Reshaping Movement Distributions With Limit-Push Robotic Training.

High-cost situations need to be avoided. However, occasionally, cost may only be learned by experience. Here, we tested whether an artificially induced unstable and invisible high-cost region, a "limit-push" force field, might reshape people's motion distributions. Healthy and neurologically impaired (chronic stroke) populations attempted 600 interceptions of a projectile while holding a robot handle that could render forces to the hand. The "limit-push," in the middle of the study, pushed the hand outward unless the hand stayed within a box-shaped region. Both healthy and some stroke survivors adapted through selection of safer actions, avoiding the high-cost regions (outside the box); they stayed more inside and even kept a greater distance from the box's boundaries. This was supported by other measures that showed subjects distributed their hand movements within the box more uniformly. These effects lasted a very short time after returning to the no-force condition. Although most robotic teaching approaches focus on shifting the mean, this limit-push treatment demonstrates how both mean and variance might be reshaped in motor training and neurorehabilitation.

Dissociating two sources of variability using a safety-margin model.

Neurological trauma can have a devastating effect on activities of daily living. One of the consequences is an increased amount of variability in the system, which can challenge individuals to stay within safe and stable regions of operation. There are multiple sources of movement variability; two of these are neuromotor noise and action-tolerance variability. The amount of neuromotor noise that is uncontrollable can impose limitations on reshaping variability. Action-tolerance variability, which can be reshaped through experience, and neuromotor noise, a certain amount of which cannot be altered, are often conflated when discussing motor variability. We attempted to disambiguate the two using an adaptive model, producing distinct "signatures" of neuromotor noise and action-tolerance variability within a task and compare with experimental data on stroke and healthy. Not all stroke survivors could adapt to the task, as predicted for those with greater neuromotor noise. Possible applications of this model can inform us of potential to influence distributions in stroke survivors and other individuals who have had a neurological injury. Additionally, we could design new training environments specifically tailored to the needs of the individual. This technique may also help disambiguate the type of brain injury suffered by stroke survivors.

The super thin external pudendal artery (STEPA) flap.

BACKGROUND: The need for improved microsurgical reconstructive techniques is ongoing given the "ideal" free flap still does not exist. When reconstruction requires a thin flap, options have remained limited and flaps with minimal donor site morbidity that do not require secondary de-bulking have been elusive thus far. The importance of a thin and supple flap cannot be understated when dealing with challenging cases such as the dorsum of the hand or foot. This also applies to other areas such as the head and neck and over the large joints of the knee and elbow. The authors propose a previously un-described free tissue transfer based on the external pudendal artery that fulfills many of the aforementioned goals. An anatomical cadaveric study has been performed describing the super thin external pudendal artery (STEPA) flap. METHODS: Six fresh cadavers were used in the raising of eight hemiscrotal flaps and two bipedicled scrotal flaps based on the external pudendal vessels. 2 hemipelvises underwent cannulation of the external pudendal artery followed by injection of a barium sulphate/gelatin mixture and three-dimensional computed tomographic angiography to evaluate vascular anatomy. Colored-latex was injected into two raised hemiscrotal flaps. Measurements were made on the cadaveric dissections and on a computed tomography workstation. RESULTS: The average external diameter of the external pudendal artery measured 2.81 mm at its origin from the femoral artery, the vein 4.44 mm. The mean pedicle length measured 11 cm (range, 10-12 cm). The mean thickness of the flap measured 1.1 mm. CONCLUSIONS: A new free flap, the STEPA flap, has been described that is the thinnest myocutaneous free flap with over 80% of the thickness of the flap less than 1.1 mm. It has been demonstrated to have reliable anatomy with more than adequate vessel caliber. It has a large surface area and a generous pedicle length for free tissue transfer. Donor site morbidity is favorable. It is accepted that there may be cosmetic issues regarding flap pigmentation and a variable degree of hair in patients where the reconstruction is visible. We would contend that there exist many successful techniques which address pigmentation and depilation, and that this trade-off is acceptable given the functionality and characteristics of this uniquely thin flap. It has the potential to be used in many clinical scenarios where thin supple reconstruction is a high priority.

Factors affecting solubilization of a poorly soluble novel tubulin-binding agent.

JCA112 is a novel tubulin-binding agent with limited aqueous solubility and high hydrophobicity. Three strategies; cyclodextrin inclusion complexation, solid dispersion (SD) formation, and liposome incorporation were evaluated to enhance the solubility of JCA112. Phase-solubility studies were carried out with hydroxypropyl ß-cyclodextrin (HPßCD), SDs were prepared by solvent evaporation method and liposomes were prepared by thin-film hydration method. Saturation solubility of the prepared formulations resulted in a significant increase in the solubility of JCA112 by all three methods. Cyclodextrin complexation resulted in a higher order complex formation increasing the aqueous solubility by 30-fold up to 105 µg/mL. Amongst the selected polymers, Poloxamer 188 (Pluronic(®) F68) was the most effective polymer in enhancing the aqueous solubility via SD, resulting in an equilibrium solubility of 50 µg/mL, independent of the drug loading. Liposomes were the most effective amongst all three techniques, with a saturation solubility of 1.8 mg/mL contributing to greater than 500-fold increase in the solubility of JCA112. The solubility enhancement by liposome was directly proportional to the drug loading. All the three strategies were successful in enhancing the solubility of the drug. Solubility enhancement by the three techniques can be attributed to the geometry/structure and the lipophilicity of the drug.

Physico chemical characterization of a novel anti-cancer agent and its comparison to Taxol(®).

Every year several thousand compounds are screened for their anti-cancer activity by a general test procedure amongst which only few selected move past the in vitro screening process. This may be due to the intrinsic property of the drug substance. Therefore, a complete physicochemical characterization of a New Chemical Entity (NCE) is essential to understand the effect of these properties on the in vitro and possibly in vivo behavior of these compounds. Various physicochemical properties such as dissociation constant, octanol-water partition co-efficient, pH solubility, stability, thermal characterization and membrane permeability were evaluated for a novel tubulin-binding agent JCA112 and were compared to that of Taxol(®). The drug exhibited a pKa value of 10.9, log P value of 2.3, pH dependent solubility, and low artificial membrane permeability. Stability of the drug substance in the in vitro screening media suggested a significant degradation during the 48-hour study duration. The results demonstrate that due to low aqueous solubility, limited membrane permeability and due to insufficient stability of JCA112 in the in vitro screening media, the drug exhibited limited anti-cancer activity. Along with challenging physicochemical characteristics, a generalization of the in vitro testing procedure may also result in loss of important anti-cancer agents. As a result, a complete understanding of the physico-chemical properties of the drug leading to prototype formulation with acceptable physico-chemical properties may be required for successful in vitro screening.

A large thumb mass.

A 31-year-old man presented with a 5-year history of a spontaneously occurring soft tissue mass on the palmar aspect of his left non dominant thumb. Over 5 months he was having progressive difficulty flexing at the interphalangeal joint. Magnetic resonance imaging demonstrated an heterogeneously enhancing soft tissue mass likely to be either a peripheral fibromatosis or giant cell tumour of the flexor tendon (Figure 1). Intraoperatively a large neuroma in continuity with the ulnar digital nerve was found and debulked (Figure 2). The diagnosis was confirmed histologically.

Recent advances and novel strategies in pre-clinical formulation development: an overview.

Preclinical profiling for a New Chemical Entity (NCE), if carried out carefully, can be a good predictor of human clinical outcome. Along with the pre-clinical study design a thorough understanding of the physico-chemical properties of the drug candidate and a careful selection of the formulation development strategy are of high importance. The study scientist can experience various challenges in executing a pre-clinical study. This review article provides an overview of the significance of pre-formulation study parameters and their relevance to preclinical studies. Various physico-chemical properties such as solubility, partition co-efficient, and permeability are attributes critical to the performance of the drug substance. This article presents unique formulation development strategies for the successful completion of pre-clinical studies. Formulation development approach for a pre-clinical study involves taking into consideration various important factors such as duration of the study, Biopharmaceutics Classification System (BCS) of the drug, intended duration of action and the desired route of administration. These parameters play key role in the selection of solubilizers, surfactants, co-solvents and optimum pH for the formulation. Two most common routes of administration in the early screening of pharmaceuticals viz., oral and intravenous are emphasized. The article also describes recent advances in preclinical formulation development including selected examples of in vivo preclinical models for anti-cancer, anti-viral, anti-diabetic and anti-hypertensive drugs. Adherence to the regulatory requirement is also the key to successful completion of the preclinical development. An overview of preclinical formulation development along with basic concepts and the recent studies conducted in the past decade are presented in this review.

Sinus pericranii--"Don't judge a lump by its surface".

An interesting and unusual vascular malformation, sinus pericranii is presented. Originally referred as a cyst, a "community conundrum" was solved and treated successfully in the hospital setting. A discussion of sinus pericranii follows, and the teaching values of this particular case are highlighted.

Intravascular papillary endothelial hyperplasia (Masson's tumour) causing a soft-tissue mass in the upper limb.

Masson's tumour (intravascular papillary endothelial hyperplasia) is a benign vascular tumour, which can present in a similar manner to a soft-tissue sarcoma. Rapid differentiation between these two differing pathologies is the most important part of the initial management of this problem. We report a case of Masson's tumour presenting in a 32-year-old woman as a painful lump around her elbow.

Aortic elongation induced aortic stenosis (AEAS).

We present a case of a 71-year-old man who presented with aortic stenosis. This was pseudo-aortic obstruction resulting from the mitral valve subvalvular apparatus impacting into a normal aortic valve as a result of elongation of the ascending aorta. To place this case in context, we also provide a review of left ventricular outflow obstruction with an emphasis on subvalvular stenosis.