Neurophysiology of prehension. I. Posterior parietal cortex and object-oriented hand behaviors

Hand manipulation neurons in areas 5 and 7b/anterior intraparietal area (AIP) of posterior parietal cortex were analyzed in three macaque monkeys during a trained prehension task. Digital video recordings of hand kinematics synchronized to neuronal spike trains were used to correlate firing rates of 128 neurons with hand actions as the animals grasped and lifted rectangular and round objects. We distinguished seven task stages: approach, contact, grasp, lift, hold, lower, and relax. Posterior parietal cortex (PPC) firing rates were highest during object acquisition; 88% of task-related area 5 neurons and 77% in AIP/7b fired maximally during stages 1, 2, or 3. Firing rates rose 200-500 ms before contact, peaked at contact, and declined after grasp was secured. 83% of area 5 neurons and 72% in AIP/7b showed significant increases in mean rates during approach as the fingers were preshaped for grasp. Somatosensory signals at contact provided feedback concerning the accuracy of reach and helped guide the hand to grasp sites. In error trials, tactile information was used to abort grasp, or to initiate corrective actions to achieve task goals. Firing rates declined as lift began. 41% of area 5 neurons and 38% in AIP/7b were inhibited during holding, and returned to baseline when grasp was relaxed. Anatomical connections suggest that area 5 provides somesthetic information to circuits linking AIP/7b to frontal motor areas involved in grasping. Area 5 may also participate in sensorimotor transformations coordinating reach and grasp behaviors and provide on-line feedback needed for goal-directed hand movements.     

Interleukin-6 mediates neutrophil mobilization from bone marrow in pulmonary hypertension

Myeloid cells, such as neutrophils, are produced in the bone marrow in high quantities and are important in the pathogenesis of vascular diseases such as pulmonary hypertension (PH). Although neutrophil recruitment into sites of inflammation has been well studied, the mechanisms of neutrophil egress from the bone marrow are not well understood. Using computational flow cytometry, we observed increased neutrophils in the lungs of patients and mice with PH. Moreover, we found elevated levels of IL-6 in the blood and lungs of patients and mice with PH. We observed that transgenic mice overexpressing Il-6 in the lungs displayed elevated neutrophil egress from the bone marrow and exaggerated neutrophil recruitment to the lungs, resulting in exacerbated pulmonary vascular remodeling, and dysfunctional hemodynamics. Mechanistically, we found that IL-6-induced neutrophil egress from the bone marrow was dependent on interferon regulatory factor 4 (IRF-4)-mediated CX₃CR1 expression in neutrophils. Consequently, Cx₃cr1 genetic deficiency in hematopoietic cells in Il-6-transgenic mice significantly reduced neutrophil egress from bone marrow and decreased neutrophil counts in the lungs, thus ameliorating pulmonary remodeling and hemodynamics. In summary, these findings define a novel mechanism of IL-6-induced neutrophil egress from the bone marrow and reveal a new therapeutic target to curtail neutrophil-mediated inflammation in pulmonary vascular disease.     

Path-length-resolved measurements of multiple scattered photons in static and dynamic turbid media using phase-modulated low-coherence interferometry

In optical Doppler measurements, the path length of the light is unknown. To facilitate quantitative measurements, we develop a phase-modulated Mach-Zehnder interferometer with separate fibers for illumination and detection. With this setup, path-length-resolved dynamic light scattering measurements of multiple scattered light in static and dynamic turbid media are performed. Optical path length distributions spanning a range from 0 to 11 mm are measured from the area under the phase modulation peak around the modulation frequency in the power spectrum. A Doppler-broadened phase modulation interference peak is observed that shows an increase in the average Doppler shift with optical path length, independent of absorption. Validation of the estimated path length distributions is done by measuring their deformation for increasing absorption and comparing these observations with predictions based on Lambert-Beer's law.     

Surgical management of multivalvular heart disease

Background This study of patients with multivalvular lesions was undertaken to assess optimal surgical management and identify risk factors for prognosis. Methods Five hundred and twenty one patients underwent valve repair or replacement surgery between January’90 and December’98. Mean age was 30.19±12.2 years and 342 were males. All patients had dyspnoea on exertion, 467 (89.6%) were in New York Heart Association (NYHA) Class III and 47 (9.0%) were in Class IV. Congestive Heart Failure in 67 (12.3%) and prior cardiac procedure in 66 (12.2%) were other risk factors. The valves affected were mitral and aortic in 483 (Group 1), mitral and tricuspid in 43 (Group II) and mitral, aortic and tricuspid in 40 (Group III) patients. Surgical procedures included, several different combinations using repair or replacement with prosthetic or biological substitutes. Results Operative mortality was 9.8% (51 patients). Follow up (1 to 108 months, mean 45 months) was 94% complete. Late mortality occurred in 48 patients (10.4%). Causes included, left ventricular dysfunction (n=21), valve thrombosis (n=10) and, endocarditis (n=8). Freedom from late events was 50.7±8.5% at 9 years. At their last visit 40 patients were in Class IV, 18 were in Class III, 59 in Class II and the remaining in Class I (NYHA). Conclusions Important predictors of early mortality were NYHA Class IV, congestive heart failure, tricuspid valve disease and prior cardiac surgery. Left ventricular dysfunction was an important determinant of late outcome.     

Maxillofacial Injuries in Counter Proxy War Posture of the Armed Forces

Background

Various maxillofacial injuries, sustained in counter insurgency operations in the counter proxy war posture (CPWP) of the Armed Forces in the Kashmir valley are being treated at various maxillofacial surgical centres.

Method

Proper triage, documentation of injuries and mode of injuries along with various clinical, radiological and other investigations were carried out before operating these individuals for primary reconstruction of skeletal tissue and facial soft tissue.

Result

A total of 324 persons with various types of maxillofacial injuries were treated within the period ranging from 01 January 2000 to 30 June 2002 successfully in this centre as a part of the advanced trauma life support (ATLS) system of Combat Medical Support.

Conclusion

Proper primary reconstruction (soft tissue and skeletal tissue) of the facial region goes a long way in reducing subsequent disfigurement and morbidity. Improving the structural design of the combat head gear for safety and comfort will go a long way in preventing majority of maxillofacial injuries or can at least reduce the severity of these injuries.Key Words: Battle accident, Battle casualties, Counter proxy war posture, Maxillofacial injuries     

Increased dissolution rate and bioavailability through comicronization with microcrystalline cellulose

Micronization is a commonly used enabling technology to improve the bioavailability of compounds where absorption is dissolution rate limited. However, decreasing particle size often results in increased Van der Waals' interactions and electrostatic attraction between particles. This causes agglomeration of particles, thereby compromising the increase in surface area gained by micronization. Comicronization with excipients has been reported to offer significant advantages over neat micronization. The present work describes the comicronization of a model compound CI-1040 at a high drug load that shows an increase in the dissolution rate and bioavailability in male Wistar rats. Physicochemical characterization of the comicronized and neat micronized material is presented to help explain the in-vitro and in-vivo data.     

In vivo pharmacokinetic and tissue distribution studies in mice of alternative formulations for local and systemic delivery of Paclitaxel: gel, film, prodrug, liposomes and micelles

The aim of this study was to increase the understanding on the pharmacokinetic and tissue distribution of paclitaxel as influenced by formulation approach. For this purpose, various formulations investigated in Swiss mice included liposomes, poloxamer 407 gel and chitosan film for subcutaneous route; and water-soluble methacrylate prodrug, liposomes and poloxamer micelles for systemic administration. During this study, the currently marketed formulation of Cremophor EL of paclitaxel was used as the reference. A highest plasma concentration following intravenous administration of paclitaxel was observed for rigid and 'Stealth((R))' liposomes containing the prodrug while, least was for covalently incorporated paclitaxel micelles. Further, poloxamer micelles demonstrated both the highest mean residence time of 7.34 h and volume of distribution (VSS=4.82 and VZ=5.87 L/kg) for paclitaxel. This was followed by prodrug loaded 'Stealth' liposomes, which showed a mean residence time of 4.96 h but were least distributed into apparent physiological volume (VSS=2.12 and VZ=3.16 L/kg). These results clearly signify the role of formulation/excipient in drug disposition and possible interactions. Importantly, due to decrease in the clearance rate of drug, the area under curve values of paclitaxel increased by 1.64- and 2.5-fold for micellar and prodrug loaded 'Stealth' liposomal formulations, respectively over reference formulation. While thermoreversible gels served to decrease plasma concentration of paclitaxel (8-fold) after subcutaneous administration, systemic levels were totally absent after implantation of films. In tissue distribution studies, maximum percent of paclitaxel was observed in liver for reference formulation, conventional liposomes and micelles whereas highest levels of prodrug and 'Stealth((R))' liposomes were in kidney and spleen, respectively. The novel formulations significantly altered tissue accumulation profiles of paclitaxel relative to the reference formulation, for example, reduction in uptake by heart from liposomes and micelles, as well as the major recognition mechanism for elimination. It is proposed that a combination therapy with liposomes and micelles of paclitaxel for systemic delivery along with implantation of chitosan film for local delivery, may serve not only to improve patient compliance by obliterating the need to administer Cremophor EL, but also increase patient survival.     

Design, Synthesis and Evaluation of Trisubstituted Thiazoles Targeting Plasmodium Falciparum Cysteine Proteases

The Plasmodium falciparum cysteine proteases, falcipains, have been established as novel targets for antimalarial drug design. Using the de novo design approach, several trisubstituted thiazole analogs were generated as potential inhibitors of these enzymes. A general and convenient synthetic approach for these novel trisubstituted thiazoles is reported here. Substituents at the 4^th and 5^th positions of the target thiazoles were introduced by a Hantzsch reaction, and the chain at the second position was extended through a Sandmeyer reaction, formylation, and Wittig olefination. In vitro enzyme inhibition studies have identified three inhibitors (14, 16, 23) of the falcipains with one (14) showing dual activity against both falcipain-2 and falcipain-3 and IC₅₀ values of 6.6 and 29.4 μM, respectively.     

Skin targeted DNA vaccine delivery using electroporation in rabbits. I: efficacy

Genetic immunization through skin is highly desirable as skin has plenty of antigen presenting cells (APCs) and is easily accessible. The purpose of this study was to investigate the effects of electroporation pulse amplitude, pulse length and number of pulses on cutaneous plasmid DNA vaccine delivery and immune responses, following intradermal injection in vivo in rabbits. Expression of the delivered plasmid was studied using a reporter plasmid, coding for beta-galactosidase. The efficiency of DNA vaccine delivery was investigated using a DNA vaccine against Hepatitis B, coding for Hepatitis B surface antigen (HBsAg). Serum samples and peripheral blood mononuclear cells (PBMC) were analyzed for humoral and cellular immunity, respectively, following immunization. The expression of transgene in the skin was transient and reached its peak in 2 days post-delivery with 200 and 300 V pulses. The expression levels with 200 and 300 V pulses were 48- and 129-fold higher, respectively, compared with the passive on day 2. In situ histochemical staining of skin with X-gal demonstrated the localized expression of beta-galactosidase with electroporation pulses of 200 and 300 V. Electroporation mediated cutaneous DNA vaccine delivery significantly enhanced both humoral and cellular immune responses (p<0.05) to Hepatitis B compared to passive delivery. The present study demonstrates the enhanced DNA vaccine delivery to skin and immune responses by topical electroporation. Hence, electroporation mediated cutaneous DNA vaccine delivery could be developed as a potential alternative for DNA vaccine delivery.     

Markers for differentiation of tubercular pleural effusion from non-tubercular effusion

Background

The limitations of the conventional methods for diagnosing tuberculosis (TB) have spurred multi-faceted research activities throughout the world. This study aims to explore the levels of adenosine deaminase (ADA) and interleukins in pleural effusion of tuberculous, malignant, and miscellaneous origin for differential diagnosis of tubercular and non-tubercular effusion.

Method

Adenosine deaminase was estimated by kinetic method employing xanthine oxidase while interleukins were measured using commercially available ELISA kits in pleural fluids of tubercular and non-tubercular origin.

Results

Pleural fluids INF-γ, sIL-2R, TNF-α and ADA were significantly higher in TB group (n = 48) as compared to the non-TB group (n = 33) (mean ± SD: INF-γ; 1,958.7 ± 896.5 pg/mL vs 356.9 ± 733.6 pg/mL, sIL-2R; 6,101 ± 1,753.8 pg/mL vs 3,166 ± 2,611.1 ± pg/mL, TNF-α; 195.5 ± 292.1 pg/mL vs 59.7 ± 128.9 pg/mL, ADA; 123.6 ± 81.8 IU/L vs 48 ± 48.5 IU/L, P < 0.01).

Conclusion

INF-(is more sensitive and specific than ADA for the diagnosis of TB and should be added to the armamentarium of the diagnostic workup of pleural fluids for timely and accurate diagnosis of TB and differentiation of tubercular pleural effusion from non-tubercular effusion.