Effect of poloxamer 188 on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles for bioavailability enhancement

The present work aimed to investigate the effect of different concentrations of poloxamer 188, a surfactant, on lymphatic uptake of carvedilol-loaded solid lipid nanoparticles (SLNs) for oral bioavailability enhancement. Microemulsion technique was employed to prepare the SLN formulations having varying concentrations of poloxamer 188, which were subsequently subjected to various in vitro and in vivo evaluations to study their release pattern. On increasing the percentage concentration of poloxamer 188, the bioavailability decreased from 4.91- to 2.84-fold after intraduodenal administration in the male Wister rat. It could be attributed to the increase in particle size as well as reduction in hydrophobicity of SLNs. As indicated by pharmacokinetic data, the AUC_(0–t) of all three (SLN) formulations (6.27?±?0.24 μgh/mL with FZ-1, 4.13?± 0.11 μgh/mL with FZ-2, and 3.63?±?0.10 μgh/mL with FZ-3) were significantly higher (p?<?0.05) than that of carvedilol suspension (1.27?±?0.23 μgh/mL). These findings augur well with the possibility of enhancement of the oral bioavailability of drug, via the lymphatic system bypassing hepatic first pass metabolism.     

Biomarkers in overactive bladder

A biomarker is an indicator of a particular disease. It is generally used to define the presence (diagnostic biomarker), severity, progression (prognostic biomarker) of a condition and/or its response to a specific treatment (predictive biomarker). Biomarkers can be specific cells, enzymes, hormones, genes or gene products, which can be detected and measured in parts of the body such as blood, urine or tissue. Therefore, biomarkers have been suggested to play an important role in both the clinical assessment and the management of patients, as well as in the research setting. Recently, interest has gathered in urinary biomarkers as a tool to assess overactive bladder (OAB), potentially playing a role in the diagnosis, disease progression and monitoring response to treatment. Urinary biomarkers identified so far include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), prostaglandins, cytokines and C-reactive protein. The aim of this review was to review the published literature on biomarkers in OAB. A literature review using Pub Med, clinicaltrials.gov and the controlled trials online registries was performed from 1970 up to June 2012. The search keywords were: the International Continence Society (ICS) definition of "OAB", “nerve growth fac- tor” (NGF), “brain derived growth factor” (BDNF), “prostaglandins,” “cytokines,” “genetic biomarkers” and “C reactive protein”. The results were limited for fully published English-language articles. The search was then subsequently expanded to include urinary biomarkers in interstitial cystitis and bladder pain where relevant. Each of the studies/articles was reviewed, interpreted and discussed to consider the role of urinary biomarkers in OAB. Using the search criteria, a total of 20 studies (animal and human) that investigated the role of urinary biomarkers in OAB were identified. Full text versions of these articles were obtained and reviewed. Studies on NGF suggested that urinary levels were higher in OAB patients and decreased with antimuscarinic and botulinum toxin treatment. BDNF studies have demonstrated raised levels in OAB and also increased levels in situations of acute bladder inflammation. The role of urinary prostaglandins, cytokines and CRP does not appear to be specific to the OAB disease process according to the current available evidence. Based on the evidence so far NGF and BDNF appear to be the most promising biomarkers in OAB. Although still in their infancy these neurotrophic factors could potentially diagnose OAB, replacing urodynamics and aiding in monitoring disease progression and response to treatment in addition to clinical symptoms.     

Perspectives on cancer stem cells in osteosarcoma

Osteosarcoma is an aggressive pediatric tumor of growing bones that, despite surgery and chemotherapy, is prone to relapse. These mesenchymal tumors are derived from progenitor cells in the osteoblast lineage that have accumulated mutations to escape cell cycle checkpoints leading to excessive proliferation and defects in their ability to differentiate appropriately into mature bone-forming osteoblasts. Like other malignant tumors, osteosarcoma is often heterogeneous, consisting of phenotypically distinct cells with features of different stages of differentiation. The cancer stem cell hypothesis posits that tumors are maintained by stem cells and it is the incomplete eradication of a refractory population of tumor-initiating stem cells that accounts for drug resistance and tumor relapse. In this review we present our current knowledge about the biology of osteosarcoma stem cells from mouse and human tumors, highlighting new insights and unresolved issues in the identification of this elusive population. We focus on factors and pathways that are implicated in maintaining such cells, and differences from paradigms of epithelial cancers. Targeting of the cancer stem cells in osteosarcoma is a promising avenue to explore to develop new therapies for this devastating childhood cancer.     

Morphometric evaluation of endometrial blood vessels

Five hundred endometrial specimens were studied to document the changes in blood vessels in various phases of menstrual cycle, menstrual disturbances and in unexplained infertility. Sixty-three cases were taken as control and 437 cases as study group which included cases of dysfunctional uterine bleeding (DUB), endometrial polyps, fibroids, adenomyosis, infertility and atrophic endometrium. Using light microscopy, the vascular morphology was studied. The blood vessels were concentrated more in basal layer in the proliferative phase and in functional layer in the secretory phase. Cases of complex hyperplasia and pill endometrium had significantly higher vessel concentration. Congestion and dilatation of blood vessels were significantly higher in cases of DUB. The present study showed a positive correlation between endometrial angiogenesis and menstrual disorders. The alteration in blood vessel morphology has significant role in prognosis and in various anti-angiogenic therapies.     

Intrarenal pure yolk sac tumor: an extremely rare entity

Yolk sac tumor (endodermal sinus tumor) is a malignant germ cell tumor that usually arises in the gonads. Extragonadal germ cell tumors are rare and have been described in case reports. We report a pure intrarenal yolk sac tumor in a 1-year-old boy who presented with a huge abdominal mass and was operated for suspected Wilms tumor. The tumor exhibited histopathologic and immunohistochemical features identical to those of an endodermal sinus tumor of gonadal origin. The purpose of this report is to add a rare tumor to the differential diagnosis of pediatric renal neoplasms.     

Body mass index and serum leptin concentration independently estimate percentage body fat in older adults

BACKGROUND: Because serum concentrations of leptin, a hormone produced by adipocytes, can be relatively reliably and inexpensively measured, it may be considered complementary to, or even a substitute for, body mass index (BMI) as a measure of adiposity. OBJECTIVE: We examined the ability of BMI and leptin concentrations, separately and together, to estimate total percentage fat in older adults. DESIGN: Total percentage fat measured by dual-energy X-ray absorptiometry and fasting serum leptin concentrations were measured in 2911 well-functioning 70-79-y-old participants (42% black, 51% women) in the Health, Aging, and Body Composition Study. RESULTS: Mean (+/-SD) total percentage fat was 29.2 +/-5.0% in men and 40.5 +/- 5.7% in women, and the geometric mean (+/-SD) serum leptin concentration was 5.6 +/- 2.5 ng/mL in the men and 16.4 +/- 2.3 ng/mL in the women. Among men, total percentage fat was strongly associated with both BMI (R(2) = 0.56) and leptin (R(2) = 0.57) in separate linear regression analyses and in a combined linear regression analysis (R(2) = 0.68). Similarly, among women, total percentage fat was associated with both BMI (R(2) = 0.65) and leptin (R(2) = 0.54) separately and in combination (model R(2) = 0.71). Independent relations of BMI and leptin with total percentage fat were also found among both black and white participants. With the population divided into quintiles according to percentage fat, BMI and serum leptin correctly classified 49% of men and 50% of women in the correct quintile. CONCLUSIONS: Among older adults, total percentage fat was better estimated by using both serum leptin concentrations and BMI than by using either alone. However, their performance does not suggest that they can substitute for more accurate measures.     

Role of granulosa cell mitogen-activated protein kinase 3/1 in gonadotropin-mediated meiotic resumption from diplotene arrest of mammalian oocytes

In mammals, preovulatory oocytes are encircled by several layers of granulosa cells (GCs) in follicular microenvironment. These follicular oocytes are arrested at diplotene arrest due to high level of cyclic nucleotides from encircling GCs. Pituitary gonadotropin acts at the level of encircling GCs and increases adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP) and activates mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathway. The MAPK3/1 disrupts the gap junctions between encircling GCs and oocyte. The disruption of gap junctions interrupts the transfer of cyclic nucleotides to the oocyte that results a drop in intraoocyte cAMP level. A transient decrease in oocyte cAMP level triggers maturation promoting factor (MPF) destabilization. The destabilized MPF finally triggers meiotic resumption from diplotene arrest in follicular oocyte. Thus, MAPK3/1 from GCs origin plays important role in gonadotropin-mediated meiotic resumption from diplotene arrest in follicular oocyte of mammals.     

Knockdown of PINCH-1 protein sensitizes the estrogen positive breast cancer cells to chemotherapy induced apoptosis

Introduction

PINCH-1 is a ubiquitously expressed protein belonging to the focal adhesion protein group which has a role in cell survival, spreading, adhesion and migration. It has been implicated in pathogenesis of several cancers. In the present study we aimed to investigate the role of this protein in estrogen positive and negative breast cancer subtypes.

Hypereosinophilia in Acute Lymphoblastic Leukemia: Two Cases with Review of Literature

Eosinophilia is rare in acute leukemia at presentation. Discrete reports and case studies in recent years have created significant interest in the field of “Acute leukemia with eosinophilia”. We herein present two cases of eosinophilia in association with acute lymphoblastic leukemia with brief review of literature in this field. First case is about 21-year-old female who presented with mediastinal mass along with leukocytosis and hypereosinophilia. On evaluation, she was found to have T cell acute lymphoblastic leukemia. After ruling out benign causes of eosinophilia, she was treated with modified BFM-90 protocol. Her eosinophilia resolved after 4 weeks of induction therapy. Second case is about 32-year-old male who was diagnosed as a case of mixed phenotype leukemia (B cell/myeloid type) along with severe eosinophilia. His hypereosinophilia finally resolved by week 16 of modified BFM-90 protocol. Diagnosing ALL is challenging when eosinophilia is the initial presentation. These two cases emphasize on the importance of considering ALL amongst one of the etiological causes of eosinophilia as delay in diagnosis endangers patient’s life at risk. Also eosinophilia per se is an independent poor risk factor, hence prompt diagnosis and early treatment is the key in all such cases.