3 (7.5 µg) with various compositions of two different grades of Methocel E4M and K100M premium (30% to 90%), and/or SimpleCap/Lactose (10% to 70%) were examined. Quality assessment of the capsules was conducted by standard quality control criteria of the United States Pharmacopeia (i.e., weight variation, content uniformity) to ensure their compliance. The dissolution release profile of the formulations was evaluated using United States Pharmacopeia Apparatus type II (paddle method) at a speed of 50 rpm and temperature of 37°C in phosphate buffered saline media ( pH = 7.2 to 7.4). Aliquots from the media were taken periodically up to 24 hours and analyzed using a validated enzyme-linked immunosorbent assay method. The cumulative percentage of drug release for each formulation was fitted to eleven major release kinetic equations to determine the best-fit model of drug release, as well as the mechanism of release. Assay sensitivity was as low as 1 ng/mL and the optimal calibration range was found to be between 0 ng/mL and 7.5 ng/mL, which corresponded well with the average physiological plasma concentrations of T3. Liothyronine sodium with either SimpleCap (100%) or Methocel E4M (100%) exhibited slowrelease kinetic patterns of Peppas and Zero Order, respectively. The formulation with SimpleCap (100%) had a higher percentage of drug release (as compared to 100% Methocel E4M) within the first four hours; this formulation released 80% of the drug within 12 hours when the release was plateaued thereafter. The formulation with 30% Methocel E4M and 70% SimpleCap released 100% of the drug within the initial 12 hours and exhibited a Zero Order slow-release kinetic pattern. In general, the release kinetic rate of the formulations containing Methocel K100M appeared to be slower than Methocel E4M. This alteration may be due to a higher molecular weight and apparent viscosity of Methocel K100M. While most of the formulations were fitted to a slow-release kinetic pattern, several others including Methocel E4M 100%, 30% Methocel E4M+ 70% Simple Cap, 40% Methocel K100M+ 60% SimpleCap, 50% Methocel K100M+ 50% SimpleCap, 30% Methocel E4M+ 70% Lactose, 90% Methocel E4M+ 10% Lactose, 40% Methocel K100M+ 60% Lactose, and 50% Methocel K100M+ 50% Lactose followed an ideal slow-release kinetic pattern of Zero Order or Higuchi. The results of this study successfully demonstrated the optiomal composition of slow-release compounded capsules of T3. Future studies are warranted to evaluate the in vivo performance of the optimal formulations and to establish an in vitro-in vivo correlation.

Microdialysis-directed Intra-tumor Pharmacokinetic Modeling of Methotrexate in Mice and Humans.

PURPOSE: To develop a quantitative pharmacokinetic model to characterize the disposition of methotrexate (MTX) at tumor site in tumor-bearing mice and to predict MTX concentrations in the human tumor. METHODS: The plasma profiles of MTX were obtained from normal mice, while microdialysis technique was employed to characterize the time course of MTX in tumor from breast tumor-bearing mice. Disposition profiles of plasma and tumor were analyzed by a hybrid physiologically-based pharmacokinetic (hPBPK) model that incorporates physiologically-relevant parameters such as tumor blood flow and volume, while plasma concentrations were used as a forcing input into the vascular-interstitial spaces of the tumor. The plasma profiles were initially described by a biexponential decay model to obtain a forcing function that enters into the vascular-interstitial spaces in the tumor. Using a defined forcing function, the tumor free concentrations were fitted to the hPBPK model. Based on the model developed, sensitivity analysis was conducted with a perturbation of PK parameters to predict different scenarios of intratumoral MTX transport. The relevant physiological PK parameters from the mouse model were then scaled-up and utilized to simulate human tumor concentrations. RESULTS: The mouse hPBPK model adequately characterized the concentration-time profiles of MTX in both plasma and tumor and produced various transfer rate constants between plasma and tumor. Our model was also able to reasonably predict MTX concentrations in the human tumor when human physiological data were utilized. CONCLUSIONS: The hPBPK model was able to quantitatively characterize the atypical transport of MTX in the tumor, supporting the idea that microdialysis is a valuable tool to study tumor biodistribution of drugs and to predict tumor concentrations in humans based on the pre-clinical data. This information can ultimately aid in the development of anticancer drugs with improved PK profiles. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Spike sorting for large, dense electrode arrays.

Developments in microfabrication technology have enabled the production of neural electrode arrays with hundreds of closely spaced recording sites, and electrodes with thousands of sites are under development. These probes in principle allow the simultaneous recording of very large numbers of neurons. However, use of this technology requires the development of techniques for decoding the spike times of the recorded neurons from the raw data captured from the probes. Here we present a set of tools to solve this problem, implemented in a suite of practical, user-friendly, open-source software. We validate these methods on data from the cortex, hippocampus and thalamus of rat, mouse, macaque and marmoset, demonstrating error rates as low as 5%.

High-dimensional cluster analysis with the masked EM algorithm.

Cluster analysis faces two problems in high dimensions: the "curse of dimensionality" that can lead to overfitting and poor generalization performance and the sheer time taken for conventional algorithms to process large amounts of high-dimensional data. We describe a solution to these problems, designed for the application of spike sorting for next-generation, high-channel-count neural probes. In this problem, only a small subset of features provides information about the cluster membership of any one data vector, but this informative feature subset is not the same for all data points, rendering classical feature selection ineffective. We introduce a "masked EM" algorithm that allows accurate and time-efficient clustering of up to millions of points in thousands of dimensions. We demonstrate its applicability to synthetic data and to real-world high-channel-count spike sorting data.

The effects of drug transporter inhibitors on the pharmacokinetics and tissue distribution of methotrexate in normal and tumor-bearing mice: a microdialysis study.

PURPOSE: To examine methotrexate (MTX) tumor delivery in a mouse model using an in vivo microdialysis technique and to characterize the impact of prior administration of the known transporter inhibitors probenecid and cyclosporine (CsA), alone and in combination, on plasma and tumor pharmacokinetics of MTX. METHODS: Different groups of mice were used to evaluate the plasma pharmacokinetics of MTX and the impact of prior administration of probenecid and/or CsA on the plasma pharmacokinetics. Xenografted nude mice were used for microdialysis experiments to measure the subcutaneous (SC), peri- and intratumoral pharmacokinetics of MTX without and with coadministration of probenecid, CsA, and both probenecid and CsA. RESULTS: The SC dialysates in pre-treated groups demonstrated a delayed disappearance and an enhanced MTX exposure. Similar effects were observed in the tumor peripheral zone. However, this increase was less pronounced. The central tumor findings demonstrated that CsA had a more significant impact on the enhancement of MTX exposure. Probenecid did not increase the exposure of MTX inside the tumor, but caused a longer half-life of central MTX. CONCLUSIONS: This study revealed significant differences in the relative estimated PK parameters of the plasma, SC, peri-, and intratumoral zones. Additionally, this study demonstrated that the coadministration of MTX with CsA can enhance the intratumoral exposure levels of the drug, whereas coadministration of MTX with probenecid alone, or with a combination of probenecid and CsA, increases intratumoral half-life.

Effect of microfluidization parameters on the physical properties of PEG-PLGA nanoparticles prepared using high pressure microfluidization.

The objective of this work was to develop uniformly distributed poly(ethylene glycol) grafted poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles of mean size range approximately 100-200 nm using ethyl acetate as the solvent. In the multiple emulsion solvent evaporation method a high pressure microfluidization process was adopted to produce the W/O/W multiple emulsion. Non-toxic ethyl acetate was used to solubilize PEG-PLGA. The mean size of nanoparticles obtained was less than 180 nm. The particle size and size distribution were dependent on the microfluidization conditions applied. Mean particle size steadily increased from 121 nm at three passes to 172 nm at 20 passes of the microfluidizer, indicating that over-processing may be detrimental to PEG-PLGA nanoparticles prepared using this technique. There was no significant alteration of the PEG-PLGA matrix, as evidenced from the differential scanning calorimetric studies.