Enhanced antitumour activity of doxorubicin and simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma

Doxorubicin (DOX) is the most commonly used anticancer drug; however, it has limited use because prolonged administration may result in severe cardiotoxicity. Simvastatin (SIM), generally prescribed for hypercholesterolaemia, has also shown salubrious results in the monotherapy or combinational drug therapy of different cancers in various models. Nanoparticle drug delivery systems are a novel way of improving therapeutics and also improving the absorption and specificity of drugs towards tumour cells. In this study, we exploited this technology to increase drug specificity and minimize imminent adverse effects. In this study, the antitumour activity of the combination formulas of DOX and SIM, either loaded in water (DOX‐SIM‐Solution) or nanoemulsions (NEs) (DOX‐SIM‐NE), was evaluated in a Swiss albino mouse model of Ehrlich ascites carcinoma. The anticancer effect was assessed by quantifying the change in body weight, mean survival time, and percent increase in lifespan (%ILS), determining haematological and serum biochemical parameters (liver function test, kidney function test and lipid profile parameters) as well as studying the histopathological alterations in liver tissues. We observed a clear increase in %ILS of the DOX‐SIM‐Solution group (265.30) that was double the %ILS of the DOX‐SIM‐NE group (134.70). However, DOX‐SIM‐NE had a non‐toxic effect on the haematological parameters, whereas DOX‐SIM‐Solution increased the levels of haemoglobin and lymphocytes. Furthermore, the encapsulation of SIM and DOX into NEs improved the levels of all serum biochemical parameters compared to the DOX‐SIM‐Solution. A reduction in the side effects of DOX‐SIM‐NE on the liver was also established using light microscopy, which revealed that the morphologies of the hepatocytes of the mice were less affected by administration of the DOX‐SIM‐NE treatment than with the DOX‐SIM‐Solution treatment. The study showed that incorporating SIM into the DOX‐loaded‐NE formulation remarkably improved its efficiency and simultaneously reduced its adverse effects.     

Stage 1 acute kidney injury is independently associated with infection following cardiac surgery

ObjectivesSevere acute kidney injury (AKI) is a known risk factor for infection and mortality. However, whether stage 1 AKI is a risk factor for infection has not been evaluated in adults. We hypothesized that stage 1 AKI following cardiac surgery would independently associate with infection and mortality.MethodsIn this retrospective propensity score–matched study, we evaluated 1620 adult patients who underwent nonemergent cardiac surgery at the University of Colorado Hospital from 2011 to 2017. Patients who developed stage 1 AKI by Kidney Disease Improving Global Outcomes creatinine criteria within 72 hours of surgery were matched to patients who did not develop AKI. The primary outcome was an infection, defined as a new surgical-site infection, positive blood or urine culture, or development of pneumonia. Secondary outcomes included in-hospital mortality, stroke, and intensive care unit (ICU) and hospital length of stay (LOS).ResultsStage 1 AKI occurred in 293 patients (18.3%). Infection occurred in 20.9% of patients with stage 1 AKI compared with 8.1% in the no-AKI group (P < .001). In propensity-score matched analysis, stage 1 AKI independently associated with increased infection (odds ratio [OR]; 2.24, 95% confidence interval [CI], 1.37-3.17), ICU LOS (OR, 2.38; 95% CI, 1.71–3.31), and hospital LOS (OR, 1.30; 95% CI, 1.17-1.45).ConclusionsStage 1 AKI is independently associated with postoperative infection, ICU LOS, and hospital LOS. Treatment strategies focused on prevention, early recognition, and optimal medical management of AKI may decrease significant postoperative morbidity.     

Management of psychopharmacologic agents in children and adolescents

This article summarizes the ways in which a clinician should think about medication use in children and describes practical usage of the most frequently used child psychopharmacologic agents.Leena Ranade, M.D., and Aftab Qadir, M.D., were Fellows in Child Psychiatry, State University of New York at Stony Brook at the time of writing this article.     

Identification of HIV-1 epitopes that induce the synthesis of a R5 HIV-1 suppression factor by human CD4+ T cells isolated from HIV-1 immunized hu-PBL SCID mice

We have previously reported that immunization of the severe combined immunodeficiency (SCID) mice reconstituted with human peripheral blood mononuclear cells (PBMC) (hu-PBL-SCID mice) with inactivated human immunodeficiency virus type-1 (HIV-1)-pulsed-autologous dendritic cells (HIV-DC) elicits HIV-1-reactive CD4(+) T cells that produce an as yet to be defined novel soluble factor in vitro with anti-viral properties against CCR5 tropic (R5) HIV-1 infection. These findings led us to perform studies designed to identify the lineage of the cell that synthesizes such a factor in vivo and define the epitopes of HIV-1 protein that have specificity for the induction of such anti-viral factor. Results of our studies show that this property is a function of CD4(+) but not CD8(+) T cells. Human CD4(+) T cells were thus recovered from the HIV-DC-immunized hu-PBL-SCID mice and were re-stimulated in vitro by co-culture for 2 days with autologous adherent PBMC as antigen presenting cells, APC previously pulsed with inactivated HIV in IL-2-containing medium to expand HIV-1-reactive CD4(+) T cells. Aliquots of these re-stimulated CD4(+) T cells were then co-cultured with similar APC's that were previously pulsed with 10 microg/ml of a panel of HIV peptides for an additional 2 days, and their culture supernatants were examined for the production of both the R5 HIV-1 suppression factor and IFN-gamma. The data presented herein show that the HIV-1 primed CD4(+) T cells produced the R5 suppression factor in response to a wide variety of HIV-1 gag, env, pol, nef or vif peptides, depending on the donor of the CD4(+) T cells. Simultaneous production of human interferon (IFN)-gamma was observed in some cases. These results indicate that human CD4(+) T cells in PBMC of HIV-1 naive donors have a wide variety of HIV-1 epitope-specific CD4(+) T cell precursors that are capable of producing the R5 HIV-1 suppression factor upon DC-based vaccination with whole inactivated HIV-1.     

The effects of distant and on-line visual information on the control of approach phase and step over an obstacle during locomotion

One of the goals of this study was to examine the nature and role of distant visual information sampled during locomotion in the feedforward control of leading and trailing limb while an individual is required to step over an obstacle in the travel path. In addition we were interested in whether or not on-line visual information available while the limb (lead or trail) is stepping over the obstacle influences limb trajectory control and whether the information provided during lead limb cross would be used to calibrate movement of the trail limb. Towards this end, we manipulated availability of vision following an initial dynamic sampling period during the approach phase in proximity to the obstacle and during the lead and trail limb stepping over the obstacle. Ten participants completed 40 trials of obstacle crossing in 8 testing conditions. Initial dynamic visual sampling was sufficient to ensure successful task performance in the absence of vision in the approach phase and during both lead and trail limb stepping over the obstacle. Despite successful task performance, foot placement of the lead and trail limb before obstacle crossing and limb elevation over the obstacle were increased after withdrawal of vision in the approach area. Furthermore, the correlation between toe clearance and foot placement was diminished. While both limbs require feedforward visual information to control the step over the obstacle, only lead limb elevation was influenced by availability of on-line visual information during obstacle crossing. Results were in agreement with the notion of primacy of information inherent in the optic array over those from static samples of the environment in guiding locomotion. It is suggested that the expected proprioceptive feedback information associated with the limb posture before the obstacle, reconstructed using visual memory from dynamic sampling of the environment, mismatched with those from the actual limb position. Accordingly, participants adopted a different strategy that enabled them to clear the obstacle with a higher safety margin.Financial assistance was provided by a grant from the Office of Naval Research, USA, NSERC/Canada, and CAPES/Brazil. We would like to thank Milad G. Ishac, Mike Greig, Zinat Shafaei-Shirazi, and Candida T. Goncalves for their assistance     

A Comparative Analysis of the Murine Thymic Microenvironment in Normal,Autoimmune, and Immunodeficiency States

It is widely accepted that the thymic microenvironment regulates normal thymopoiesis through a highly coordinated and complex series of cellular and cytokine interactions. A direct corollary of this is that abnormalities within the microenvironment could be of etiologic significance in T-cell-based diseases. Our laboratory has developed a large panel of monoclonal antibodies (mAbs) that react specifically with epithelial or nonepithelial markers in the thymus. We have taken advantage of these reagents to characterize the thymic microenvironment of several genetic strains of mice, including BALB/cJ, C57BL/6J, NZB/BlnJ, SM/J, NOD/Ltz, NOD/Ltz-scid/sz, C57BL/6J-Hcph m^e/Hcph m^e, and ALY/NscJcl-aly/aly mice, and littermate control animals. We report herein that control mice, including strains of several backgrounds, have a very consistent phenotypic profile with this panel of monoclonal antibodies, including reactivity with thymic epithelial cells in the cortex, the medulla and the corticomedullary junction, and the extracellular matrix. In contrast, the disease-prone strains studied have unique, abnormal staining of thymic cortex and medulla at both the structural and cellular levels. These phenotypic data suggest that abnormalities in interactions between developing thymocytes and stromal cells characterize disease-prone mice.     

Strategies and determinants for selection of alternate foot placement during human locomotion: influence of spatial and temporal constraints

During locomotion in a cluttered terrain, certain terrain surfaces such as an icy one are not appropriate for foot placement; an alternate choice is required. In a previous study we showed that the selection of foot placement is not random but systematic; the dominant choices made are not uniquely defined by the available or predicted sensory inputs. We argued that selection is guided by specific rules and involves minimal displacement of the foot from its normal landing spot. The experimental protocol involved implicit spatial constraint by requiring individuals to step on the force plate that could trigger a lighted area to be avoided, thereby requiring individuals to respond within one step-cycle. Alternate foot placement was visually identified, but not measured. The purpose of this study was to directly measure foot placement, validate and/or refine the rules used to guide selection, and identify whether the alternate foot placement choices are influenced by spatial and temporal constraints on response selection. The area to be avoided was visible from the start and therefore individuals could plan and implement appropriate avoidance strategies without any temporal constraint. Spatial constraint introduced in this experiment included requirement both to step on a specific location and to avoid stepping on a specific location on the next step. The results provide support for the rules previously identified in guiding foot placement to an alternate location. Minimal displacement of the foot from its normal landing spot was validated as an important factor for selecting alternate foot placement. When several choices satisfied this factor, additional factors guide alternate foot placement. Modifications in the plane of progression are preferred while stepping wide is avoided. When no temporal constraints are imposed on the response selection, enhancing forward progression of the body becomes the dominant determinant followed by stability and lastly by energy costs associated with the modifications. A decision algorithm for selecting foot placement is proposed based on these findings. It is clear that while visual input plays a critical role in guiding foot placement, it is not entirely based on reactive control. This has implications for implementing visually guided adaptive locomotion in legged robots.     

The development of mouse APECED models provides new insight into the role of AIRE in immune regulation

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed.     

Atypical squamous cells. A case-series study of the association between papanicolaou smear results and human papillomavirus DNA genotype.

Thirty women with "atypical" squamous cells but not cervical intraepithelial neoplasia (CIN) on their Papanicolaou smears were tested for the presence of human papillomavirus (HPV) with the Southern blot hybridization technique. The Papanicolaou smears were reviewed for the presence of atypical squamous cells according to Patten's criteria. Comparison groups consisted of 30 patients with normal, 29 patients with CIN I and 24 patients with CIN II Papanicolaou smears. Ten of the 30 women (33%) with atypical cells on Papanicolaou smears were positive for HPV DNA as compared to 17% with normal and 59% with CIN I or II Papanicolaou smears. HPV 16 was present in 70-80% of the HPV DNA-positive patients in each Papanicolaou smear group. Concurrent CIN was also identified on colposcopically directed biopsies in 27% of the patients with squamous atypia. Patients with atypical squamous cells on Papanicolaou smears had coexisting HPV infection and CIN in about one-third of the cases. Colposcopy and further follow-up are recommended for such patients.     

Thoracic venous injuries: an imaging and management overview

Thoracic venous injuries are predominantly attributed to traumatic and iatrogenic causes. Gunshot wounds and knife stabbings make up the vast majority of penetrating trauma whereas motor vehicle collisions are the leading cause of blunt trauma to the chest. Iatrogenic injuries, mostly from central venous catheter complications are being described in growing detail. Although these injuries are rare, they pose a diagnostic challenge as their clinical presentation does not substantially differ from that of arterial injury. Furthermore, the highly lethal nature of some of these injuries provides limited literature for review and probably underestimates their true incidence. The widespread use of multi-detector computed tomography (MDCT) has increased the detection rate of these lesions in hemodynamically stable patients that survive the initial traumatic event. In this article, we will discuss and illustrate various causes of injury to each vein and their supporting CT findings while briefly discussing management. The available literature will be reviewed for penetrating, blunt, and iatrogenic injuries to the vena cava, innominate, subclavian, axillary, azygos, and pulmonary veins.