VISCOELASTIC, SWELLING KINETIC AND DRUG RELEASE CHARACTERIZATION OF POLY (ACRYLIC ACID)-GRAFTED-GELLAN

Lyophilic, viscoelastic, swelling kinetic and drug release characterizations of poly (acrylic acid) –grafted-gellan (PAAc-g-GG) were the main objective of this study. At first, a suitable solvent for PAA-g-GG was found out by lyophilicity study followed by viscoelastic study on PAAc-g-GG with different degree of grafting. The study showed that the degree of grafting greatly influences the viscoelastic nature of copolymer, which further governs the drug release pattern from the polymer matrix. The copolymer with highest grafting showed much higher starting % strain (17.73%), stress (53.3 Pa) for structural breakdown at Gꞌ = Gꞌꞌ (213.5 Pa), higher storage modulus (G’), much higher values of complex viscosity (11.46 Pa.s) and cross-over point (Gꞌ = Gꞌꞌ =271.86 Pa) compared to that of low-grafted copolymer. In 0.1N HCl, swelling index (%WE) is found to be directly proportional to percentage grafting (%G) and batches with higher grafting exhibited lowest initial swelling rate demonstrating its inversely proportional relation to %G. Equilibrium swelling and hydration are also found to be proportional to %G. The same effect has been observed in PBS with exception that the magnitude of the parameters obtained in PBS is very much higher compared to that in 0.1N HCl. The copolymer showed sustained drug release over 10 hours period and the study revealed Case-1 Fickian diffusion or square root of time kinetic based release mechanism. The study reveales that viscoelastic and swelling study might be useful to understand how the degree of grafting governs the drug release

New-onset hyperglycemia: a potential clue to detect early pancreatic cancer

Pancreatic adenocarcinoma has an incidence rate nearly equal to the mortality rate and this is mostly due to late symptom onset and diagnosis. Evidence has indicated that new-onset diabetes may be a manifestation of occult pancreatic carcinoma. Authors report the case of a young female who presented with new-onset severe hyperglycemia and superficial thrombophlebitis. She was subsequently diagnosed with pancreatic cancer confirmed by histopathology. Her glycemic status evaluated 6 months prior to her presentation during institutional health check-up was entirely normal. This case report will serve to emphasize that new-onset diabetes in certain patients could be a presenting feature of pancreatic cancer.Pancreatic adenocarcinoma has an incidence rate nearly equal to the mortality rate and this is mostly due to late onset of symptoms and delay in diagnosis. Early diagnosis of this cancer gives the opportunity for total resection of pancreas and creates hope for a full recovery. Compelling evidence now indicates that new-onset diabetes may be a manifestation of occult pancreatic carcinoma. Authors report a young female who presented with new-onset severe hyperglycemia and superficial thrombophlebitis. She was subse­quently diagnosed with pancreatic cancer confirmed by histopathology. Her glycemic status evaluated 6 months prior to her presentation during institutional health check-up was entirely normal. This case report will serve to emphasize that new-onset diabetes in certain patients could be a presenting feature of pancreatic cancer. (Clin Diabetol 2017; 6, 3: 115–117

Myxedema Coma: A New Look into an Old Crisis

Myxedema crisis is a severe life threatening form of decompensated hypothyroidism which is associated with a high mortality rate. Infections and discontinuation of thyroid supplements are the major precipitating factors while hypothermia may not play a major role in tropical countries. Low intracellular T3 leads to cardiogenic shock, respiratory depression, hypothermia and coma. Patients are identified on the basis of a low index of suspicion with a careful history and examination focused on features of hypothyroidism and precipitating factors. Arrythmias and coagulation disorders are increasingly being identified in myxedema crisis. Thyroid replacement should be initiated as early as possible with careful attention to hypotension, fluid replacement and steroid replacement in an intensive care facility. Studies have shown that replacement of thyroid hormone through ryles tube with a loading dose and maintenance therapy is as efficacious as intravenous therapy. In many countries T3 is not available and oral therapy with T4 can be used effectively without major significant difference in outcomes. Hypotension, bradycardia at presentation, need for mechanical ventilation, hypothermia unresponsive to treatment, sepsis, intake of sedative drugs, lower GCS and high APACHE II scores and Sequential Organ Failure Assessment (SOFA) scores more than 6 are significant predictors of mortality in myxedema crisis. Early intervention in hypothyroid patients developing sepsis and other precipitating factors and ensuring continued intake of thyroid supplements may prevent mortality and morbidity associated with myxedema crisis

Loss of the scavenger receptor MARCO results in uncontrolled vomocytosis of fungi from macrophages

Vomocytosis, also known as nonlytic exocytosis, is a process whereby fully phagocytosed microbes are expelled from phagocytes without discernible damage to either the phagocyte or microbe. Although this phenomenon was first described in the opportunistic fungal pathogen Cryptococcus neoformans in 2006, to date, mechanistic studies have been hampered by an inability to reliably stimulate or inhibit vomocytosis. Here we present the fortuitous discovery that macrophages lacking the scavenger receptor MAcrophage Receptor with COllagenous domain (MARCO), exhibit near‐total vomocytosis of internalised cryptococci within a few hours of infection. Marco−/− macrophages also showed elevated vomocytosis of a yeast‐locked C. albicans strain, suggesting this to be a broadly relevant observation. We go on to show that MARCO's role in modulating vomocytosis is independent of its role as a phagocytic receptor, suggesting that this protein may play an important and hitherto unrecognised role in modulating macrophage behaviour

Nowo wykryta hiperglikemia: wskazówka umożliwiająca wczesne rozpoznanie raka trzustki

 W raku gruczołowym trzustki wskaźnik umieralności jest niemal równoważny ze wskaźnikiem zapadalno­ści, co jest spowodowanie głównie tym, że choroba długo przebiega bezobjawowo i zwykle zostaje późno wykryta. Wczesne rozpoznanie raka trzustki umożliwia całkowitą resekcję guza i daje nadzieję na zupełne wyleczenie. Dostępne obecnie dowody naukowe wskazują, że cukrzyca de novo może być manifestacją kliniczną utajonego raka trzustki. Autorzy opisują przy­padek młodej kobiety, która zgłosiła się z objawami ciężkiej hiperglikemii i zakrzepowym zapaleniem żył powierzchownych. Następnie u chorej rozpoznano raka trzustki, a rozpoznanie potwierdzono w badaniu histo­patologicznym. Wartość glikemii zmierzonej podczas rutynowych badań kontrolnych przeprowadzonych 6 miesięcy wcześniej mieściły się w granicach normy. Niniejszy opis przypadku zwraca uwagę na to, że u niektórych pacjentów nowo rozpoznana cukrzyca może być objawem wskazującym na obecność raka trzustki

Chronic inflammation in polycystic ovary syndrome: A case–control study using multiple markers

Background: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and elevated risk of cardiovascular disease and diabetes. Chronic inflammation has been observed in PCOS in several studies but there is also opposing evidence and a dearth of research in Indians. Objective: To estimate chronic inflammation in PCOS and find its relationship with appropriate anthropometric and biochemical parameters. Materials and Methods: Chronic inflammation was assessed in 30 women with PCOS (Group A) and 30 healthy controls (Group B) with highly sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), and platelet microparticles (PMP). In group A, the relationship of chronic inflammation with insulin resistance, waist hip ratio (WHR) serum testosterone, and serum glutamate pyruvate transaminase (SGPT) were examined. Results: In group A, the hsCRP, TNFα, and PMP were significantly elevated compared to group B. However, IL-6 level was similar between the groups. In group A, PMP showed a significant positive correlation with waist-hip ratio and serum testosterone. IL-6 showed a significant positive correlation with insulin sensitivity and significant negative correlation with insulin resistance and serum glutamate pyruvate transaminase. Conclusion: PCOS is associated with chronic inflammation and PMP correlates positively with central adiposity and biochemical hyperandrogenism in women with PCOS. Key words: Polycystic ovary syndrome, Inflammation, C-reactive protein, Interleukin-6, Tumor necrosis factor, Microparticles

Potential of Inhaled Bacteriophage Therapy for Bacterial Lung Infection

Phage therapy as a promising alternative antimicrobial to treat multidrug resistant (MDR) bacteria related lung infections, has drawn significant attention in clinical trials and bench-scale study in the recent decade, and the therapeutic effect of local delivery of phage has been demonstrated by several clinical reports. This book chapter discusses the current clinical development of inhaled phage therapy followed by the advancement of phage formulation designs for respiratory delivery of phage using various inhalation devices and their in vivo efficacy. The development of combination therapy of phage and antibiotics to combat MDR bacteria associated lung infections is also covered to reflect the current clinical practice. Lastly, we also share our insights on the challenges of advancing inhaled phage therapy and potential directions for future research

MUC4 overexpression augments cell migration and metastasis through EGFR family proteins in triple negative breast cancer cells.

INTRODUCTION: Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs. METHOD: In the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue and normal breast tissue by immunostaining. RESULTS: MUC4 promotes proliferation, anchorage-dependent and-independent growth of TNBC cells, augments TNBC cell migratory and invasive potential in vitro, and enhances tumorigenicity and metastasis in vivo. In addition, our studies demonstrated that MUC4 up-regulates the EGFR family of proteins, and augments downstream Erk1/2, PKC-γ, and FAK mediated oncogenic signaling. Moreover, our studies also showed that knockdown of MUC4 in TNBC cells induced molecular changes suggestive of mesenchymal to epithelial transition. We also demonstrated in this study, for the first time, that knockdown of MUC4 was associated with reduced expression of EGFR and ErbB3 (EGFR family proteins) in TNBC cells, suggesting that MUC4 uses an alternative to ErbB2 mechanism to promote aggressiveness. We further demonstrate that MUC4 is differentially over-expressed in invasive TNBC tissues compared to normal breast tissue. CONCLUSIONS: MUC4 mucin expression is associated with TNBC pathobiology, and its knockdown reduced aggressiveness in vitro, and tumorigenesis and metastasis in vivo. Overall, our findings suggest that MUC4 mucin promotes invasive activities of TNBC cells by altering the expression of EGFR, ErbB2, and ErbB3 molecules and their downstream signaling

The Rab32/BLOC-3-dependent pathway mediates host defense against different pathogens in human macrophages.

Macrophages provide a first line of defense against microorganisms, and while some mechanisms to kill pathogens such as the oxidative burst are well described, others are still undefined or unknown. Here, we report that the Rab32 guanosine triphosphatase and its guanine nucleotide exchange factor BLOC-3 (biogenesis of lysosome-related organelles complex-3) are central components of a trafficking pathway that controls both bacterial and fungal intracellular pathogens. This host-defense mechanism is active in both human and murine macrophages and is independent of well-known antimicrobial mechanisms such as the NADPH (reduced form of nicotinamide adenine dinucleotide phosphate)-dependent oxidative burst, production of nitric oxide, and antimicrobial peptides. To survive in human macrophages, Salmonella Typhi actively counteracts the Rab32/BLOC-3 pathway through its Salmonella pathogenicity island-1-encoded type III secretion system. These findings demonstrate that the Rab32/BLOC-3 pathway is a novel and universal host-defense pathway and protects mammalian species from various pathogens

GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump.

The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. We report that the G protein-coupled receptor GPR35 interacted with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca2+ to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). In contrast, a common T108M polymorphism in GPR35 was hypermorphic and had the opposite effects to Gpr35 deletion on Src activation and metabolic activity. The T108M polymorphism is associated with ulcerative colitis and primary sclerosing cholangitis, inflammatory diseases with a high cancer risk. GPR35 promoted homeostatic IEC turnover, whereas Gpr35 deletion or inhibition by a selective pepducin prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Thus, GPR35 acts as a central signaling and metabolic pacesetter, which reveals an unexpected role of Na/K-ATPase in macrophage and IEC biology.European Research Council Consolidator Grant n° 648889 to A.K. Scientia Fellowship (FP7-PEOPLE-2013-COFUND) grant agreement n° 609020 to G.S. Addenbrooke’s Charitable Trust (ACT 25/16A) to J.E.E. UniNA and Compagnia Di San Paolo ‘STAR program for young researchers’ fellowship to E.P