Efficient delivery of anti-miR-210 using Tachyplesin, a cell penetrating peptide, for glioblastoma treatment.

The levels of microRNAs (miRNAs) are altered in various diseases including glioblastoma (GBM) and this alteration may have widespread effects on various hallmarks of cancer cells. MiR210 is overexpressed in GBM and functions as an oncogenic miRNA. Anti-miR210 therapy holds great promise but its efficient delivery remains a major challenge. Our work here explores a novel role of Tachyplesin (Tpl), a cell-penetrating antimicrobial peptide, as a nanocarrier for anti-miR210. Tpl electrostatically interacts with anti-miR210 at 1:25 and 1:50 (anti-miR:Tpl) weight ratios to form a complex and efficiently delivers anti-miR210 inside GBM cells cultured as 2D and 3D spheroid model. Treatment of GBM cells with the complex significantly inhibited miR210 levels (~90%), proliferation, migration and spheroid formation ability and induced apoptosis as evident by increased levels of caspase 3/7 and ROS. GBM cells pre-treated with anti-miR210:Tpl complex were also found to be sensitive to TMZ mediated action. Uptake of the complex in GBM cells induced the levels of miR210 targeted tumor suppressor genes, NeuroD2 and HIF3A. Overall, our work reveals a novel and efficient miRNA delivery ability of Tpl in glioma cells, holding a great promise for treatment of GBM and potentially for other cancers.

Racioethnic differences in the biomechanical response of the lamina cribrosa.

Glaucoma is the second leading cause of irreversible blindness in the world with a higher prevalence in those of African Descent (AD) and Hispanic Ethnicity (HE) than in those of European Descent (ED). The objective of this study was to investigate the pressure dependent biomechanical response of the lamina cribrosa (LC) in normal human donor tissues from these racioethnic backgrounds. Pressure inflation tests were performed on 24 human LCs (n = 9 AD, n = 6 ED, and n = 9 HE) capturing the second harmonic generation (SHG) signal of collagen at 5, 15, 30, and 45 mmHg from an anterior view. A non-rigid image registration technique was utilized to determine the 3D displacement field in each LC from which 3D Green strains were calculated. The peak shear strain in the superior quadrant of the LC in those of ED was significantly higher than in those of AD and HE (p-value = 0.005 & 0.034, respectively) where ED = 0.017 [IQR = 0.012-0.027], AD = 0.0002 [IQR = -0.001-0.007], HE = 0.0016 [IQR = -0.002-0.012]). There were also significant differences in the regional strain heterogeneity in those of AD and HE that were absent in those of ED. This work represents, to our knowledge, the first ex-vivo study identifying significant differences in the biomechanical response of the LC in populations at increased risk of glaucoma. Future work will be necessary to assess if and how these differences play a role in predisposing those of Hispanic Ethnicity and African Descent to the onset and/or progression of primary open angle glaucoma. STATEMENT OF SIGNIFICANCE: Glaucoma is the second leading cause of irreversible blindness in the world and occurs more frequently in those of African Descent and Hispanic Ethnicity than in those of European Descent. To date, there has been no ex-vivo study quantifying differences in the biomechanical response of the non-glaucomatous lamina cribrosa (LC) across these racioethnic backgrounds. In this work we report, for the first time, differences in the pressure dependent biomechanical response of LC across different racioethnic groups as quantified using nonlinear optical microscopy. This study lays the foundation for future work investigating if and how these differences may play a role in predisposing those at increased risk to the onset and/or progression of primary open angle glaucoma.

Liver abscess caused by Burkholderia pseudomallei in a young man: A case report and review of literature.

Pyogenic liver abscess is a common entity in Indian subcontinent and is mostly caused by gram negative bacteria. Melioidosis is not commonly seen in India and only a few cases are reported. It can give rise to multiple abscesses at different sites including liver. We report a case of isolated liver abscess caused by Burkholderia pseudomallei (B. pseudomallei) in a 29-year-old recently diagnosed diabetic, immunocompetent male. Diagnosis was made by imaging and culture of pus aspirated from the abscess and he was treated with percutaneous pigtail catheter drainage followed by antibiotics (meropenem and trimethoprim-sulphmethoxazole). Melioidosis is an emerging infection in India and has high mortality rate, so early diagnosis and prompt management is warranted which requires clinical vigilance and an intensive microbiological workup. Clinicians should be aware of isolated liver abscess caused by B. pseudomallei in appropriate clinical settings.

Vivax malaria presenting with myelitis: a rare complication.

Neurological complications may occur with the Plasmodium falciparum infection. However, the association of neurological manifestations with vivax malaria remains doubtful. Of late, there are isolated case reports/studies which have implicated P. vivax in the pathogenesis of severe malaria which is characterized by the features of different organ dysfunctions, which were previously thought to be caused by P. falciparum alone. Though several case studies have mentioned the association of the P. vivax infection with cerebral malaria, a causal correlation has yet to be established. Dorsal cord myelitis (which leads to paraplegia) during the febrile illness, is rarely described in association with vivax malaria, though there are reports on the Post Malaria Neurological Syndrome (PMNS) and acute disseminated encephalomyelitis following vivax malaria. We are reporting a case of P. Vivax malaria which presented with myelitis, which responded well to the antimalarial treatment.

The importance of patient-specific regionally varying wall thickness in abdominal aortic aneurysm biomechanics.

Abdominal aortic aneurysm (AAA) is a vascular condition where the use of a biomechanics-based assessment for patient-specific risk assessment is a promising approach for clinical management of the disease. Among various factors that affect such assessment, AAA wall thickness is expected to be an important factor. However, regionally varying patient-specific wall thickness has not been incorporated as a modeling feature in AAA biomechanics. To the best our knowledge, the present work is the first to incorporate patient-specific variable wall thickness without an underlying empirical assumption on its distribution for AAA wall mechanics estimation. In this work, we present a novel method for incorporating regionally varying wall thickness (the "PSNUT" modeling strategy) in AAA finite element modeling and the application of this method to a diameter-matched cohort of 28 AAA geometries to assess differences in wall mechanics originating from the conventional assumption of a uniform wall thickness. For the latter, we used both a literature-derived population average wall thickness (1.5 mm; the "UT" strategy) as well as the spatial average of our patient-specific variable wall thickness (the "PSUT" strategy). For the three different wall thickness modeling strategies, wall mechanics were assessed by four biomechanical parameters: the spatial maxima of the first principal stress, strain, strain-energy density, and displacement. A statistical analysis was performed to address the hypothesis that the use of any uniform wall thickness model resulted in significantly different biomechanical parameters compared to a patient-specific regionally varying wall thickness model. Statistically significant differences were obtained with the UT modeling strategy compared to the PSNUT strategy for the spatial maxima of the first principal stress (p = 0.002), strain (p = 0.0005), and strain-energy density (p = 7.83 e-5) but not for displacement (p = 0.773). Likewise, significant differences were obtained comparing the PSUT modeling strategy with the PSNUT strategy for the spatial maxima of the first principal stress (p = 9.68 e-7), strain (p = 1.03 e-8), strain-energy density (p = 9.94 e-8), and displacement (p = 0.0059). No significant differences were obtained comparing the UT and PSUT strategies for the spatial maxima of the first principal stress (p = 0.285), strain (p = 0.152), strain-energy density (p = 0.222), and displacement (p = 0.0981). This work strongly recommends the use of patient-specific regionally varying wall thickness derived from the segmentation of abdominal computed tomography (CT) scans if the AAA finite element analysis is focused on estimating peak biomechanical parameters, such as stress, strain, and strain-energy density.

Fluid-structure interaction modeling of abdominal aortic aneurysms: the impact of patient-specific inflow conditions and fluid/solid coupling.

Rupture risk assessment of abdominal aortic aneurysms (AAA) by means of biomechanical analysis is a viable alternative to the traditional clinical practice of using a critical diameter for recommending elective repair. However, an accurate prediction of biomechanical parameters, such as mechanical stress, strain, and shear stress, is possible if the AAA models and boundary conditions are truly patient specific. In this work, we present a complete fluid-structure interaction (FSI) framework for patient-specific AAA passive mechanics assessment that utilizes individualized inflow and outflow boundary conditions. The purpose of the study is two-fold: (1) to develop a novel semiautomated methodology that derives velocity components from phase-contrast magnetic resonance images (PC-MRI) in the infrarenal aorta and successfully apply it as an inflow boundary condition for a patient-specific fully coupled FSI analysis and (2) to apply a one-way-coupled FSI analysis and test its efficiency compared to transient computational solid stress and fully coupled FSI analyses for the estimation of AAA biomechanical parameters. For a fully coupled FSI simulation, our results indicate that an inlet velocity profile modeled with three patient-specific velocity components and a velocity profile modeled with only the axial velocity component yield nearly identical maximum principal stress (σ1), maximum principal strain (ε1), and wall shear stress (WSS) distributions. An inlet Womersley velocity profile leads to a 5% difference in peak σ1, 3% in peak ε1, and 14% in peak WSS compared to the three-component inlet velocity profile in the fully coupled FSI analysis. The peak wall stress and strain were found to be in phase with the systolic inlet flow rate, therefore indicating the necessity to capture the patient-specific hemodynamics by means of FSI modeling. The proposed one-way-coupled FSI approach showed potential for reasonably accurate biomechanical assessment with less computational effort, leading to differences in peak σ1, ε1, and WSS of 14%, 4%, and 18%, respectively, compared to the axial component inlet velocity profile in the fully coupled FSI analysis. The transient computational solid stress approach yielded significantly higher differences in these parameters and is not recommended for accurate assessment of AAA wall passive mechanics. This work demonstrates the influence of the flow dynamics resulting from patient-specific inflow boundary conditions on AAA biomechanical assessment and describes methods to evaluate it through fully coupled and one-way-coupled fluid-structure interaction analysis.

Importance of Normal Values of CSF Parameters in Term Versus Preterm Neonates.

BACKGROUND: Evaluation of the cerebrospinal fluid (CSF) white blood cell (WBC) count and glucose and protein concentrations is used to assess the probability of the presence of central nervous system (CNS) infection. Although normal values are well established for CSF cell counts and protein and glucose contents in children and adults, this is not the case for neonates. AIMS: The purpose of this study was to evaluate the composition of noninfected CSF obtained by nontraumatic lumbar puncture in neonates (age<28 days), specifically distinguishing CSF profiles of those term babies compared with those premature infants. MATERIALS AND METHODS: The CSF samples obtained by lumbar puncture from 120 neonates were examined by routine procedures. RESULTS: By comparing CSF parameters between term gestation neonate group with premature neonate one, nontraumatic puncture, there was no statistically significant difference (P<0.05) in the mean WBC (P=0.6). The mean protein concentration was significantly greater in those premature neonates (P<0.04). The mean glucose concentration was also analogous in both groups (P=0.5). CONCLUSION: The CSF profile, like any other laboratory determination, should be evaluated within the clinical context of the individual case.

Systemic Sclerosis Presenting with Simultaneous Retinal Vasculitis in One Eye and Optic Neuritis in the other along with Severe Immune Haemolytic Anaemia.

Systemic Sclerosis (SSc) is a connective tissue disorder which involves multiple systems in a chronic progressive manner. Micro-angiopathic haemolytic anaemia is a distinguished feature of "scleroderma renal crisis", which is manifested by severe hypertension, a rapidly progressing renal dysfunction and hyperreninaemia and is seen in patients with an early, diffuse form of the disease. A nervous system involvement is rare, though entrapment neuropathies have been reported. Who presented with a sequential loss of vision in both eyes; due to retinal vasculitis in right eye and optic nerve demyelination in the left eye. She also had severe Coombs' negative haemolytic anaemia in absence of any renal dysfunction or hypertension. Both the ophthalmologic and the haematologic manifestations are very rare and both responded well to oral prednisolone therapy.

Impact of introducing the pneumococcal and rotavirus vaccines into the routine immunization program in Niger.

OBJECTIVES: We investigated whether introducing the rotavirus and pneumococcal vaccines, which are greatly needed in West Africa, would overwhelm existing supply chains (i.e., the series of steps required to get a vaccine from the manufacturers to the target population) in Niger. METHODS: As part of the Bill and Melinda Gates Foundation-funded Vaccine Modeling Initiative, we developed a computational model to determine the impact of introducing these new vaccines to Niger's Expanded Program on Immunization vaccine supply chain. RESULTS: Introducing either the rotavirus vaccine or the 7-valent pneumococcal conjugate vaccine could overwhelm available storage and transport refrigerator space, creating bottlenecks that would prevent the flow of vaccines down to the clinics. As a result, the availability of all World Health Organization Expanded Program on Immunization vaccines to patients might decrease from an average of 69% to 28.2% (range = 10%-51%). Addition of refrigerator and transport capacity could alleviate this bottleneck. CONCLUSIONS: Our results suggest that the effects on the vaccine supply chain should be considered when introducing a new vaccine and that computational models can help assess evolving needs and prevent problems with vaccine delivery.

Maintaining vaccine delivery following the introduction of the rotavirus and pneumococcal vaccines in Thailand.

Although the substantial burdens of rotavirus and pneumococcal disease have motivated many countries to consider introducing the rotavirus vaccine (RV) and heptavalent pneumococcal conjugate vaccine (PCV-7) to their National Immunization Programs (EPIs), these new vaccines could affect the countries' vaccine supply chains (i.e., the series of steps required to get a vaccine from their manufacturers to patients). We developed detailed computational models of the Trang Province, Thailand, vaccine supply chain to simulate introducing various RV and PCV-7 vaccine presentations and their combinations. Our results showed that the volumes of these new vaccines in addition to current routine vaccines could meet and even exceed (1) the refrigerator space at the provincial district and sub-district levels and (2) the transport cold space at district and sub-district levels preventing other vaccines from being available to patients who arrive to be immunized. Besides the smallest RV presentation (17.1 cm³/dose), all other vaccine introduction scenarios required added storage capacity at the provincial level (range: 20 L-1151 L per month) for the three largest formulations, and district level (range: 1 L-124 L per month) across all introduction scenarios. Similarly, with the exception of the two smallest RV presentation (17.1 cm³/dose), added transport capacity was required at both district and sub-district levels. Added transport capacity required across introduction scenarios from the provincial to district levels ranged from 1 L-187 L, and district to sub-district levels ranged from 1 L-13 L per shipment. Finally, only the smallest RV vaccine presentation (17.1 cm³/dose) had no appreciable effect on vaccine availability at sub-districts. All other RV and PCV-7 vaccines were too large for the current supply chain to handle without modifications such as increasing storage or transport capacity. Introducing these new vaccines to Thailand could have dynamic effects on the availability of all vaccines that may not be initially apparent to decision-makers.

Impact of changing the measles vaccine vial size on Niger's vaccine supply chain: a computational model.

BACKGROUND: Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. METHODS: We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. RESULTS: Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. CONCLUSIONS: The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child.

Lactam nonanic acid, a new substance from Cleome viscosa with allelopathic and antimicrobial properties.

Cleome viscosa L. (Capparidaceae) is well known for its medicinal properties. Lactam nonanoic acid (LNA) [2-amino-9-(4-oxoazetidin-2-yl)-nonanoic acid; C12H22N2O3, mol. wt. 242] has been isolated and purified from the root exudates of Cleome viscosa. The aqueous solution of this pure compound has been tested on bacteria (Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus) and fungi (Aspergillus fumigatus, A. niger and A. tamarii). At a dosage of 500 ppm and above, P. aeruginosa and S. aureus were totally inhibited while E. coli remained unaffected. On the other hand, growth of A. niger and A. tamarii was stimulated while there was no effect on A. fumigatus. This pure compound showed concentration-dependent inhibitory activity on rice, gram and mustard seeds.

Replacing the measles ten-dose vaccine presentation with the single-dose presentation in Thailand.

Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes involved in distributing vaccines from manufacturers to patients). We developed a computational model of Thailand's Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose measles-mumps-rubella vaccine (which Thailand is currently considering) or a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations' storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage.

Mass sensing based on deterministic and stochastic responses of elastically coupled nanocantilevers.

Coupled nanomechanical systems and their entangled eigenstates offer unique opportunities for the detection of ultrasmall masses. In this paper we show theoretically and experimentally that the stochastic and deterministic responses of a pair of coupled nanocantilevers provide different and complementary information about the added mass of an analyte and its location. This method allows the sensitive detection of minute quantities of mass even in the presence of large initial differences in the active masses of the two cantilevers. Finally, we show the fundamental limits in mass detection of this sensing paradigm.