Enhanced Oral Bioavailability of Griseofulvin via Niosomes

The aim of the present report was to develop nonionic surfactant vesicles (niosomes) to improve poor and variable oral bioavailability of griseofulvin. Niosomes were prepared by using different nonionic surfactants span 20, span 40, and span 60. The lipid mixture consisted of surfactant, cholesterol, and dicetyl phosphate in the molar ratio of 125:25:1.5, 100:50:1.5, and 75:75:1.5, respectively. The niosomal formulations were prepared by thin film method and ether injection method. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for size distribution and entrapment efficiency for both methods. Result indicated that the niosomes prepared by thin film method with span 60 provided higher entrapment efficiency. The niosomal formulation exhibited significantly retarded in vitro release as compared with free drug. The in vivo study revealed that the niosomal dispersion significantly improved the oral bioavailability of griseofulvin in albino rats after a single oral dose. The maximum concentration (C _max) achieved in case of niosomal formulation was approximately double (2.98 μg/ml) as compared to free drug (1.54 μg/ml). Plasma drug profile also suggested that the developed niosomal system also has the potential of maintaining therapeutic level of griseofulvin for a longer period of time as compared to free griseofulvin. The niosomal formulation showed significant increase in area under the curve_0-24 (AUC; 41.56 μg/ml h) as compared to free griseofulvin (22.36 μg/ml h) reflecting sustained release characteristics. In conclusion, the niosomal formulation could be one of the promising delivery system for griseofulvin with improved oral bioavailability and prolonged drug release profiles.     

Mechanism of cellulase reaction on pure cellulosic substrates

Cellulase reaction mechanism was investigated with the use of following pure cellulosic substrates: Microcrystalline cellulose (Avicel), α‐cellulose (Sigma), filter paper, cotton, and non‐crystalline cellulose (NCC). NCC is amorphous cellulose prepared in our laboratory by treatment with concentrated sulfuric acid. When hydrolyzed with cellulase, NCC produces significant amount of cello‐oligosaccharides (COS) as reaction intermediates along with glucose and cellobiose. The COS produced by cellulase were categorized into two different moieties based upon their degree of polymerization (DP): low DP (less than 7) COS (LD‐COS) and high DP COS (HD‐COS). Endo‐glucanase (Endo‐G) reacts rapidly on the NCC reducing its DP to 30–60, after which the Endo‐G reaction with NCC ceases. HD‐COS is produced from NCC by the action of Endo‐G, whereas LD‐COS is produced by exo‐glucanase (Exo‐G). β‐Glucosidase (β‐G) hydrolyzes LD‐COS to produce cellobiose, but it does not hydrolyze HD‐COS. DP of NCC affects the action of Exo‐G in such a way that the overall yield is high for high DP NCC. This is in line with previous findings that substrate‐recognition by Exo‐G requires binding on β‐glucan chain with DP of 10 for the hydrolysis to take place. The individual cellulose chain residues within solid having DP less than 10 therefore remain unreacted. The percentage of the unreacted portion would be lower for high DP NCC, which results high overall conversion. The surface area and the number of reactive sites on the substrate facilitate adsorption of enzyme therefore the initial rate of the hydrolysis. The overall extent of conversion of cellulose, however, is controlled primarily by its inherent characteristics such as DP and crystallinity. Biotechnol. Bioeng. 2009;102: 1570–1581. © 2008 Wiley Periodicals, Inc.     

Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146

CD146, also known as melanoma cell adhesion molecule or MCAM, is a key cell adhesion protein in vascular endothelial cell activity and angiogenesis. CD146 promotes tumor progression of many cancers including melanoma and prostate. Strikingly, its expression is frequently lost in breast carcinoma cells, and it may act as a suppressor of breast cancer progression. While upstream mechanisms regulating CD146 are well documented, our understanding of the downstream molecular events underlying its mode of action remains to be elucidated. This review aims to focus on the progress in understanding the signaling mechanisms and the functional relevance of CD146, a multifaceted molecule, in cancer with particular emphasis on its role in inhibiting breast cancer progression.     

Polymorphism of cytokine and innate immunity genes associated with bovine brucellosis in cattle

Genetic susceptibility to brucellosis is multifactorial, and it is known that impairment of the immune system could contribute to risk for getting brucellosis. The aim of the study was to find association of bovine brucellosis with 20 SNPs pertaining to bovine cytokine (IFNG, IFNGR1, IFNGR2, TNFA) and innate immunity (SLC11A1, TLR1, TLR4, and TLR9) genes using PCR-RFLP genotyping technique and it was observed that SLC11A1 (+1066 C/G), TLR1 (+1446 C/A), TLR1 (+1380 G/A), TLR4 (+10 C/T) and TLR4 (+399 C/T) loci were significantly (P ≤ 0.05) associated with bovine brucellosis. The odds ratios (OR) of CG and CC genotypes versus GG genotype were 0.31 (0.12–0.82; 95 % CI) and 0.18 (0.03–1.06; 95 % CI) at SLC11A1 (+1066 C/G) locus in cases of brucellosis affected cattle. For TLR1 (+1380 G/A) locus, the OR for AG and AA genotypes versus GG genotypes were 0.15 (0.05–0.44; 95 % CI) and 0.26 (0.04–1.47; 95 % CI) which indicated that proportion of GG homozygote was significantly higher in brucellosis affected animals as compared to control. At TLR1 (+1446 C/A) locus the OR of AC genotype versus CC genotype was 0.24 (0.08–0.68; 95 % CI) which revealed that relative proportion CC genotypes was significantly higher in case population. The TLR4 (+10 C/T) locus had three genotypes (TT, CT and CC) where OR of CT and CC genotypes versus TT genotype were near to zero. The OR of CT genotypes versus CC genotypes was 8.25 (0.94–71.92; 95 % CI) at TLR4 (+399 C/T) locus and indicated that CT genotype had higher odds of bovine brucellosis than control animals.     

The association between ownership of common household devices and obesity and diabetes in high,middle and low income countries

Background:

Household devices (e.g., television, car, computer) are common in high income countries, and their use has been linked to obesity and type 2 diabetes mellitus. We hypothesized that device ownership is associated with obesity and diabetes and that these effects are explained through reduced physical activity, increased sitting time and increased energy intake.

Methods:

We performed a cross-sectional analysis using data from the Prospective Urban Rural Epidemiology study involving 153 996 adults from high, upper-middle, lower-middle and low income countries. We used multilevel regression models to account for clustering at the community and country levels.

Results:

Ownership of a household device increased from low to high income countries (4% to 83% for all 3 devices) and was associated with decreased physical activity and increased sitting, dietary energy intake, body mass index and waist circumference. There was an increased odds of obesity and diabetes with the ownership of any 1 household device compared to no device ownership (obesity: odds ratio [OR] 1.43, 95% confidence interval [CI] 1.32–1.55; diabetes: OR 1.38, 95% CI 1.28–1.50). Ownership of a second device increased the odds further but ownership of a third device did not. Subsequent adjustment for lifestyle factors modestly attenuated these associations. Of the 3 devices, ownership of a television had the strongest association with obesity (OR 1.39, 95% CI 1.29–1.49) and diabetes (OR 1.33, 95% CI 1.23–1.44). When stratified by country income level, the odds of obesity and diabetes when owning all 3 devices was greatest in low income countries (obesity: OR 3.15, 95% CI 2.33–4.25; diabetes: OR 1.97, 95% CI 1.53–2.53) and decreased through country income levels such that we did not detect an association in high income countries.

Interpretation:

The ownership of household devices increased the likelihood of obesity and diabetes, and this was mediated in part by effects on physical activity, sitting time and dietary energy intake. With increasing ownership of household devices in developing countries, societal interventions are needed to mitigate their effects on poor health.The increasing global prevalence of obesity and type 2 diabetes mellitus has been driven predominantly by increases in high income countries.^1,2 However, increases are expected in low and middle income countries, due in part to rapid development and industrialization.Proximal determinants of obesity and diabetes include energy expenditure and intake;^3–5 however, the upstream factors are complex and entail numerous environmental factors. Of these, the increased use of common household devices (e.g., televisions, cars, computers) has been linked to increased sitting, decreased physical activity, obesity, metabolic syndrome and diabetes.^6–12 Time spent watching television has also been linked to poor diet¹³ and increased caloric intake.¹⁴ However, these findings are based on studies in high income countries where the ownership of these devices is common.^15,16 In low and middle income countries, such household devices are less prevalent, but their prevalence is rapidly increasing. Studies in countries with greater variability in the ownership of household devices are needed to understand the full effect of owning such devices on the risk of obesity and diabetes.We hypothesized that the ownership of a television, car or computer would be associated with an increased risk of obesity and diabetes and that these effects would be explained by reduced physical activity, increased sitting time and increased energy intake.     

Geospatial Analysis on the Distributions of Tobacco Smoking and Alcohol Drinking in India

Background

Tobacco smoking and binge alcohol drinking are two of the leading risk factors for premature mortality worldwide. In India, studies have examined the geographic distributions of tobacco smoking and alcohol drinking only at the state-level; sub-state variations and the spatial association between the two consumptions are poorly understood.

Methodology

We used data from the Special Fertility and Mortality Survey conducted in 1998 to examine the geographic distributions of tobacco smoking and alcohol drinking at the district and postal code levels. We used kriging interpolation to generate smoking and drinking distributions at the postal code level. We also examined spatial autocorrelations and identified spatial clusters of high and low prevalence of smoking and drinking. Finally, we used bivariate analyses to examine the spatial correlations between smoking and drinking, and between cigarette and bidi smoking.

Results

There was a high prevalence of any smoking in the central and northeastern states, and a high prevalence of any drinking in Himachal Pradesh, Arunachal Pradesh, and eastern Madhya Pradesh. Spatial clusters of early smoking (started smoking before age 20) were identified in the central states. Cigarette and bidi smoking showed distinctly different geographic patterns, with high levels of cigarette smoking in the northeastern states and high levels of bidi smoking in the central states. The geographic pattern of bidi smoking was similar to early smoking. Cigarette smoking was spatially associated with any drinking. Smoking prevalences in 1998 were correlated with prevalences in 2004 at the district level and 2010 at the state level.

Conclusion

These results along with earlier evidence on the complementarities between tobacco smoking and alcohol drinking suggest that local public health action on smoking might also help to reduce alcohol consumption, and vice versa. Surveys that properly represent tobacco and alcohol consumptions at the district level are recommended.     

Evaluation of Publicly Financed and Privately Delivered Model of Emergency Referral Services for Maternal and Child Health Care in India

Background

Emergency referral services (ERS) are being strengthened in India to improve access for institutional delivery. We evaluated a publicly financed and privately delivered model of ERS in Punjab state, India, to assess its extent and pattern of utilization, impact on institutional delivery, quality and unit cost.

Methods

Data for almost 0.4 million calls received from April 2012 to March 2013 was analysed to assess the extent and pattern of utilization. Segmented linear regression was used to analyse month-wise data on number of institutional deliveries in public sector health facilities from 2008 to 2013. We inspected ambulances in 2 districts against the Basic Life Support (BLS) standards. Timeliness of ERS was assessed for determining quality. Finally, we computed economic cost of implementing ERS from a health system perspective.

Results

On an average, an ambulance transported 3–4 patients per day. Poor and those farther away from the health facility had a higher likelihood of using the ambulance. Although the ERS had an abrupt positive effect on increasing the institutional deliveries in the unadjusted model, there was no effect on institutional delivery after adjustment for autocorrelation. Cost of operating the ambulance service was INR 1361 (USD 22.7) per patient transported or INR 21 (USD 0.35) per km travelled.

Conclusion

Emergency referral services in Punjab did not result in a significant change in public sector institutional deliveries. This could be due to high baseline coverage of institutional delivery and low barriers to physical access. Choice of interventions for reduction in Maternal Mortality Ratio (MMR) should be context-specific to have high value for resources spent. The ERS in Punjab needs improvement in terms of quality and reduction of cost to health system.     

Comparative Structural Modeling of Six Old Yellow Enzymes (OYEs) from the Necrotrophic Fungus Ascochyta rabiei : Insight into Novel OYE Classes with Differences in Cofactor Binding,Organization of Active Site Residues and Stereopreferences

Old Yellow Enzyme (OYE1) was the first flavin-dependent enzyme identified and characterized in detail by the entire range of physical techniques. Irrespective of this scrutiny, true physiological role of the enzyme remains a mystery. In a recent study, we systematically identified OYE proteins from various fungi and classified them into three classes viz. Class I, II and III. However, there is no information about the structural organization of Class III OYEs, eukaryotic Class II OYEs and Class I OYEs of filamentous fungi. Ascochyta rabiei, a filamentous phytopathogen which causes Ascochyta blight (AB) in chickpea possesses six OYEs (ArOYE1-6) belonging to the three OYE classes. Here we carried out comparative homology modeling of six ArOYEs representing all the three classes to get an in depth idea of structural and functional aspects of fungal OYEs. The predicted 3D structures of A. rabiei OYEs were refined and evaluated using various validation tools for their structural integrity. Analysis of FMN binding environment of Class III OYE revealed novel residues involved in interaction. The ligand para-hydroxybenzaldehyde (PHB) was docked into the active site of the enzymes and interacting residues were analyzed. We observed a unique active site organization of Class III OYE in comparison to Class I and II OYEs. Subsequently, analysis of stereopreference through structural features of ArOYEs was carried out, suggesting differences in R/S selectivity of these proteins. Therefore, our comparative modeling study provides insights into the FMN binding, active site organization and stereopreference of different classes of ArOYEs and indicates towards functional differences of these enzymes. This study provides the basis for future investigations towards the biochemical and functional characterization of these enigmatic enzymes.     

Prefrontal Response and Frontostriatal Functional Connectivity to Monetary Reward in Abstinent Alcohol-Dependent Young Adults

Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence.