Prenatal exposure to environmental toxins and comprehensive dental findings in a population cohort of children.

Environmental toxins are known to have many impacts on growth and development in humans, starting in utero. Alterations in amelogenesis, caused by chemical and physical trauma that occur during the antenatal, perinatal and postnatal time periods, may result in developmental defects in deciduous and permanent tooth enamel, as demonstrated in animal studies. These defects can be clinically visible and result in a variety of morphological and functional problems in the dentition. Since enamel does not remodel after formation, it may serve as a permanent record of insults during organ development.Our primary purpose was to investigate any possible relationship between intrauterine exposure to endocrine disrupting chemicals (phenols and phthalates) and developmental defects in enamel in children, while also accounting for fluoride exposure. Our secondary purpose was to report descriptively on findings from comprehensive dental examinations performed on 356 children that were drawn from the general paediatric population. A cohort of children from the Utah Children's Project (N = 356) that had full medical exams, comprehensive medical and family histories and available biospecimens were given extraoral and intraoral examinations. They also completed an oral health questionnaire. Standardized intraoral photographs were taken of the teeth and viewed by standardised examiners and the dental observations were recorded for a full inventory of findings, including: tooth morphology, caries, restorations, colorations, attrition, erosion, fractures and hypomineralization. Perinatal maternal urine samples were assessed for the concentration of fluoride, phenols and phthalates, including bisphenol A (BPA).Pairwise statistical analyses were done to correlate the dental findings with one another and with the presence of environment chemicals found in the urine samples. Hypomineralization was the most common finding (96% of children; 37% of deciduous teeth, 42% of permanent teeth), consistent with molar incisor hypomineralization (MIH) described in other human populations. No consistent correlations were seen between dental findings and the presence of phenols and phthalates in prenatal urine, but the number of samples available for the assessment was limited (n = 35).In conclusion, we found a high proportion of dental hypomineralization in a population based paediatric cohort, but did not find an association with prenatal exposure to phenols and phthalates.

Nuclear Morphological Abnormalities in Cancer: A Search for Unifying Mechanisms.

Irregularities in nuclear shape and/or alterations to nuclear size are a hallmark of malignancy in a broad range of cancer types. Though these abnormalities are commonly used for diagnostic purposes and are often used to assess cancer progression in the clinic, the mechanisms through which they occur are not well understood. Nuclear size alterations in cancer could potentially arise from aneuploidy, changes in osmotic coupling with the cytoplasm, and perturbations to nucleocytoplasmic transport. Nuclear shape changes may occur due to alterations to cell-generated mechanical stresses and/or alterations to nuclear structural components, which balance those stresses, such as the nuclear lamina and chromatin. A better understanding of the mechanisms underlying abnormal nuclear morphology and size may allow the development of new therapeutics to target nuclear aberrations in cancer.

Examining thein vivofunctionality of the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI).

Objective. Although neural-enabled prostheses have been used to restore some lost functionality in clinical trials, they have faced difficulty in achieving high degree of freedom, natural use compared to healthy limbs. This study investigated thein vivofunctionality of a flexible and scalable regenerative peripheral-nerve interface suspended within a microchannel-embedded, tissue-engineered hydrogel (the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI)) as a potential approach to improving current issues in peripheral nerve interfaces.Approach. Assembled MARTEENI devices were implanted in the gaps of severed sciatic nerves in Lewis rats. Both acute and chronic electrophysiology were recorded, and channel-isolated activity was examined. In terminal experiments, evoked activity during paw compression and stimulus response curves generated from proximal nerve stimulation were examined. Electrochemical impedance spectroscopy was performed to assess the complex impedance of recording sites during chronic data collection. Features of the foreign-body response (FBR) in non-functional implants were examined using immunohistological methods.Main results. Channel-isolated activity was observed in acute, chronic, and terminal experiments and showed a typically biphasic morphology with peak-to-peak amplitudes varying between 50 and 500µV. For chronic experiments, electrophysiology was observed for 77 days post-implant. Within the templated hydrogel, regenerating axons formed minifascicles that varied in both size and axon count and were also found to surround device threads. No axons were found to penetrate the FBR. Together these results suggest the MARTEENI is a promising approach for interfacing with peripheral nerves.Significance. Findings demonstrate a high likelihood that observed electrophysiological activity recorded from implanted MARTEENIs originated from neural tissue. The variation in minifascicle size seen histologically suggests that amplitude distributions observed in functional MARTEENIs may be due to a combination of individual axon and mini-compound action potentials. This study provided an assessment of a functional MARTEENI in anin vivoanimal model for the first time.

Development of a magnetically aligned regenerative tissue-engineered electronic nerve interface for peripheral nerve applications.

Peripheral nerve injuries can be debilitating to motor and sensory function, with severe cases often resulting in complete limb amputation. Over the past two decades, prosthetic limb technology has rapidly advanced to provide users with crude motor control of up to 20° of freedom; however, the nerve-interfacing technology required to provide high movement selectivity has not progressed at the same rate. The work presented here focuses on the development of a magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI) that combines polyimide "threads" encapsulated within a magnetically aligned hydrogel scaffold. The technology exploits tissue-engineered strategies to address concerns over traditional peripheral nerve interfaces including poor axonal sampling through the nerve and rigid substrates. A magnetically templated hydrogel is used to physically support the polyimide threads while also promoting regeneration in close proximity to the electrode sites on the polyimide. This work demonstrates the utility of magnetic templating for use in tuning the mechanical properties of hydrogel scaffolds to match the stiffness of native nerve tissue while providing an aligned substrate for Schwann cell migration in vitro. MARTEENI devices were fabricated and implanted within a 5-mm-long rat sciatic-nerve transection model to assess regeneration at 6 and 12 weeks. MARTEENI devices do not disrupt tissue remodeling and show axon densities equivalent to fresh tissue controls around the polyimide substrates. Devices are observed to have attenuated foreign-body responses around the polyimide threads. It is expected that future studies with functional MARTEENI devices will be able to record and stimulate single axons with high selectivity and low stimulation regimes.

Exosomes released by breast cancer cells under mild hyperthermic stress possess immunogenic potential and modulate polarization in vitro in macrophages.

Macrophages play a dual role in tumor initiation and progression, with both tumor-promoting and tumor-suppressive effects; hence, it is essential to understand the distinct responses of macrophages to tumor progression and therapy. Mild hyperthermia has gained importance as a therapeutic regimen against cancer due to its immunogenic nature, efficacy, and potential synergy with other therapies, yet the response of macrophages to molecular signals from hyperthermic cancer cells has not yet been clearly defined. Due to limited response rate of breast cancer to conventional therapeutics the development, and understanding of alternative therapies like hyperthermia is pertinent. In order to determine conditions corresponding to mild thermal dose, cytotoxicity of different hyperthermic temperatures and treatment durations were tested in normal murine macrophages and breast cancer cell lines. Examination of exosome release in hyperthermia-treated cancer cells revealed enhanced efflux and a larger size of exosomes released under hyperthermic stress. Exposure of naïve murine macrophages to exosomes released from 4T1 and EMT-6 cells posthyperthermia treatment, led to an increased expression of specific macrophage activation markers. Further, exosomes released by hyperthermia-treated cancer cells had increased content of heat shock protein 70 (Hsp70). Together, these results suggest a potential immunogenic role for exosomes released from cancer cells treated with mild hyperthermia.

Preparation and evaluation of microfluidic magnetic alginate microparticles for magnetically templated hydrogels.

Our aim is to develop a hydrogel-based scaffold containing porous microchannels that mimic complex tissue microarchitecture and provide physical cues to guide cell growth for scalable, cost-effective tissue repair. These hydrogels are patterned through the novel process of magnetic templating where magnetic alginate microparticles (MAMs) are dispersed in a hydrogel precursor and aligned in a magnetic field before hydrogel crosslinking and subsequent MAM degradation, leaving behind an aligned, porous architecture. Here, a protocol for fabricating uniform MAMs using microfluidics was developed for improved reproducibility and tunability of templated microarchitecture. Through iron quantification, we find that this approach allows control over magnetic iron oxide loading of the MAMs. Using Brownian dynamics simulations and nano-computed tomography of templated hydrogels to examine MAM chain length and alignment, we find agreement between simulated and measured areal densities of MAM chains. Oscillatory rheology and stress relaxation experiments demonstrate that magnetically templated microchannels alter bulk hydrogel mechanical properties. Finally, in vitro studies where rat Schwann cells were cultured on templated hydrogels to model peripheral nerve injury repair demonstrate their propensity for providing cell guidance along the length of the channels. Our results show promise for a micro-structured biomaterial that could aid in tissue repair applications.

Magnetic particle templating of hydrogels: engineering naturally derived hydrogel scaffolds with 3D aligned microarchitecture for nerve repair.

OBJECTIVE: Hydrogel scaffolds hold promise for a myriad of tissue engineering applications, but often lack tissue-mimetic architecture. Therefore, in this work, we sought to develop a new technology for the incorporation of aligned tubular architecture within hydrogel scaffolds engineered from the bottom-up. APPROACH: We report a platform fabrication technology-magnetic templating-distinct from other approaches in that it uses dissolvable magnetic alginate microparticles (MAMs) to form aligned columnar structures under an applied magnetic field. Removal of the MAMs yields scaffolds with aligned tubular microarchitecture that can promote cell remodeling for a variety of applications. This approach affords control of microstructure diameter and biological modification for advanced applications. Here, we sought to replicate the microarchitecture of the native nerve basal lamina using magnetic templating of hydrogels composed of glycidyl methacrylate hyaluronic acid and collagen I. MAIN RESULTS: Magnetically templated hydrogels were characterized for particle alignment and micro-porosity. Overall MAM removal efficacy was verified by 96.8% removal of iron oxide nanoparticles. Compressive mechanical properties were well-matched to peripheral nerve tissue at 0.93 kPa and 1.29 kPa, respectively. In vitro, templated hydrogels exhibited approximately 36% faster degradation over 12 h, and were found to guide axon extension from dorsal root ganglia. Finally, in a pilot in vivo study utilizing a 10 mm rat sciatic nerve defect model, magnetically templated hydrogels demonstrated promising results with qualitatively increased remodeling and axon regeneration compared to non-templated controls. SIGNIFICANCE: This simple and scalable technology has the flexibility to control tubular microstructure over long length scales, and thus the potential to meet the need for engineered scaffolds for tissue regeneration, including nerve guidance scaffolds.

Amebic Liver Abscess and Kawasaki Disease.

BACKGROUND: Co-occurrence of amebic hepatitis and Kawasaki disease has not been reported previously. CASE CHARACTERISTICS: We describe two children (aged 4 y and 5 y) with Kawasaki disease and coexisting liver abscess. They were treated with intravenous immunoglobulins with/without percutaneous drainage in combination with amebicidal agents. OUTCOME: Both the children were completely cured of the amebic hepatitis, and had normalization and regression of coronaries at follow-up. MESSAGE: We report the co-existence of amebic hepatitis with Kawasaki disease.

18F-FDG-PET SUV AS A PROGNOSTIC MARKER OF INCREASING SIZE IN THYROID CANCER TUMORS.

OBJECTIVE: Positron emission tomography/computed tomography (PET/CT) scans with 2-[fluorine-18] fluoro-2-deoxy-D-glucose (18F-FDG) are used in high-risk thyroid cancer patients to identify metastasis. The prognostic significance of increases in standardized uptake values (SUVs) has not been clearly defined. This pilot study investigated the correlation between SUV increases and subsequent changes in individual lesion size. METHODS: A retrospective chart review of patients with histologically confirmed thyroid cancer who were monitored with serial 18F-FDG-PET/CT scans from 2008 to 2013 was performed. Forty-seven patients were selected for analysis. A mixed-effects statistical model was used after data normalization. RESULTS: For a 10% increase in SUV, a 6% increase in tumor area was observed (P<.0001). Analysis on cube root-transformed data from serial scans was significant in 4 of 5 groups: scans 1 to 2 (P = .0001), scans 2 to 3 (P = .0005), scans 3 to 4 (P = .008), scans 4 to 5 (P = .66), and overall (P<.0001). After exclusion of outliers, for a 10% increase in SUV, the expected percentage increases in area on subsequent scans were found to be 3.4% (P = .0006), 2.6% (P = .005), 4% (P = .074), and 4.1% (P = .27) for the second, third, fourth, and fifth scans, respectively. The association was similarly significant in cases with a ≥25% increase in SUV. Secondary analysis showed a significant association of SUV with thyroglobulin (Tg) level (P = .035) but not with thyroid-stimulating hormone (TSH) level (P = .85). CONCLUSIONS: A significant positive correlation was noted between the increase in lesional SUV and subsequent increase in lesion area. An increase in lesional SUV in subsequent scans may portend tumor growth and could prompt consideration for earlier or more aggressive intervention. ABBREVIATIONS: DTC = differentiated thyroid cancer EORTC = European Organization for Research and Treatment of Cancer 18F-FDG = 2-[fluorine-18] fluoro-2-deoxy-D-glucose FNA = fine-needle aspiration MTC = medullary thyroid cancer PET/CT = positron emission tomography/computed tomography PVE = partial volume effect RAI = radioactive iodine SUV = standardized uptake value Tg = thyroglobulin TSH = thyroid-stimulating hormone.

Pathogenesis of Hyperthyroidism.

Hyperthyroidism is a form of thyrotoxicosis in which there is excess thyroid hormone synthesis and secretion. Multiple etiologies can lead to a common clinical state of "thyrotoxicosis," which is a consequence of the high thyroid hormone levels and their action on different tissues of the body. The most common cause of thyrotoxicosis is Graves' disease, an autoimmune disorder in which stimulating thyrotropin receptor antibodies bind to thyroid stimulating hormone (TSH) receptors on thyroid cells and cause overproduction of thyroid hormones. Other etiologies include: forms of thyroiditis in which inflammation causes release of preformed hormone, following thyroid gland insult that is autoimmune, infectious, mechanical or medication induced; secretion of human chorionic gonadotropin in the setting of transient gestational thyrotoxicosis and trophoblastic tumors; pituitary thyrotropin release, and exposure to extra-thyroidal sources of thyroid hormone that may be endogenous or exogenous. © 2017 American Physiological Society. Compr Physiol 7:67-79, 2017.

Enzyme dehydration using Microglassification™ preserves the protein's structure and function.

Controlled enzyme dehydration using a new processing technique of Microglassification™ has been investigated. Aqueous solution microdroplets of lysozyme, α-chymotrypsin, catalase, and horseradish peroxidase were dehydrated in n-pentanol, n-octanol, n-decanol, triacetin, or butyl lactate, and changes in their structure and function were analyzed upon rehydration. Water solubility and microdroplet dissolution rate in each solvent decreased in the order: butyl lactate > n-pentanol > triacetin > n-octanol > n-decanol. Enzymes Microglassified™ in n-pentanol retained higher activity (93%-98%) than n-octanol (78%-85%) or n-decanol (75%-89%), whereas those Microglassified™ in triacetin (36%-75%) and butyl lactate (48%-79%) retained markedly lower activity. FTIR spectroscopy analyses showed α-helix to ß-sheet transformation for all enzymes upon Microglassification™, reflecting a loss of bound water in the dried state; however, the enzymes reverted to native-like conformation upon rehydration. Accelerated stressed-storage tests using Microglassified™ lysozyme showed a significant (p < 0.01) decrease in enzymatic activity from 46,560 ± 2736 to 31,060 ± 4327 units/mg after 3 months of incubation; however, it was comparable to the activity of the lyophilized formulation throughout the test period. These results establish Microglassification™ as a viable technique for enzyme preservation without affecting its structure or function.

Necrolytic migratory erythema associated with glucagonoma syndrome diagnosed by 68Ga-DOTANOC PET-CT.

Necrolytic migratory erythema (NME) is a rare dermatological condition which presents a diagnostic challenge. Repeated negative skin biopsies and non-detection of any pancreatic tumor in conventional imaging modalities like a computed tomography (CT) scan and ultrasonogram (USG) make the diagnosis more difficult. By the time the diagnosis is made, the patient usually presents with metastasis. We present a rare case of difficult to diagnose NME, as repeated skin biopsies and conventional imaging modalities like CT and USG could not detect the underlying glucagonoma. A (68)Ga-DOTANOC positron emission tomography PET-CT was able to detect the underlying cause of NME as glucagonoma of the pancreas and the same investigation confirmed the absence of any metastasis elsewhere in the body. The tumor was excised and patient dramatically improved, and all skin lesions disappeared.