MRI evaluation of articular cartilage in patients with juvenile osteochondritis dissecans (JOCD) using T2∗ mapping at 3T.

OBJECTIVE: Evaluate articular cartilage by magnetic resonance imaging (MRI) T2∗ mapping within the distal femur and proximal tibia in adolescents with juvenile osteochondritis dissecans (JOCD). DESIGN: JOCD imaging studies acquired between August 2011 and February 2019 with clinical and T2∗ mapping MRI knee images were retrospectively collected and analyzed for 31 participants (9F/22M, 15.0 ± 3.8 years old) with JOCD lesions in the medial femoral condyle (MFC). In total, N = 32 knees with JOCD lesions and N = 14 control knees were assessed. Mean T2∗ values in four articular cartilage regions-of-interest (MFC, lateral femoral condyle (LFC), medial tibia (MT), and lateral tibia (LT)) and lesion volume were measured and analyzed using Wilcoxon-rank-sum tests and Spearman correlation coefficients (R). RESULTS: Mean ± standard error T2∗ differences observed between the lesion-sided MFC and the LFC in JOCD-affected knees (28.5 ± 0.9 95% confidence interval [26.8, 30.3] vs 26.3 ± 0.7 [24.8, 27.7] ms, P = 0.088) and between the affected- and control-knee MFC (28.5 ± 0.9 [26.8, 30.3] vs 28.5 ± 0.6 [27.1, 29.9] ms, P = 0.719) were nonsignificant. T2∗ was significantly increased in the lesion-sided MT vs the LT for the JOCD-affected knees (21.5 ± 0.7 [20.1, 22.9] vs 18.0 ± 0.7 [16.5, 19.5] ms, P = 0.002), but this same difference was also observed between the MT and LT in control knees (21.0 ± 0.6 [19.7, 22.3] vs 18.1 ± 1.1 [15.8, 20.4] ms, P = 0.037). There was no significant T2∗ difference between the affected- and control-knee MT (21.5 ± 0.7 [20.1, 22.9] vs 21.0 ± 0.6 [19.7, 22.3] ms, P = 0.905). T2∗ within the lesion-sided MFC was not correlated with patient age (R = 0.20, P = 0.28) or lesion volume (R = 0.06, P = 0.75). T2∗ values were slightly increased near lesions in later-stage JOCD subjects but without statistical significance. CONCLUSIONS: T2∗ relaxations times were not significantly different from control sites in the articular cartilage overlying JOCD lesions in the MFC or adjacent MT cartilage in early-stage JOCD.

Automated tracheal intubation in an airway manikin using a robotic endoscope: a proof of concept study.

Robotic endoscope-automated via laryngeal imaging for tracheal intubation (REALITI) has been developed to enable automated tracheal intubation. This proof-of-concept study using a convenience sample of participants, comprised of trained anaesthetists and lay participants with no medical training, assessed the performance of a robotic device for the insertion of a tracheal tube into a manikin. A prototype robotic endoscope device was inserted into the trachea of an airway manikin by seven anaesthetists and seven participants with no medical training. Each individual performed six device insertions into the trachea in manual mode and six in automated mode. The anaesthetists succeeded with 40/42 (95%) manual insertions (median (IQR [range]) 17 (12-26 [4-132]) s) and 40/42 (95%) automated insertions (15 (13-18 [7-25]) s). The non-trained participants succeeded in 41/42 (98%) manual insertions (median (IQR [range]) 18 (13-21 [8-133]) s) and 42/42 (100%) automated insertions (16 (13-23 [10-58])] s). The duration of insertion did not differ between groups. An effect of increasing experience was observed in both groups in manual mode. A Likert scale for 'ease of use' (0 = very difficult to 10 = very easy) showed similar results within the two groups; the mean (SD) was 5.9 (2.1) for the anaesthetists and 6.9 (1.3) for the non-trained participants. We have successfully performed the first automated tracheal device insertion in a manikin with comparable results in a convenience sample of anaesthetists and lay participants with no medical training.

Dexterous helical magnetic robot for improved endovascular access.

Treating vascular diseases in the brain requires access to the affected region inside the body. This is usually accomplished through a minimally invasive technique that involves the use of long, thin devices, such as wires and tubes, that are manually maneuvered by a clinician within the bloodstream. By pushing, pulling, and twisting, these devices are navigated through the tortuous pathways of the blood vessels. The outcome of the procedure heavily relies on the clinician's skill and the device's ability to navigate to the affected target region in the bloodstream, which is often inhibited by tortuous blood vessels. Sharp turns require high flexibility, but this flexibility inhibits translation of proximal insertion to distal tip advancement. We present a highly dexterous, magnetically steered continuum robot that overcomes pushability limitations through rotation. A helical protrusion on the device's surface engages with the vessel wall and translates rotation to forward motion at every point of contact. An articulating magnetic tip allows for active steerability, enabling navigation from the aortic arch to millimeter-sized arteries of the brain. The effectiveness of the magnetic continuum robot has been demonstrated through successful navigation in models of the human vasculature and in blood vessels of a live pig.

Precise control of the number of walls formed during carbon nanotube growth using chemical vapor deposition.

We demonstrate a one-step approach for selecting the number of walls formed during carbon nanotube (CNT) growth by catalytic decomposition of CH(4) over Fe-Mo/MgO catalysts. Scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), thermal gravimetric analysis (TGA) and Raman spectroscopy analyses indicate that high purity single-walled, double-walled and triple-walled carbon nanotubes can be synthesized by tuning the Fe:Mo atomic ratio of catalysts. The results reveal that the concentration of Mo in the catalyst plays an important role in the size of catalyst particles and in the deposition rate of carbon atoms during CNT growth. Thus, the wall numbers of CNTs can be controlled precisely.

Structural and magnetic characterization of batch-fabricated nickel encapsulated multi-walled carbon nanotubes.

We report on the growth and fabrication of Ni-filled multi-walled carbon nanotubes (Ni-MWNTs) with an average diameter of 115 nm and variable length of 400 nm-1 µm. The Ni-MWNTs were grown using template-assisted electrodeposition and low pressure chemical vapor deposition (LPCVD) techniques. Anodized alumina oxide (AAO) templates were fabricated on Si using a current controlled process. This was followed by the electrodeposition of Ni nanowires (NWs) using galvanostatic pulsed current (PC) electrodeposition. Ni NWs served as the catalyst to grow Ni-MWNTs in an atmosphere of H2/C2H2 at a temperature of 700 °C. Time dependent depositions were carried out to understand the diffusion and growth mechanism of Ni-MWNTs. Characterization was carried out using scanning electron microscopy (SEM), focused ion beam (FIB) milling, transmission electron microscopy (TEM), Raman spectroscopy and energy dispersive x-ray spectroscopy (EDX). TEM analysis revealed that the Ni nanowires possess a fcc structure. To understand the effects of the electrodeposition parameters, and also the effects of the high temperatures encountered during MWNT growth on the magnetic properties of the Ni-MWNTs, vibrating sample magnetometer (VSM) measurements were performed. The template-based fabrication method is repeatable, efficient, enables batch fabrication and provides good control on the dimensions of the Ni-MWNTs.

Image-based 3D reconstruction using helical nanobelts for localized rotations.

A variety of different methods exist for gathering three-dimensional information for micro- and nanoscale objects. Tilting of samples in a scanning electron microscope provides a non-destructive way of generating these data. Traditionally, the reconstruction of this image data is performed by stereo photogrammetric methods that compare features from two or three frames. We propose the application of techniques from the structure-from-motion community as being efficient, high-precision alternatives to stereo methods, which allows for automated utilization of a large number of sampled images. We propose the use of nanobelts to generate localized rotational motions. Using this method alleviates the demand of high-precision actuators, allows 360 degrees rotations, and provides a useful tool for micro- and nanomanipulation.

Mechanically interlocked 3D multi-material micromachines.

Metals and polymers are dissimilar materials in terms of their physicochemical properties, but complementary in terms of functionality. As a result, metal-organic structures can introduce a wealth of novel applications in small-scale robotics. However, current fabrication techniques are unable to process three-dimensional metallic and polymeric components. Here, we show that hybrid microstructures can be interlocked by combining 3D lithography, mold casting, and electrodeposition. Our method can be used to achieve complex multi-material microdevices with unprecedented resolution and topological complexity. We show that metallic components can be combined with structures made of different classes of polymers. Properties of both metals and polymers can be exploited in parallel, resulting in structures with high magnetic responsiveness, elevated drug loading capacity, on-demand shape transformation, and elastic behavior. We showcase the advantages of our approach by demonstrating new microrobotic locomotion modes and controlled agglomeration of swarms.

Stability and analysis of configuration-tunable bi-directional MWNT bearings.

We report on the energetic and structural stability of configuration-tunable, bi-directional linear bearings based on cap-less, partial segments engineered within individual multi-walled carbon nanotubes (MWNTs). Using computational models, we show that an externally applied excitation force can be used to select an operating bearing configuration with a desired stiffness and operating frequency. Our models also demonstrate the possibility of simultaneous, independent operation of multiple bearings within a single NT segment, paving the way towards ultra-high device densities with molecular-scale footprints.

Adaptive locomotion of artificial microswimmers.

Bacteria can exploit mechanics to display remarkable plasticity in response to locally changing physical and chemical conditions. Compliant structures play a notable role in their taxis behavior, specifically for navigation inside complex and structured environments. Bioinspired mechanisms with rationally designed architectures capable of large, nonlinear deformation present opportunities for introducing autonomy into engineered small-scale devices. This work analyzes the effect of hydrodynamic forces and rheology of local surroundings on swimming at low Reynolds number, identifies the challenges and benefits of using elastohydrodynamic coupling in locomotion, and further develops a suite of machinery for building untethered microrobots with self-regulated mobility. We demonstrate that coupling the structural and magnetic properties of artificial microswimmers with the dynamic properties of the fluid leads to adaptive locomotion in the absence of on-board sensors.

Synthetic and living micropropellers for convection-enhanced nanoparticle transport.

Nanoparticles (NPs) have emerged as an advantageous drug delivery platform for the treatment of various ailments including cancer and cardiovascular and inflammatory diseases. However, their efficacy in shuttling materials to diseased tissue is hampered by a number of physiological barriers. One hurdle is transport out of the blood vessels, compounded by difficulties in subsequent penetration into the target tissue. Here, we report the use of two distinct micropropellers powered by rotating magnetic fields to increase diffusion-limited NP transport by enhancing local fluid convection. In the first approach, we used a single synthetic magnetic microrobot called an artificial bacterial flagellum (ABF), and in the second approach, we used swarms of magnetotactic bacteria (MTB) to create a directable "living ferrofluid" by exploiting ferrohydrodynamics. Both approaches enhance NP transport in a microfluidic model of blood extravasation and tissue penetration that consists of microchannels bordered by a collagen matrix.

Antiangiogenic activity of prostate-specific antigen.

BACKGROUND: Measurement of serum levels of prostate-specific antigen (PSA) is widely used as a screening tool for prostate cancer. However, PSA is not prostate specific, having been detected in breast, lung, and uterine cancers. In one study, patients whose breast tumors had higher levels of PSA had a better prognosis than patients whose tumors had lower PSA levels. To test the hypothesis that PSA may have antiangiogenic properties, we evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion, which are key steps in angiogenesis, the process by which tumors develop a blood supply. METHODS: To assess the antiproliferative effects of PSA, we treated bovine endothelial cells and human endothelial cell lines (HUVEC and HMVEC-d) with purified human PSA (0.1-10 microM) and then stimulated them with 10 ng/mL fibroblast growth factor-2 (FGF-2). Effects on FGF-2- or vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration, invasion, and tube formation were measured by use of one cell line only (HUVEC). PSA was administered to mice at 9 microM for 11 consecutive days after intravenous inoculation of B16BL6 melanoma cells to assess its ability to inhibit the formation of lung colonies (i.e., metastatic tumors). RESULTS: PSA inhibited endothelial cell proliferation, migration, and invasion at IC(50) (i. e., the concentration at which inhibition was 50%) values ranging from 0.3-5 microM. In addition, PSA inhibited endothelial cell responses to both angiogenic stimulators tested, FGF-2 and VEGF. In a mouse model of metastatic disease, daily PSA treatment resulted in a 40% reduction in the mean number of lung tumor nodules compared with phosphate-buffered saline treatment (two-sided P =.003). CONCLUSION: To our knowledge, this is the first report that PSA may function in tumors as an endogenous antiangiogenic protein. This function may explain, in part, the naturally slow progression of prostate cancer. Our findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer.

A smart multifunctional drug delivery nanoplatform for targeting cancer cells.

Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.

Electrochemically synthesized amorphous and crystalline nanowires: dissimilar nanomechanical behavior in comparison with homologous flat films.

The effects of constrained sample dimensions on the mechanical behavior of crystalline materials have been extensively investigated. However, there is no clear understanding of these effects in nano-sized amorphous samples. Herein, nanoindentation together with finite element simulations are used to compare the properties of crystalline and glassy CoNi(Re)P electrodeposited nanowires (ϕ ≈ 100 nm) with films (3 µm thick) of analogous composition and structure. The results reveal that amorphous nanowires exhibit a larger hardness, lower Young's modulus and higher plasticity index than glassy films. Conversely, the very large hardness and higher Young's modulus of crystalline nanowires are accompanied by a decrease in plasticity with respect to the homologous crystalline films. Remarkably, proper interpretation of the mechanical properties of the nanowires requires taking the curved geometry of the indented surface and sink-in effects into account. These findings are of high relevance for optimizing the performance of new, mechanically-robust, nanoscale materials for increasingly complex miniaturized devices.

Interleukin-2 suppresses activated macrophage intracellular killing activity by inducing macrophages to secrete TGF-beta.

Phorbol myristate acetate (PMA) treatment of an EL-4 thymoma cell line (EL-4FARRAR) induced secretion of a factor that inhibited intracellular killing of Leishmania major amastigotes by activated macrophages. Analysis of the cytokines produced by EL-4 cells after PMA stimulation identified interleukin-2 (IL-2, 2500 U/ml), IL-4 (1280 U/ml), interferon-gamma (IFN-gamma; 100 U/ml), and granulocyte-macrophage colony-stimulating factor (GM-CSF; 50 U/ml). Neither tumor necrosis factor nor transforming growth factor beta (TGF-beta) was detected. Each of the cytokines present in EL-4 fluids was assessed for capacity to activate macrophages for destruction of parasites or to suppress intracellular killing. IFN-gamma and GM-CSF both activated macrophages to kill Leishmania; IL-2 and IL-4 had no activity for induction of this antimicrobial effector function. IL-2 and IL-4 were tested for their capacity to inhibit lymphokine- or IFN-gamma-induced destruction of L. major by macrophages: IL-4 was ineffective, but IL-2 markedly suppressed the activation of macrophages for intracellular killing. Addition of > or = 10 U/ml of IL-2 at the time of infection, or up to 4 h before, blocked up to 100% of the capacity of activated macrophages to kill intracellular amastigotes. Immunoaffinity treatment of EL-4 fluids with anti-IL-2 antibody resulted in > 80% reduction in suppression of intracellular killing. The suppressive effects of IL-2 were not direct, but mediated by TGF-beta. IL-2 induced resident peritoneal macrophages to secrete > 5000 pg/ml TGF-beta 1, a quantity that is > 500-fold higher than constitutive background levels (20-40 pg/ml) and is sufficient to block intracellular killing activities. This increase in secretion of TGF-beta was not dependent increases in TGF-beta 1 mRNA. Treatment of cultures with EL-4 fluids or recombinant IL-2 in the presence of antibody to TGF-beta 1 blocked the suppressive activity of both. Thus, IL-2 was the major suppressor factor in EL-4 fluids, and it acted indirectly through the induction and autocrine action of TGF-beta.

A magnetic force sensor on a catheter tip for minimally invasive surgery.

This paper presents a magnetically guided catheter for minimally invasive surgery (MIS) with a magnetic force sensing tip. The force sensing element utilizes a magnetic Hall sensor and a miniature permanent magnet mounted on a flexible encapsulation acting as the sensing membrane. It is capable of high sensitivity and robust force measurements suitable for in-vivo applications. A second larger magnet placed on the catheter allows the catheter to be guided by applying magnetic fields. Precise orientation control can be achieved with an external magnetic manipulation system. The proposed device can be used in many applications of minimally invasive surgery (MIS) to detect forces applied on tissue during procedures or to characterize different types of tissue for diagnosis.

Comparison of renin and converting enzyme inhibition in sodium-deficient dogs.

While renin is a highly specific protease, converting enzyme has at least two principal substrates, angiotensin I and bradykinin. Changes in the rate of formation of angiotensin II or degradation of bradykinin can influence the hypotensive action of angiotensin converting enzyme inhibitors. The present study was designed to determine if there were differences in the maximal blood pressure reduction in Na-deficient dogs after angiotensin converting enzyme or renin inhibitor treatment. Five conscious dogs received 0.1, 0.5, and 1.0 mg/kg of i.v. enalaprilat, a potent angiotensin converting enzyme inhibitor, which reduced blood pressure to 75 +/- 4, 71 +/- 5, and 71 +/- 5 mm Hg. Plasma immunoreactive angiotensin II levels were reduced in a dose-related fashion to 35% of control level at the highest dose. Infusion of a maximally effective dose of a statine-containing renin inhibitor (SCRIP) with the high dose of enalaprilat produced no further fall in blood pressure (68 +/- 7 mm Hg), but immunoreactive angiotensin II levels fell to essentially zero in four of five dogs. The order of drug administration was reversed in another experiment in a group of nine dogs in which SCRIP reduced plasma immunoreactive angiotensin II to 25% of control at 0.04 mg/kg/minute (n = 5), with reduction to near zero levels at higher doses. Maximal blood pressure reduction was achieved at 0.32 to 0.64 mg/kg/minute (76 +/- 4 mm Hg); 1 mg/kg of enalaprilat lowered blood pressure an additional 11 +/- 2 mm Hg (p less than 0.01) while not further decreasing immunoreactive angiotensin II levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative study of glutamate decarboxylase immunoreactive boutons in the mammalian inferior olive.

An antiserum raised against rat glutamate decarboxylase was used to map GABAergic boutons in the inferior olive of rabbit, cat, rhesus monkey, and human. A description of the human periolivary region is also included. The inferior olive of each species contained a dense GABAergic innervation, but immunostaining intensities varied among regions. These intensities were evaluated visually and photometrically, and the sizes and frequencies of occurrence of boutons in various olivary subnuclei were measured. The beta nucleus in all species was intensely immunostained and contained the largest boutons. The caudal subdivision of the dorsal accessory olive stained with a lower intensity than the beta nucleus, but contained similarly large GABAergic boutons. By visual analysis, the rostral subdivision and the subnucleus a of the medial accessory olive and the principal olive were stained with an intermediate intensity, and these regions contained small GABAergic boutons. Photometric analysis of focal regions of the neuropil, however, revealed species differences in teh staining intensity of the principal olive, which was lowest in rabbits and highest in primates. In all species, the lowest immunostaining intensity was observed in the subnucleus b of the medial accessory olive. Species variations in bouton sizes and regional staining intensities were observed in the dorsal cap and the dorsomedial cell column. The heterogeneous staining pattern and regional variation of bouton size argue for the existence of separate GABAergic projections to discrete regions of the inferior olive. Since glutamate decarboxylase immunostaining patterns in the olive are largely similar across species, the afferent projections producing these patterns may also be similar.

Comprehensive viral immunology of multiple sclerosis. I. Clinical, epidemiological, and CSF studies.

Epidemiological, clinical, and CSF data were collected on 87 patients with clinically definite multiple sclerosis (MS) and 50 with probable MS. As part of a study of immunologic reactivity to viral antigens, a control group separated into 26 patients with probable inflammatory neural disease and 140 with noninflammatory neural disease was similarly studied. Among the groups with MS, females predominated and both Oriental and Spanish surnamed patients were under-represented. The spinal cord, optic nerves, and brainstem were the most common sites of initial disease and more than 20% of the patients had only cord symptoms after several years of disease activity. Of several CSF assays used, determination of oligoclonal IgG bands by agarose electrophoresis was most useful diagnostically.

Agarose electrophoresis of cerebrospinal fluid in multiple sclerosis. A simplified method for demonstrating cerebrospinal fluid oligoclonal immunoglobulin bands.

The gamma globulins in cerebrospinal fluid from almost all patients with multiple sclerosis migrate in agarose electrophoresis as abnormal discrete populations, so-called oligoclonal bands. Such bands have also appeared in cerebrospinal fluid from patients with other types of inflammatory pathology such as neurosyphilis, acute idiopathic polyneuropathy, and subacute sclerosing panencephalitis. The demonstration of cerebrospinal fluid oligoclonal bands may aid in the evaluation of patients with early or atypical multiple sclerosis. This report describes a simple method for demonstrating cerebrospinal fluid oligoclonal bands using readily available commercial reagents and apparatus. Oligoclonal bands were seen in cerebrospinal fluid from all patients with clinically definite multiple sclerosis, even though some had normal cerebrospinal fluid gamma globulin levels, and in most patients with presumptive multiple sclerosis or other inflammatory conditions of the nervous system. They were not seen in cerebrospinal fluid of control patients with a variety of other neurologic diseases.

Immunologic response in an elderly population with a mean age of 85.

Previous studies of changes in immune responses in the elderly have been limited in both number and age of elderly subjects and have produced conflicting results. Using 260 subjects, mean age 84.6, the present study conclusively demonstrates that T cell response is decreased in the elderly. Decreases in response to phytohemagglutinin and concanavalin A were demonstrated in groups aged 70 to 79, 80 to 84, and 85 to 89, although a group 90 to 106 years old showed a decreased response only to phytohemagglutinin. None of the groups had a decreased response to pokeweed mitogen. No response to all three mitogens was observed in 13 percent of the group aged 70 to 89, but in none of the group aged 90 to 106 or in the young groups. No differences in natural killer cell cytotoxicity were observed among the elderly groups. In contrast to previous studies, these results suggest that: the decreased immune response of the elderly is not directly related to age, over age 70; and there may be a selection process in which subjects who live to the age of 90 are those in whom the least decrease in immune response is demonstrated.