Magnetic Lateral Ladder for Unidirectional Transport of Microrobots: Design Principles and Potential Applications of Cells-on-Chip.

Functionalized microrobots, which are directionally manipulated in a controlled and precise manner for specific tasks, face challenges. However, magnetic field-based controls constrain all microrobots to move in a coordinated manner, limiting their functions and independent behaviors. This article presents a design principle for achieving unidirectional microrobot transport using an asymmetric magnetic texture in the shape of a lateral ladder, which the authors call the "railway track." An asymmetric magnetic energy distribution along the axis allows for the continuous movement of microrobots in a fixed direction regardless of the direction of the magnetic field rotation. The authors demonstrated precise control and simple utilization of this method. Specifically, by placing magnetic textures with different directionalities, an integrated cell/particle collector can collect microrobots distributed in a large area and move them along a complex trajectory to a predetermined location.  The authors can leverage the versatile capabilities offered by this texture concept, including hierarchical isolation, switchable collection, programmable pairing, selective drug-response test, and local fluid mixing for target objects. The results demonstrate the importance of microrobot directionality in achieving complex individual control. This novel concept represents significant advancement over conventional magnetic field-based control technology and paves the way for further research in biofunctionalized microrobotics.

Autonomous Magnetic Microrobots by Navigating Gates for Multiple Biomolecules Delivery.

The precise delivery of biofunctionalized matters is of great interest from the fundamental and applied viewpoints. In spite of significant progress achieved during the last decade, a parallel and automated isolation and manipulation of rare analyte, and their simultaneous on-chip separation and trapping, still remain challenging. Here, a universal micromagnet junction for self-navigating gates of microrobotic particles to deliver the biomolecules to specific sites using a remote magnetic field is described. In the proposed concept, the nonmagnetic gap between the lithographically defined donor and acceptor micromagnets creates a crucial energy barrier to restrict particle gating. It is shown that by carefully designing the geometry of the junctions, it becomes possible to deliver multiple protein-functionalized carriers in high resolution, as well as MCF-7 and THP-1 cells from the mixture, with high fidelity and trap them in individual apartments. Integration of such junctions with magnetophoretic circuitry elements could lead to novel platforms without retrieving for the synchronous digital manipulation of particles/biomolecules in microfluidic multiplex arrays for next-generation biochips.

Magnetically Selective Versatile Transport of Microrobotic Carriers.

Field-driven transport systems offer great promise for use as biofunctionalized carriers in microrobotics, biomedicine, and cell delivery applications. Despite the construction of artificial microtubules using several micromagnets, which provide a promising transport pathway for the synchronous delivery of microrobotic carriers to the targeted location inside microvascular networks, the selective transport of different microrobotic carriers remains an unexplored challenge. This study demonstrated the selective manipulation and transport of microrobotics along a patterned micromagnet using applied magnetic fields. Owing to varied field strengths, the magnetic beads used as the microrobotic carriers with different sizes revealed varied locomotion, including all of them moving along the same direction, selective rotation, bidirectional locomotion, and all of them moving in a reversed direction. Furthermore, cells immobilized with magnetic beads and nanoparticles also revealed varied locomotion. It is expected that such steering strategies of microrobotic carriers can be used in microvascular channels for the targeted delivery of drugs or cells in an organized manner.

Ultrasonic alignment of bio-functionalized magnetic beads and live cells in PDMS micro-fluidic channel.

In this work, we demonstrated the alignment of polystyrene latex microspheres (diameter of 1 ~45 µm), bio-functionalized superparamagnetic beads (diameter 2.8 µm), and live cells (average diameter 1 ~2 µm) using an ultrasonic standing wave (USW) in a PDMS microfluidic channel (330 µm width) attached on a Si substrate for bio-medical applications. To generate a standing wave inside the channel, ultrasound of 2.25 MHz resonance frequency (for the channel width) was applied by two ultrasound transducers installed at both sides of the channel which caused the radiation force to concentrate the micro-particles at the single pressure nodal plane of USW. By increasing the frequency to the next resonance condition of the channel, the particles were concentrated in dual nodal planes. Migration time of the micro-particles towards the single nodal plane was recorded as 108 s, 17 s, and 115 s for polystyrene particles of 2 µm diameter, bio-functionalized magnetic beads, and live cells, respectively. These successful alignments of the bio-functionalized magnetic beads along the desired part of the channel can enhance the performance of a sensor which is applicable for the bio-hybrid system and the alignment of live cells without any damage can be used for sample pre-treatment for the application of lab-on-a-chip type bioassays.

Effect of the Graphene- Ni/NiFe2O4 Composite on Bacterial Inhibition Mediated by Protein Degradation.

Recent investigations have demonstrated that nickel ferrite nanoparticles and their derivatives have toxicity effects on bacterial cells. In this study, we have prepared nickel ferrite nanoparticles (Ni/NiFe2O4) and nickel/nickel ferrite graphene oxide (Ni/NiFe2O4-GO) nanocomposite and evaluated their toxic effects on E. coli cells ATCC 25922. The prepared nanomaterials were characterized using X-ray diffraction, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, and vibrating sample magnetometry techniques. The toxicity was evaluated using variations in cell viability, cell morphology, protein degradation, and oxidative stress. Ni/NiFe2O4-GO nanocomposites likewise prompt oxidative stress proved by the age of reactive oxygen species (ROS) and exhaustion of antioxidant glutathione. This is the first report indicating that Ni/NiFe2O4-GO nanocomposite-initiated cell death in E. coli through ROS age and oxidative stress.

Reversible right-sided heart failure and pulmonary hypertension caused by scurvy in a 7-year-old boy with autism spectrum disorder and a review of the literature.

Scurvy, a condition caused by vitamin C deficiency, is rare, especially in high-income countries. Symptoms of scurvy are typically characterised by dermatological disorders such as poor wound healing and tooth loss, but there is not usually cardiac involvement. A case of reversible pulmonary hypertension and right-sided heart failure owing to scurvy in a 7-year-old boy with autism spectrum disorder is reported. He had a very restricted diet and presented with polyarthralgia, gingival hyperplasia with ecchymosis, and fatigue. His condition, including pulmonary hypertension and right-sided heart failure, completely resolved with vitamin C supplementation. Paediatricians should have a high index of suspicion for scurvy in children with nutritional selectivity and be aware that it can manifest with cardiac symptoms. Scurvy may be life-threatening if not treated, but the symptoms can improve rapidly with vitamin C supplementation.

Additional Inhibition of Wnt/ß-Catenin Signaling by Metformin in DAA Treatments as a Novel Therapeutic Strategy for HCV-Infected Patients.

Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/ß-catenin signaling activation due to the inhibition of GSK-3ß activity via serine 9 phosphorylation (p-ser9-GSK-3ß) leading to stable non-phosphorylated ß-catenin. Immunohistochemical staining demonstrated the upregulation of both ß-catenin and p-Ser9-GSK-3ß in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of ß-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/ß-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3ß-mediated ß-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/ß-catenin signaling for HCV-infected patients.

Extracellular Vesicle Release Promotes Viral Replication during Persistent HCV Infection.

Hepatitis C virus (HCV) infection promotes autophagic degradation of viral replicative intermediates for sustaining replication and spread. The excessive activation of autophagy can induce cell death and terminate infection without proper regulation. A prior publication from this laboratory showed that an adaptive cellular response to HCV microbial stress inhibits autophagy through beclin 1 degradation. The mechanisms of how secretory and degradative autophagy are regulated during persistent HCV infection is unknown. This study was performed to understand the mechanisms of viral persistence in the absence of degradative autophagy, which is essential for virus survival. Using HCV infection of a CD63-green fluorescence protein (CD63-GFP), labeled stable transfected Huh-7.5 cell, we found that autophagy induction at the early stage of HCV infection increased the degradation of CD63-GFP that favored virus replication. However, the late-stage of persistent HCV infection showed impaired autophagic degradation, leading to the accumulation of CD63-GFP. We found that impaired autophagic degradation promoted the release of extracellular vesicles and exosomes. The impact of blocking the release of extracellular vesicles (EVs) on virus survival was investigated in persistently infected cells and sub-genomic replicon cells. Our study illustrates that blocking EV and exosome release severely suppresses virus replication without effecting host cell viability. Furthermore, we found that blocking EV release triggers interferon lambda 1 secretion. These findings suggest that the release of EVs is an innate immune escape mechanism that promotes persistent HCV infection. We propose that inhibition of extracellular vesicle release can be explored as a potential antiviral strategy for the treatment of HCV and other emerging RNA viruses.

Streptococcal emm types in Hawaii: a region with high incidence of acute rheumatic fever.

BACKGROUND: The clinical epidemiology of group A streptococcal (GAS) infections in Hawaii seems different from that in the continental United States with frequent skin infections and endemically high rates of acute rheumatic fever (ARF). METHODS: GAS emm types in Hawaii were determined to identify any possible association between the emm types and specific clinical manifestations. A convenience sample of 1482 Hawaii GAS isolates collected between February 2000 and December 2005 was used. All isolates were characterized by emm sequence typing. The distribution of emm types in Hawaii was compared with the published continental US data for pharyngeal and invasive GAS strains, the CDC database from similar time periods, as well as with emm types present in a candidate GAS vaccine. RESULTS: Ninety-three distinct emm types were recognized among the 1482 GAS isolates. The most frequently identified emm types in order of decreasing frequency were 12, 1, 28, 4, 22, 77, 81, 58, 65/69, 49, 74, 85, 92, 75, 101 and 2. Of this study sample, 27 of the 50 invasive GAS isolates belonged to uncommon continental US emm types (54% in Hawaii cultures vs. 10% reported from the continental US). Of the 1179 pharyngeal isolates, 509 belonged uncommon continental US emm types (43% in Hawaii cultures vs. 27% reported from the continental US). CONCLUSIONS: The prevalent emm types in Hawaii differ from those in the continental US. The prevalence of these unusual emm types might limit the effectiveness of any proposed multivalent type-specific GAS vaccine in Hawaii.

Paroxysmal Nocturnal Dyspnea Secondary to Right Ventricular Myxoma: A Novel Presentation of an Unusual Tumor.

A 14-month-old male presented with paroxysmal nocturnal dyspnea and grade III/VI systolic ejection murmur at the upper left sternal border with an S4 gallop and was subsequently found to have a right ventricular cardiac myxoma. Prior presentations of these tumors have been with exertional syncope and murmur, asymptomatic murmur, or exertional dyspnea; the presentation of such a tumor with paroxysmal nocturnal dyspnea is novel.

Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) - A phase II clinical trial.

BACKGROUND: Kawasaki disease (KD) is the most common acquired heart disease in children of the developed world, and triggers progressive coronary artery lesions (CAL) in 30% of cases if left untreated. Despite standard anti-inflammatory treatment for KD, CAL (dilation or aneurysm) still occurs in 5-10% of children, increasing their risk for fatal coronary artery complications. CAL is mediated by enhanced matrix metalloproteinase activity and elastin breakdown induced by the inflammatory process in the coronary artery wall. Doxycycline is an effective inhibitor of matrix metalloproteinases, and has been shown to reduce elastin breakdown and CAL in a mouse model of KD, but has not been evaluated in patients. OBJECTIVE: We aim to evaluate the efficacy of doxycycline in the prevention of CAL in children during the acute phase of KD. DESIGN: This is a phase II prospective, randomized, double-blinded, clinical trial in two steps. In Step 1, any child older than 1month with the diagnosis of KD will be included. Children with KD will be included in Step 2 if they develop coronary artery dilation (z-score≥2.5) within 20days from the onset of fever. Study subjects in Step 2 will be randomized to receive a 3-week course of doxycycline or placebo. EVALUATION: The efficacy of a 3-week doxycycline course during the acute phase of KD will be evaluated by measuring the decline in coronary artery z-scores from baseline with doxycycline treatment compared to placebo. CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov (NCT01917721).

Group A streptococcal isolates temporally associated with acute rheumatic fever in Hawaii: differences from the continental United States.

BACKGROUND: The annual incidence of acute rheumatic fever (ARF) in Hawaii has remained several times higher than that in the continental United States, particularly among ethnic Polynesians. The emm types of Streptococcus pyogenes that are associated with this nonsuppurative complication have, to our knowledge, not been previously reported in Hawaii. METHODS: Patients with ARF were identified through an active surveillance system at Kapiolani Medical Center (Honolulu, HI), the only pediatric tertiary care referral hospital in Hawaii. Specimens were obtained by throat culture from patients who met the Jones criteria for ARF at the time of presentation (63 patients), prior to penicillin treatment, and from consenting family contacts (10 individuals). Eight patients and 2 close family contacts with positive throat culture results were identified from February 2000 through December 2005. Group A streptococci isolates were characterized by emm sequence typing. RESULTS: Unusual emm types were temporally associated with the onset of ARF. Emm types 65/69 (from 2 patients), 71, 92, 93, 98, 103, and 122 were isolated from the 8 patients with ARF, and emm types 52 and 101 were isolated from the 2 household contacts. CONCLUSIONS: So-called rheumatogenic emm types and/or serotypes, which were previously associated with ARF in the continental United States, were not found in this study. Instead, emm types that are not commonly included among group A streptococci isolates in the continental United States and that are seldom, if ever, temporally associated with ARF were identified. These findings suggest that unusual group A streptococci emm types play a significant role in the epidemiology of ARF in Hawaii.

Relative suppression of magical thinking: a transcranial magnetic stimulation study.

The tendency to perceive meaning in noise (apophenia) has been linked to "magical thinking" (MT), a distinctive form of thinking associated with a range of normal cognitive styles, anomalous perceptual experiences and frank psychosis. Important aspects of MT include the propensity to imbue meaning or causality to events that might otherwise be considered coincidental. Structures in the lateral temporal lobes have been hypothesised to be involved in both the clinical and nonclinical aspects of MT. Accordingly, in this study we used single-pulse transcranial magnetic stimulation (TMS) to stimulate either the left or right lateral temporal areas, or the vertex, of 12 healthy participants (balanced for similar levels of MT, delusional ideation and temporal lobe disturbance) while they were required to indicate if they had "detected" pictures, claimed to be present by the experimenters, in visual noise. Relative to the vertex, TMS inhibition of the left lateral temporal area produced significant reduced tendency to report meaningful information, suggesting that left lateral temporal activation may be more important in MT and therefore producing and supporting anomalous beliefs and experiences. The effect cannot simply be explained by TMS induced cognitive slowing as reaction times were not affected.

Facile synthesis of bovine serum albumin conjugated low-dimensional ZnS nanocrystals.

We present a facile synthesis of bovine serum albumin (BSA) conjugated low-dimensional ZnS nanocrystals. The experimental parameters such as effects of BSA concentration and precursor vol ratios of Zn:S on the formation of ZnS nanoparticles in BSA matrix were investigated. The ZnS crystalline sizes of 1.9, 1.8 and 1.6nm were obtained by using the BSA concentrations of 1×10-4, 5×10-4 and 10×10-4g/mL, respectively, with a fixed Zn:S vol ratio of 1:1. The ZnS samples prepared from 1:10 and 10:1 vol ratios of Zn:S at BSA concentration of 5×10-4g/mL shows the crystalline sizes of ZnS are 2.1 and 1.5nm, respectively. FT-IR analysis suggests that the prepared ZnS nanoparticles might be conjugated through the interactions of hydroxyl and amine groups present in BSA. We evaluate the cytotoxicity of the prepared ZnS nanoparticles, the THP-1 cells showed a good viability (>88%) for all the prepared ZnS samples. The plausible mechanism for the formation of ZnS-BSA composite has also been discussed.

Electrochemical biosensor for Mycobacterium tuberculosis DNA detection based on gold nanotubes array electrode platform.

The template assisted electrochemical deposition technique was used for the synthesis of gold nanotubes array (AuNTsA). The morphological structure of the synthesized AuNTsA was observed by scanning electron microscopy and found that the individual nanotubes are around 1.5 µm in length with a diameter of 200 nm. Nanotubes are vertically aligned to the Au thick film, which is formed during the synthesis process of nanotubes. The electrochemical performance of the AuNTsA was compared with the bare Au electrode and found that AuNTsA has better electron transfer surface than bare Au electrode which is due to the high surface area. Hence, the AuNTsA was used as an electrode for the fabrication of DNA hybridization biosensor for detection of Mycobacterium Tuberculosis DNA. The DNA hybridization biosensor constructed by AuNTsA electrode was characterized by cyclic voltammetry technique with Fe(CN)6(3-/4-) as an electrochemical redox indicator. The selectivity of the fabricated biosensor was illustrated by hybridization with complementary DNA and non-complementary DNA with probe DNA immobilized AuNTsA electrode using methylene blue as a hybridization indicator. The developed electrochemical DNA biosensor shows good linear range of complementary DNA concentration from 0.01 ng/µL to 100 ng/µL with high detection limit.

Is there an association between oral submucous fibrosis and ABO blood grouping?

BACKGROUND: Oral submucous fibrosis (OSMF) is one of the most common premalignant conditions in Indian subcontinent due to the traditional use of Areca nut and its various preparations. The genetic predisposition has also been reported in its etiopathogenesis. The rate of malignant transformation is between 7% to 14%. AIM: To evaluate whether ABO blood group is related to OSMF risk. SUBJECTS AND METHODS: It was a cross-sectional hospital-based study. A convenient sample of 164 study subjects constituted the cases and 180 subjects constituted the comparison group. STATISTICAL ANALYSIS USED: The results were analyzed using chi-square test and odds ratio. RESULTS: The chi-square analysis could not establish any significant relationship between OSMF and ABO blood group. But, when the strength of the association was measured using odds ratio, subjects with blood group A had 1.181 times higher risk of developing OSMF in comparison to other groups. CONCLUSION: The subjects with blood group A were at higher risk of developing OSMF in comparison to others. By performing blood group determination using a routine method at outreach programs, the susceptible individuals can be identified and counselled to quit the habit, thereby avoiding potential complications.

Underdiagnosis of Conditions Associated with Sudden Cardiac Death in Children--Is it the Absence of a Comprehensive Screening Program or a True Low Prevalence?

This study aimed to assess the prevalence of conditions associated with sudden cardiac death (SCD) among all children and children with sudden infant death syndrome (SIDS) in the State of Hawai'i, where no comprehensive screening program is conducted for such conditions. A retrospective chart review was conducted from the single tertiary pediatric hospital in Hawai'i, from offices of all pediatric cardiologists in Hawai'i, and the Hawai'i State Department of Health from 1/1/2000 to 12/31/2013. Children aged 0-18 years were included in the study. A subset of the study analyzed records of infants aged 0-12 months. SIDS rate was calculated and compared to national data. Prevalence was calculated for known conditions associated with SCD. The identified prevalence was compared to the established prevalence of conditions associated with SCD. In Hawai'i, the infant SIDS rate (66.4/100,000) was similar to the national rate (54.4/100,000). Over 14 years, only 51 children were diagnosed with a condition associated with SCD; 28 with a cardiomyopathy and 21 with a channelopathy. A 14-year retrospective analysis in the State of Hawai'i revealed that less than 1 in 30 children, who are expected to harbor a SCD-associated condition, had been appropriately diagnosed. The underdiagnosis of conditions associated with SCD reflects that in the absence of a comprehensive screening program, conditions without obvious signs and symptoms are difficult to diagnose. Many children with these conditions will remain at risk of SCD.

Auto-PEEP: how to detect and how to prevent--a review.

Auto-positive end expiratory pressure (auto-PEEP) is a physiologic event that is common to mechanically ventilated patients. Auto-PEEP is commonly found in acute severe asthma, chronic obstructive pulmonary disease, or patients receiving inverse ratio ventilation. Factors predisposing to auto-PEEP include a reduction in expiratory time by increasing the respiratory rate, tidal volume or inspiratory time. Auto-PEEP predisposes the patient to increased work of breathing, barotrauma, hemodynamic instability and difficulty in triggering the ventilator. Failure to recognize the hemodynamic consequences of auto-PEEP may lead to inappropriate fluid restriction or unnecessary vasopressor therapy. Auto-PEEP can potentially interfere with weaning from mechanical ventilation. Many methods have been described to measure the Auto-PEEP. Although not apparent during normal ventilator operation, the auto-PEEP effect can be detected and quantified by a simple bedside maneuver: expiratory port occlusion at the end of the set exhalation period. The measurement of static and dynamic auto-PEEP differs and depends upon the heterogeneity of the airways. The work of breathing can be decreased by providing external PEEP to 75-80% of auto-PEEP in patients who are spontaneously breathing during mechanical ventilation but there is no evidence such external PEEP would be useful during controlled mechanical ventilation when there is no patient inspiratory effort. Ventilator setting should aim for a prolonged expiratory time by reducing the respiratory rate rather than increasing inspiratory flow. Routine monitoring for auto-PEEP in patients receiving controlled ventilation is recommended.

Protein immobilization onto electrochemically synthesized CoFe nanowires.

CoFe nanowires have been synthesized by the electrodeposition technique into the pores of a polycarbonate membrane with a nominal pore diameter of 50 nm, and the composition of CoFe nanowires varying by changing the source concentration of iron. The synthesized nanowire surfaces were functionalized with amine groups by treatment with aminopropyltriethoxysilane (APTES) linker, and then conjugated with streptavidin-Cy3 protein via ethyl (dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide coupling chemistry. The oxide surface of CoFe nanowire is easily modified with aminopropyltriethoxysilane to form an amine terminating group, which is covalently bonded to streptavidin-Cy3 protein. The physicochemical properties of the nanowires were analyzed through different characterization techniques such as scanning electron microscope, energy dispersive spectroscopy, and vibrating sample magnetometer. Fluorescence microscopic studies and Fourier transform infrared studies confirmed the immobilization of protein on the nanowire surface. In addition, the transmission electron microscope analysis reveals the thin protein layer which is around 12-15 nm on the nanowire surfaces.