Vascular endothelial growth factor as a marker of disease activity in neurotuberculosis

Vascular endothelial growth factor (VEGF) is a potent angiogenesis mediator. Scant reports are available defining the role of VEGF in active and inactive tubercular meningitis (TBM) with no studies on brain tuberculoma. We quantified VEGF levels by enzyme linked immunoassay (ELISA) in cerebrospinal fluid (CSF) and serum in 20 cases each with active and inactive TBM as well as 22 cases of intraparenchymal tuberculoma. VEGF expression and microvessel angiogenesis quantification was done in 7 cases where tuberculomas were excised. Significantly increased VEGF levels in CSF were found in active TBM cases (106.0+/-50.0 pg/ml) compared to inactive TBM cases (14.7+/-10.0 pg/ml) (p<0.001). Mean serum VEGF levels in active TBM, inactive TBM and tuberculoma were 694.93+/-820.66 pg/ml, 499.61+/-238.33 pg/ml and 541.0+/-389.0 pg/ml, respectively. Immunohistochemical staining of excised tuberculoma demonstrated high expression of VEGF in granulomatous areas with intense positivity in inflammatory mononuclear cells, Langhan's giant cells as well as reactive astrocytes and fibrocytes. A strong positive correlation was observed between microvessel density and VEGF expression. Serial decrease in serum VEGF levels was observed with increasing duration of therapy in tuberculoma. We conclude that increased CSF and serum VEGF levels are a measure of activity of the disease in neurotuberculosis and its gradual decrease over a period of time is probably an indicator of therapeutic response.     

Role of Animal Danders as Inhalant Allergens in Bronchial Asthma in India

The etiological significance of animal danders in Indian patients with nasobronchial disorders has not yet been investigated. In the present study, the role of animal danders in the etiology of bronchial asthma was studied. Extracts of danders from 6 animals along with guinea pig whole pelt were prepared. Intradermal and bronchial provocation tests with these extracts were performed on (i) 68 asthmatics and (ii) 20 nonallergic healthy volunteers. In patients, significant positive skin reactions (2+ to 4+) ranged from 1.4% each with guinea pig whole pelt and ox dander to 8.8% with dog dander extracts. None of the healthy volunteers elicited such a response. On bronchial provocation, 20% and 53.8% of the tests were positive in asthmatics showing 1 +and 2+skin reactivity, respectively. All the patients as well as controls eliciting negative intradermal responses demonstrated uniformly negative bronchial provocation tests to different dander extracts. Analysis of various clinical features of asthmatics with respect to skin positivity to dander/pelt extract was also carried out. Radioallergosorbent tests (RASTs) were performed to estimate dander-specific IgE levels in the sera of patients showing different grades of skin response to dander extracts of dog, horse, and goat. Sixty percent of sera from the patients showing 2+ to 4+ skin reactivity to various animal dander extracts showed positive RASTs. RAST positivity as well as RAST ratio increased with increase in the intensity of skin response. All the patients with positive cutaneous as well as positive bronchial responses also showed positive RASTs. Similarly, all the patients with positive skin and positive RASTs showed positive bronchoprovocation tests. These results suggested that animal danders play an important role in the etiology of bronchial asthma. Some of the clinical characteristics of asthmatics, such as (i) early age at onset of asthma, (ii) positive family history, and (iii) asthma with associated allergies, have significant bearing on the cutaneous response to various dander extracts.     

A 2-D/3-D model-based method to quantify the complexity of microvasculature imaged by in vivo multiphoton microscopy

This paper presents model-based information-theoretic methods to quantify the complexity of tumor microvasculature, taking into account shape, textural, and structural irregularities. The proposed techniques are completely automated, and are applicable to optical slices (3-D) or projection images (2-D). Improvements upon the prior literature include: (i) measuring local (vessel segment) as well as global (entire image) vascular complexity without requiring explicit segmentation or tracing; (ii) focusing on the vessel boundaries in the complexity estimate; and (iii) added robustness to image artifacts common to tumor microvasculature images. Vessels are modeled using a family of super-Gaussian functions that are based on the superquadric modeling primitive common in computer vision. The superquadric generalizes a simple ellipsoid by including shape parameters that allow it to approximate a cylinder with elliptical cross-sections (generalized cylinder). The super-Gaussian is obtained by composing a superquadric with an exponential function giving a form that is similar to a standard Gaussian function but with the ability to produce level sets that approximate generalized cylinders. Importantly, the super-Gaussian is continuous and differentiable so it can be fit to image data using robust non-linear regression. This fitting enables quantification of the intrinsic complexity of vessel data vis-a-vis the super-Gaussian model within a minimum message length (MML) framework. The resulting measures are expressed in units of information (bits). Synthetic and real-data examples are provided to illustrate the proposed measures.     

Platelet glycoprotein IIb/IIIa inhibition using eptifibatide with primary coronary stenting for acute myocardial infarction: a 30-day follow-up study.

The results of primary coronary stenting for acute myocardial infarction (AMI) have been reported to improve significantly with the concomitant administration of platelet glycoprotein IIb/IIIa inhibitor abciximab. There are, however, no data available with the use of eptifibatide, a more cost-effective, small-molecule GP IIb/IIIa blocker with a shorter half-life. In a prospective multicenter feasibility and efficacy study, we assigned 55 consecutive patients with AMI being taken up for primary stenting to receive eptifibatide just before the procedure (two boluses of 180 microg/kg 10 min apart and a 24-hr infusion of 2 microg/kg/min). Clinical outcomes were evaluated at 30 days after the procedure. The angiographic patency of the vessel with TIMI flow rates, TIMI myocardial perfusion (TMP) grade, and corrected TIMI frame counts were assessed at the end of procedure and before hospital discharge. At 30 days, the primary endpoint, a composite of death, myocardial infarction, and urgent target vessel revascularization (TVR) was seen in 12.7% of patients. The TIMI 3 and TMP grade 3 flow, which was seen in 93% and 86% of patient, respectively, at the end of the procedure, declined to 86% and 78%, respectively (P < 0.05) before hospital discharge. Corrected TIMI frame counts also decreased from 25.7 +/- 7.2 to 22.9 +/- 6.8 (P < 0.05). There were five (9.1%) instances of subacute thrombosis (SAT) presenting as AMI, needing urgent TVR in all, within 3-5 days of the primary procedure. No excessive bleeding complication, directly attributable to the use of eptifibatide, was observed. The study was terminated prematurely because of an unacceptable SAT rate. Administration of eptifibatide along with primary stenting for AMI is associated with a high TIMI 3 and TMP grade 3 flow acutely. However, these flows decline significantly before hospital discharge and lead to a high rate of SAT. The dosage and duration of infusion of eptifibatide in this setting needs further evaluation.     

Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design,characterization, in vitro and in vivo evaluation

Abstract

Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50?nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher (p?<?0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC_0–24) of NRG from SNEDDS formulation revealed a significant increase (p?<?0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS.     

Superiority of Higher-Volume Fresh Feces Compared to Lower-Volume Frozen Feces in Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Colitis

Digestive Diseases and Sciences - To compare the clinical outcomes of different protocols for fecal microbiota transplantation (FMT) in two community hospitals with similar patient demographics....     

Antibody Drug Conjugates: Nonclinical Safety Considerations

Antibody drug conjugates (ADCs) are biopharmaceutical molecules consisting of a cytotoxic small molecule covalently linked to a targeted protein carrier via a stable cleavable or noncleavable linker. The process of conjugation yields a highly complex molecule with biochemical properties that are distinct from those of the unconjugated components. The impact of these biochemical differences on the safety and pharmacokinetic (PK) profile of the conjugate must be considered when determining the types of nonclinical safety studies required to support clinical development of ADCs. The hybrid nature of ADCs highlights the need for a science-based approach to safety assessment that incorporates relevant aspects of small and large molecule testing paradigms. This thinking is reflected in current regulatory guidelines, where sections pertaining to conjugates allow for a flexible approach to nonclinical safety testing. The aim of this article is to review regulatory expectations regarding early assessment of nonclinical safety considerations and discuss how recent advances in our understanding of ADC-mediated toxicity can be used to guide the types of nonclinical safety studies needed to support ADC clinical development. The review will also explore nonclinical testing strategies that can be used to streamline ADC development by assessing the safety and efficacy of next generation ADC constructs using a rodent screen approach.KEY WORDS: antibody drug conjugates, regulatory guidance, safety assessment, therapeutic index