Patulin causes DNA damage leading to cell cycle arrest and apoptosis through modulation of Bax, p and p proteins in skin of mice

Patulin (PAT), a mycotoxin found in apples, grapes, oranges, pear and peaches, is a potent genotoxic compound. WHO has highlighted the need for the study of cutaneous toxicity of PAT as manual labour is employed during pre and post harvest stages, thereby causing direct exposure to skin. In the present study cutaneous toxicity of PAT was evaluated following topical application to Swiss Albino mice. Dermal exposure of PAT, to mice for 4 h resulted in a dose (40-160 μg/animal) and time (up to 6 h) dependent enhancement of ornithine decarboxylase (ODC), a marker enzyme of cell proliferation. The ODC activity was found to be normal after 12 and 24 h treatment of patulin. Topical application of PAT (160 μg/100 μl acetone) for 24-72 h caused (a) DNA damage in skin cells showing significant increase (34-63%) in olive tail moment, a parameter of Comet assay (b) significant G 1 and S-phase arrest along with induction of apoptosis (2.8-10 folds) as shown by annexin V and PI staining assay through flow cytometer. Moreover PAT leads to over expression of p^21/WAF1 (3.6-3.9 fold), pro apoptotic protein Bax (1.3-2.6) and tumor suppressor wild type p⁵³ (2.8-3.9 fold) protein. It was also shown that PAT induced apoptosis was mediated through mitochondrial intrinsic pathway as revealed through the release of cytochrome C protein in cytosol leading to enhancement of caspase-3 activity in skin cells of mice. These results suggest that PAT has a potential to induce DNA damage leading to p⁵³ mediated cell cycle arrest along with intrinsic pathway mediated apoptosis that may also be correlated with enhanced polyamine production as evident by induction of ODC activity, which may have dermal toxicological implications.     

Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: A randomised controlled trial in patients with osteoarthritis

Background  

The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year.     

Bardet–Biedl syndrome: The pleiotropic role of the chaperonin-like BBS6, 10, and 12 proteins

Bardet–Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.     

Revaccination after Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance

Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases.     

Hypertension and its severity in children with steroid sensitive nephrotic syndrome during remission

Background and objective

Hypertension is not a typical feature of steroid sensitive nephrotic syndrome (SSNS) and the presence of persistent hypertension is suggestive of significant renal lesion. There is paucity of data regarding occurrence and severity of hypertension in SSNS in pediatric population during remission and was the main objective of this study. In addition, correlation with factors like family history, BMI, and lipid profile was studied.

Methods

Cross-sectional study conducted at tertiary care center in India including 81 children of infrequent relapsing SSNS between 1 and 10 years in remission and was off steroids. Grading and severity of hypertension were assessed. Statistical analysis was done using SPSS version 21.0.

Results

Median age of presentation was 5 years, with male:female ratio of 1.3:1. Out of 81 infrequent relapsing SSNS children, 23.45% (19) had hypertension. Among those children with hypertension (n?=?19), 73.68% (14) had positive family history compared to 32.25% (20) in those without hypertension. Positive correlation was found between BP and serum cholesterol and LDL. Of the hypertensive patients, 1 (5.26%) had fundus changes, 2 (10.52%) had features of left ventricular hypertrophy, and 13 (68.42%) had non-nephrotic range proteinuria.

Conclusion

There is high incidence of hypertension in NS children during remission. Though significant positive correlation was found with positive family history of hypertension and deranged lipid profile highlighting possibility of essential hypertension in them, there is need for close active monitoring and management of hypertension in them as untreated cases may have significant target organ damage.

     

Two faces of carbon nanotube: toxicities and pharmaceutical applications

In the field of nanotechnology, carbon nanotube (CNT) is gaining importance for the delivery of therapeutic agents and diagnosis of diseases. CNT is emerging as an efficient nanocarrier system with cylindrical nanostructure. Due to its nanoscale dimensions, CNTs have a high cell-penetration quality that allows its use in site-specific targeting. Another aspect of the utilization of CNT lies in its hollow structure through which an active moiety can be delivered in a controlled manner via CNTs' nano channels. Despite these positive aspects of CNT, scientists are still working to improve its biocompatibility and solubility and eliminating toxicity in vivo, which are creating problems with the use of CNTs. Therefore, functionalization becomes an important aspect to be studied because it decreases the toxicity of CNTs and make them nonimmunogenic. In this review, different functionalization techniques of CNTs and their biomedical applications-in particular for cancer therapy to date-are reviewed in detail to present the potential of this nanovector.     

Transcending the skin barrier to deliver peptides and proteins using active technologies

Peptides and proteins have been investigated as promising therapeutic agents over the past decade. These macromolecules are conventionally administered by the parenteral route because oral delivery is associated with degradation in the gastrointestinal tract. Transdermal delivery presents a promising alternative route of drug delivery, avoiding pain associated with parenteral administration and degradation issues associated with oral delivery. However, the barrier properties of skin limit delivery to only small, moderately lipophilic molecules. Hence, hydrophilic macromolecules like peptides and proteins cannot passively permeate across skin. Active physical enhancement approaches such as iontophoresis electroporation, microneedles treatment, and sonophoresis have been developed to assist transdermal delivery of peptides and proteins. This review describes active physical transdermal enhancement approaches for transdermal delivery of peptides and proteins. The mechanisms associated with each technique and important parameters governing transdermal delivery of peptides and proteins are discussed in detail. Combinations of enhancement techniques for synergistic enhancement in protein and peptide delivery are also discussed.     

Endotherapy for pancreatic necrosis and abscess: endoscopic drainage and necrosectomy

Pancreatic necrosis and abscess are among the most severe complications of acute pancreatitis. Endoscopic drainage of pancreatic fluid collections has been increasingly performed in many tertiary care centers. The type of fluid collection that is being intervened upon determines the outcome. The development of endoscopic ultrasonography (EUS) has expanded the safety and efficacy of this modality by allowing one to access and drain more challenging fluid collections. The technique and review of current literature regarding endoscopic therapy of pancreatic necrosis and abscess will be discussed.