SfN Journals: Two Paths, One Goal: Sharing Strong Science

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Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord

After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6–C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery.

SIGNIFICANCE STATEMENT The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory–motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.

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Are Movement Preparation and Movement Initiation Truly Independent?

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Aging-Resilient Associations between the Arcuate Fasciculus and Vocabulary Knowledge: Microstructure or Morphology?

Vocabulary knowledge is one of the few cognitive functions that is relatively preserved in older adults, but the reasons for this relative preservation have not been well delineated. We tested the hypothesis that individual differences in vocabulary knowledge are influenced by arcuate fasciculus macrostructure (i.e., shape and volume) properties that remain stable during the aging process, rather than white matter microstructure that demonstrates age-related declines. Vocabulary was not associated with age compared to pronounced age-related declines in cognitive processing speed across 106 healthy adults (19.92–88.29 years) who participated in this neuroimaging experiment. Fractional anisotropy in the left arcuate fasciculus was significantly related to individual variability in vocabulary. This effect was present despite marked age-related differences in a T1-weighted/T2-weighted ratio (T1w/T2w) estimate of myelin that were observed throughout the left arcuate fasciculus and associated with age-related differences in cognitive processing speed. However, atypical patterns of arcuate fasciculus morphology or macrostructure were associated with decreased vocabulary knowledge. These results suggest that deterioration of tissue in the arcuate fasciculus occurs with normal aging, while having limited impact on tract organization that underlies individual differences in the acquisition and retrieval of lexical and semantic information.

SIGNIFICANCE STATEMENT Vocabulary knowledge is resilient to widespread age-related declines in brain structure that limit other cognitive functions. We tested the hypothesis that arcuate fasciculus morphology, which supports the development of reading skills that bolster vocabulary, could explain this relative preservation. We disentangled (1) the effects of age-related declines in arcuate microstructure (mean diffusivity; myelin content estimate) that predicted cognitive processing speed but not vocabulary, from (2) relatively stable arcuate macrostructure (shape/volume) that explained significant variance in an age-independent association between fractional anisotropy and vocabulary. This latter result may reflect differences in fiber trajectory and organization that are resilient to aging. We propose that developmental sculpting of the arcuate fasciculus determines acquisition, storage, and access of lexical information across the adult lifespan.

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Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo

How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS.

SIGNIFICANCE STATEMENT Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.

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Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice

Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3β (GSK3β) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3β expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress.

SIGNIFICANCE STATEMENT Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3β, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.

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Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI.

SIGNIFICANCE STATEMENT Currently, there are an estimated 3.2–5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of 10 of these individuals report cognitive disabilities (Thurman et al., 1999; Lew et al., 2006; Zaloshnja et al., 2008). One of the molecular mechanisms associated with chronic cognitive disabilities is impaired cAMP signaling in the hippocampus. In this study, we report that a selective phosphodiesterase 4B (PDE4B) inhibitor reduces chronic cognitive deficits after TBI and rescues deficits in hippocampal long-term potentiation. These results suggest that PDE4B inhibition has the potential to improve learning and memory ability and overall functioning for people living with TBI.

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Global Motion Processing in Human Visual Cortical Areas V2 and V3

Global motion perception entails the ability to extract the central direction tendency from an extended area of visual space containing widely disparate local directions. A substantial body of evidence suggests that local motion signals generated in primary visual cortex (V1) are spatially integrated to provide perception of global motion, beginning in the middle temporal area (MT) in macaques and its counterpart in humans, hMT. However, V2 and V3 also contain motion-sensitive neurons that have larger receptive fields than those found in V1, giving the potential for spatial integration of motion signals. Despite this, V2 and V3 have been overlooked as sites of global motion processing. To test, free of local-global confounds, whether human V2 and V3 are important for encoding global motion, we developed a visual stimulus that yields a global direction yet includes all possible local directions and is perfectly balanced at the local motion level. We then attempted to decode global motion direction in such stimuli with multivariate pattern classification of fMRI data. We found strong sensitivity to global motion in hMT, as expected, and also in several higher visual areas known to encode optic flow. Crucially, we found that global motion direction could be decoded in human V2 and, particularly, in V3. The results suggest the surprising conclusion that global motion processing is a key function of cortical visual areas V2 and V3. A possible purpose is to provide global motion signals to V6.

SIGNIFICANCE STATEMENT Humans can readily detect the overall direction of movement in a flock of birds despite large differences in the directions of individual birds at a given moment. This ability to combine disparate motion signals across space underlies many aspects of visual motion perception and has therefore received considerable research attention. The received wisdom is that spatial integration of motion signals occurs in the cortical motion complex MT+ in both human and nonhuman primates. We show here that areas V2 and V3 in humans are also able to perform this function. We suggest that different cortical areas integrate motion signals in different ways for different purposes.

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Transient Oxygen/Glucose Deprivation Causes a Delayed Loss of Mitochondria and Increases Spontaneous Calcium Signaling in Astrocytic Processes

Recently, mitochondria have been localized to astrocytic processes where they shape Ca²⁺ signaling; this relationship has not been examined in models of ischemia/reperfusion. We biolistically transfected astrocytes in rat hippocampal slice cultures to facilitate fluorescent confocal microscopy, and subjected these slices to transient oxygen/glucose deprivation (OGD) that causes delayed excitotoxic death of CA1 pyramidal neurons. This insult caused a delayed loss of mitochondria from astrocytic processes and increased colocalization of mitochondria with the autophagosome marker LC3B. The losses of neurons in area CA1 and mitochondria in astrocytic processes were blocked by ionotropic glutamate receptor (iGluR) antagonists, tetrodotoxin, ziconotide (Ca²⁺ channel blocker), two inhibitors of reversed Na⁺/Ca²⁺ exchange (KB-R7943, YM-244769), or two inhibitors of calcineurin (cyclosporin-A, FK506). The effects of OGD were mimicked by NMDA. The glutamate uptake inhibitor (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-l-aspartate increased neuronal loss after OGD or NMDA, and blocked the loss of astrocytic mitochondria. Exogenous glutamate in the presence of iGluR antagonists caused a loss of mitochondria without a decrease in neurons in area CA1. Using the genetic Ca²⁺ indicator Lck-GCaMP-6S, we observed two types of Ca²⁺ signals: (1) in the cytoplasm surrounding mitochondria (mitochondrially centered) and (2) traversing the space between mitochondria (extramitochondrial). The spatial spread, kinetics, and frequency of these events were different. The amplitude of both types was doubled and the spread of both types changed by ~2-fold 24 h after OGD. Together, these data suggest that pathologic activation of glutamate transport and increased astrocytic Ca²⁺ through reversed Na⁺/Ca²⁺ exchange triggers mitochondrial loss and dramatic increases in Ca²⁺ signaling in astrocytic processes.

SIGNIFICANCE STATEMENT Astrocytes, the most abundant cell type in the brain, are vital integrators of signaling and metabolism. Each astrocyte consists of many long, thin branches, called processes, which ensheathe vasculature and thousands of synapses. Mitochondria occupy the majority of each process. This occupancy is decreased by ~50% 24 h after an in vitro model of ischemia/reperfusion injury, due to delayed fragmentation and mitophagy. The mechanism appears to be independent of neuropathology, instead involving an extended period of high glutamate uptake into astrocytes. Our data suggest that mitochondria serve as spatial buffers, and possibly even as a source of calcium signals in astrocytic processes. Loss of mitochondria resulted in drastically altered calcium signaling that could disrupt neurovascular coupling and gliotransmission.

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Gaseous and Particulate Content of Laser Hair Removal Plume

This study characterizes the chemical composition and ultrafine particle content of the plume generated during laser hair removal.

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Hypopigmented Macules on the Face and Neck of a Man

A man in his 40s presented with a 2-year history of multiple asymptomatic hypopigmented macules on the face and neck with no hair growth at the site of the lesions. What is your diagnosis?

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Consumer Evaluations of Commercial Sunscreen

This qualitative study uses consumer online reviews to characterize the most commonly cited positive and negative features of popular sunscreens.

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Genetic Basis for Epidermolysis Bullosa Simplex With MottledPigmentation

This case report describes a novel homozygous nonsense mutation in EXPH5 causing mottled pigmentation in a patient with basal epidermolysis bullosa simplex.

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How terrorists target and attack health care facilities and personnel

"Terrorism & the Medical Environment" is designed to help save lives, money, property and medical professionals who the victims and saviors of terrorist attacks

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Second annual Hooley Awards finalists announced

LAKEVILLE, Minn. — ImageTrend, Inc. announced the 15 finalists for this year's Hooley™ Awards. The award recipients will be announced at the company's ImageTrend Connect 2016 conference on July 20, 2016. The Hooley Awards recognize innovators and thought leaders, honoring their involvement, creativity and passion in three categories: Innovation, Service and New Frontier. "We ...

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Differential studies of ovarian endometriosis cells from endometrium or oviduct

OBJECTIVE: To study the prominent differences between endometriosis (EMT) cells derived from ovary, oviduct and endometrium, and to provided new ideas about the pathogenesis of endometriosis.

PATIENTS AND METHODS: From June 2010 to June 2015, 210 patients diagnosed with endometriosis were enrolled in our study. Patients were treated by laparoscopy or conventional surgeries in our hospital. Ovarian chocolate cyst and paired normal ovarian tissues, fimbriated extremity of fallopian and uterine cavity endomembrane tissues were collected, prepared and observed by microscope. PCR was used for amplification of target genes (FMO3 and HOXA9) and Western blot was used to evaluate FMO3 and HOXA9 expression levels.

RESULTS: In 95 cases, endometriosis cells were derived from oviduct epithelial. In 110 cases, endometriosis cells were derived from the endometrium, and in 5 cases it was derived from the ovary itself. FMO3 gene transcription and protein expression were higher in oviduct cells while HOXA9 gene transcription and protein expression were higher in endometrial cells. In 89 cases the endometriosis cells were derived from oviduct epithelial and in 113 cases endometriosis cells were derived from the endometrium. Protein levels indicated that endometriosis cells in 85 cases were derived from oviduct epithelial and in 116 cases were derived from the endometrium.

CONCLUSIONS: A large number of ovarian endometriosis cells were derived from oviduct epithelial.

L'articolo Differential studies of ovarian endometriosis cells from endometrium or oviduct sembra essere il primo su European Review.

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miR-181a induces sorafenib resistance of hepatocellular carinoma cells through downregulation of RASSF1 expression

Abstract

Sorafenib, a multi-kinase inhibitor, is the only standard clinical drug against patients with advanced hepatocellular carcinoma (HCC), however, development of sorafenib resistance in HCC often prevents its long-term efficacy. Therefore, novel targets and strategies are urgently needed to improve antitumor effect of sorafenib. In the present study, we examined the novel mechanisms of sorafenib resistance of HCC cells from the difference in sorafenib resistance between two HCC cell lines. Sorafenib induced more apoptosis of HepG2 cells compared to Hep3B cells from 1 to 5 μM of its concentration. Sorafenib exposure to HepG2 cells but not Hep3B cells increased expression of proapoptotic factor PUMA, and activated PARP and caspase-3. Notably, microRNA-181a (miR-181a) expression levels were lower in HepG2 cells than in Hep3B cells. Exogenous miR-181a expression in HepG2 cells reduced apoptosis, whereas inhibition of miR-181a in Hpe3B cells increased. In addition, we demonstrated that miR-181a directly targets RASSF1, a MAPK signaling factor, and knockdown of RASSF1 increased sorafenib resistance. Taken together, these results suggest that miR-181a provokes sorafenib resistance through suppression of RASSF1. Our data provide an important insight into the novel therapeutic strategy against sorafenib resistance of HCC cells by targeting of miR-181a pathway.

This article is protected by copyright. All rights reserved.

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IL-17A-producing CD30+ Vδ1 T cells drive inflammation-induced cancer progression

Summary

Although it has been suspected that inflammation associates with increased tumor metastasis, the exact type of immune response to initiate cancer progression and metastasis remains unknown. In this study, by using an in vivo tumor progression model in which low tumorigenic cancer cells acquire malignant metastatic phenotype after exposure to inflammation, we found IL-17A is a critical cue for escalating cancer cell malignancy. We further demonstrated the length of exposure to an inflammatory microenvironment could associate with acquiring greater tumorigenicity and IL-17A was critical for amplifying such local inflammation as observed in the production of IL-1β and neutrophil infiltration following the cross-talk between cancer and host stromal cells. We further determined that γδT cells expressing Vδ1 semi-invariant TCR initiate cancer-promoting inflammation by producing IL-17A in an MyD88/IL-23 dependent manner. Finally, we identified CD30 as a key molecule in the inflammatory function of Vδ1T cells and the blockade of this pathway targeted this cancer immune-escalation process. Collectively, these results reveal the importance of IL-17A-producing CD30⁺ Vδ1T cells in triggering inflammation and orchestrating a microenvironment leading to cancer progression.

This article is protected by copyright. All rights reserved.

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Breast fine needle aspiration continues to be relevant in a large academic medical center: experience from Massachusetts General Hospital

Abstract

Fine needle aspiration (FNA) is increasingly being supplanted by core needle biopsy. However, breast surgeons continue to rely on FNA at our institution. This retrospective study evaluated breast FNA for its diagnostic accuracy and breast cancer biomarker testing utility. All breast FNAs performed at Massachusetts General Hospital 2009–2015 were reviewed. Cytology diagnoses were compared with subsequent tissue or clinical diagnoses. Immunohistochemistry and fluorescence in situ hybridization (FISH) results using formalin-fixed paraffin-embedded (FFPE) cell blocks and histologic tissue blocks were compared. 1654 consecutive breast FNAs were included. Breast FNA demonstrated the following diagnostic performance: positive predictive value of malignant cytology diagnosis 100 %, negative predictive value of benign cytology diagnosis 97.5 %, complete sensitivity 91.6 %, and specificity 95.5 %. Concordance rates for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) immunohistochemistry, and HER2 FISH were 98.2 % (κ = 0.95, p < 0.001), 100.0 % (κ = 1.000, p < 0.001), 83.1 % (κ = 0.69, p < 0.001), and 93.5 % (κ = 0.785, p < 0.001), respectively. Review of consecutive breast FNAs in a large cohort confirmed the excellent accuracy of this biopsy technique for breast lesion diagnosis. FNA FFPE cell blocks collected in the course of routine clinical care are adequate, practical, and reliable for breast cancer biomarker testing.

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Impact of a prior diagnosis of DCIS on survival from invasive breast cancer

Abstract

A diagnosis of invasive breast cancer after DCIS can be described as a new primary cancer or as a local invasive recurrence. It is of interest to determine if, among women with early-stage breast cancer, a past history of DCIS influences survival. We retrieved the records of 306,249 women diagnosed with stage I or stage II breast cancer between 2004 and 2012, in the surveillance, epidemiology, and end results registries database, of whom 5395 had a previous diagnosis of DCIS. For each patient, we extracted information on the year of diagnosis, age at diagnosis, tumor size, nodal status, grade, estrogen receptor status, type of surgery (lumpectomy/mastectomy), use of radiotherapy (no/yes), prior DCIS (no/yes), cause of death, and follow-up time. For each case with prior DCIS, we recorded information on the year of diagnosis of DCIS, laterality of DCIS, and treatments received for DCIS. We matched 3979 patients with a prior DCIS to 3979 patients without a prior DCIS, according to the various prognostic features of the invasive cancer. We estimated the risk of death from breast cancer for patients with invasive ductal carcinoma, with and without a prior diagnosis of DCIS. We identified 306,249 women with stage I/II breast cancer, of whom 2335 had a prior ipsilateral DCIS and 3060 had a prior contralateral DCIS. Breast cancer-specific survival at 9 years was 94.6 % for patients with a prior DCIS (ipsilateral or contralateral) and was 95.2 % for patients with no prior DCIS (p = 0.32). In a matched analysis (3979 matched pairs), the hazard ratio for death from breast cancer for patients with a prior ipsilateral DCIS, compared to patients with no prior DCIS, was 0.91 (95 % CI = 0.49–1.68; p = 0.75). A prior diagnosis of ipsilateral DCIS does not impact upon the prognosis of women with early-stage invasive breast cancer. This suggests that primary breast cancers and local invasive recurrences following DCIS are similar conditions and should be treated in the same way.

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Evaluation of an amplicon-based next-generation sequencing panel for detection of BRCA1 and BRCA2 genetic variants

Abstract

The recent advances in the next-generation sequencing (NGS) technology have enabled fast, accurate, and cost-effective genetic testing. Here, we evaluated the performance of a targeted NGS panel for BRCA1/2 sequencing and confirmed its applicability in routine clinical diagnostics. We tested samples from 88 patients using the TruSeq custom panel (Illumina Inc, USA) and a MiSeq sequencer (Illumina) and compared the results to the outcomes of conventional Sanger sequencing. All 1015 sequence variations identified by Sanger sequencing were detected by NGS, except for one missense variant that might have been missed due to a rare mutation on a primer-binding site. One deletion variation, c.1909 + 12delT of BRCA2, was falsely called in all samples due to a homopolymer error. In addition, seven different single-nucleotide substitutions with low variant frequencies (range: 16.2–33.3 %) were falsely called by NGS. In a separate batch, 10 different false-positive variations were found in five samples. The overall sensitivity and positive predictive value of NGS were estimated to be 99.9 and 87.5 %, respectively. The false-positive results could be excluded by setting quality and alternative allele ratio filters and/or by visual inspection using the IGV software. Targeted NGS panel for BRCA1 and BRCA2 showed an excellent agreement with Sanger sequencing results. We therefore conclude that this NGS panel can be used for routine diagnostic method in a clinical genetic laboratory.

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Cellular ageing mechanisms in osteoarthritis

Abstract

Age is the strongest independent risk factor for the development of osteoarthritis (OA) and for many years this was assumed to be due to repetitive microtrauma of the joint surface over time, the so-called 'wear and tear' arthritis. As our understanding of OA pathogenesis has become more refined, it has changed our appreciation of the role of ageing on disease. Cartilage breakdown in disease is not a passive process but one involving induction and activation of specific matrix-degrading enzymes; chondrocytes are exquisitely sensitive to changes in the mechanical, inflammatory and metabolic environment of the joint; cartilage is continuously adapting to these changes by altering its matrix. Ageing influences all of these processes. In this review, we will discuss how ageing affects tissue structure, joint use and the cellular metabolism. We describe what is known about pathways implicated in ageing in other model systems and discuss the potential value of targeting these pathways in OA.

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Plasmonic Nanohalo Optical Probes for Highly Sensitive Imaging Survivin mRNA in Living Cells

Chem. Commun., 2016, Accepted Manuscript
DOI: 10.1039/C6CC02831D, Communication

Guang-Sheng Qian, Bin Kang, Zhuo-Lei Zhang, Xiangling Li, Wei Zhao, Jing-Juan Xu, Hong-Yuan Chen
A strategy is designed for sensitive detection of tumor biomarker survivin mRNA based on resonance Rayleigh scattering of single AuNP nanohalo probe that couples large gold nanoparticles (L-AuNPs, 52 nm)...
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Synthesis of Highly Monodispersed Ga-soc-MOF Hollow Cubes, Colloidosomes and Nanocomposites

Chem. Commun., 2016, Accepted Manuscript
DOI: 10.1039/C6CC04525A, Communication

Xuechao Cai, Xiaoran Deng, Zhongxi Xie, Shouxin Bao, Yanshu Shi, Jun Lin, Maolin Pang, Mohamed Eddaoudi
Ga-soc-MOF hollow cubes with an average size about 300 nm were prepared by a Polyvinylpyrrolidone (PVP) assisted acid etching process. Colloidosomes with sizes around 5-10 [small mu ]m composed of a single-layer...
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Organocatalytic Ring-Opening Polymerization of N-Tosyl Aziridines by an N-Heterocyclic Carbene

Chem. Commun., 2016, Accepted Manuscript
DOI: 10.1039/C6CC04323B, Communication

Camille Bakkali-Hassani, Elisabeth Rieger, Joan Vignolle, Frederik R Wurm, Stephane Carlotti, Daniel Taton
The ring-opening polymerization of N-tosyl aziridines, in presence of 1,3-bis(isopropyl)-4,5(dimethyl)imidazol-2-ylidene as organocatalyst and a N-tosyl secondary amine as initiator mimicking the growing chain, provides the first metal-free route to well...
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A Microarray Immunoassay for Serum Thyrotropin and Thyroglobulin Using Antibodies Immobilized on Track-Etched Membranes

Abstract

Serum thyroglobulin (Tg) and thyroid stimulating hormone (TSH) measurements have evolved as important analytes for monitoring the prognosis of patients with differentiated thyroid cancer, post-thyroidectomy. Individual analyte immunoassay is the current practice in clinical pathology, but the simultaneous assay for all relevant analytes for a given disease, can reduce assay costs, improve patient compliance and give the clinician more information for an unequivocal diagnosis. Microarray immunoassay (MI) can achieve this goal and, hence, we have developed and validated a immuno-radiometric MI for quantitation of serum TSH and Tg by using highly micro-porous polycarbonate (PC) track-etched membranes (TEM) to immobilize the monoclonal anti-TSH and polyclonal anti-Tg antibodies in ~1 mm diameter spots. Non-competitive immunoassays were performed using mixture of ¹²⁵I labeled monoclonal anti-TSH and anti-Tg antibodies. Phosphorimager was used to quantify the bound radioactivity. TSH and Tg were detected with detection limit of 0.07 µIU/ml and 0.13 ng/ml respectively, which is lower than the clinically required cut-off level. The assay showed: acceptable intra-assay precision within 20 % and recovery in the range of 76–111.2 %. MI compared well with the established immunoradiometric assay (IRMA) with r = 0.98, p < 0.01 (n = 41). No cross-reactivity was seen between the immobilized antibodies. Although two hormones are addressed in this report, MI using PC TEM and isotopic/non-isotopic tracers has the potential for highly automated multiplexed analysis.

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Part Time Firefighter - Kingman Fire Department

KINGMAN FIRE DEPARTMENT 310 NORTH FOURTH STREET KINGMAN, ARIZONA 86401 Updated: July 05, 2016 Job Classification: Firefighter Part-Time The City of Kingman Fire Department is building an ongoing eligibility list for Firefighter Part-Time. This position requires FireTEAM and a valid CPAT through National Testing Network. Candidates must also fill out the department application found on their website ...

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Firefighter/EMT - Oldsmar Fire Rescue

OLDSMAR FIRE RESCUE 100 STATE STREET WEST OLDSMAR, FLORIDA 34677 http://myoldsmar.com Updated: July 05, 2016 Classification: Firefighter/EMT NOW HIRING FOR AN OCTOBER 1ST START DATE! Oldsmar Fire Rescue is currently hiring for Firefighter/EMT. A city application and all testing through National Testing Network (NTN) must be completed by August 15, 2016. Salary Information: $40,514 to $57,109 Benefit ...

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Both cancerous miR-21 and stromal miR-21 in urothelial carcinoma are related to tumour progression

Abstract

Background

Urothelial carcinoma (UC) is a globally common cancer. miR-21 appears to be important in the tumourigenesis of almost all types of human cancer. However, its precise localization and significance in UC have yet to be clarified. We examined miR-21 expression in UC and revealed its clinicopathological importance.

Methods

Tissue arrays of 232 UCs were examined for miR-21 using in situ hybridization. One- hundred forty-eight TUR specimens and 84 surgically resected specimens were used. After miR-21 positivity was evaluated separately in tumour cells and tumour stroma, it was compared with clinicopathological factors and overall survival.

Results

miR-21 was strongly expressed in tumour cells in 9% of cases and in cancer stroma in 6% of cases. Stromal miR-21 was less than cancerous miR-21. Both miR-21 were correlated with each other and related to tumour stage, locus, and histological grade. In addition, strong positivity of miR-21 in cancer and stroma was significantly related to poorer prognosis among surgically resected cases. In a Cox proportional hazard model, cancerous miR-21 was the only independent prognostic factor except for tumour stage.

Conclusion

miR-21 in both cancer and stromal cells is closely related to tumour progression in UC. miR-21 may be a prognostic marker for cancer progression.

This article is protected by copyright. All rights reserved.

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Atypical EWSR1 FISH signal patterns in bone and soft tissue tumours:– diagnostic experience with 135 cases

Abstract

Aims

Recurrent EWSR1 gene rearrangements characterise a select group of bone and soft tissue tumours. In our routine diagnostic practice with fluorescence in situ hybridisation (FISH), we have occasionally observed EWSR1 gene rearrangements in tumours not classically associated with EWSR1 translocations. This study aimed to review our institutional experience of this phenomenon and also to highlight the occurrence of unusual EWSR1 FISH signals (i.e. 5′ centromeric region or 3′ telomeric region signals) that do not fulfill the published diagnostic criteria for rearrangements.

Methods and Results

Using an EWSR1 break-apart probe, we performed FISH assays on formalin-fixed paraffin embedded tissue sections from 135 bone and soft tissue specimens as part of their routine diagnostic workup. EWSR1 gene rearrangements were identified in 51% of cases, 56% of which also showed an abnormal FISH signal pattern (in addition to classically rearranged signals). However, atypical FISH signals were present in 45% of the non-rearranged cases. In addition, we observed tumours unrelated to those classically described as EWSR1-associated were technically EWSR1 rearranged in 6% of cases. Borderline levels of rearrangement (affecting 10-30% of lesional cells) were present in an additional 17% of these cases.

Conclusions

While our study confirmed that FISH is a sensitive and specific tool in the diagnosis of EWSR1-associated tumours, atypical FISH signals and classical rearrangement in entities other than EWSR1-associated tumours can occur. Therefore, it is essential that the FISH result not be used as an isolated test, but must be evaluated in the context of clinical features, imaging, pathological and immunohistochemical findings.

This article is protected by copyright. All rights reserved.

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Medtech Innovator 2016 Semi-Finalists Announced

MedTech Innovator, the medtech industry's annual start-up competition and virtual accelerator, has just announced their 20 semi-finalists. 430 companies from around the globe applied for these coveted spots, and were reviewed by 90 reviewers from 50 different companies. These ground-breaking semi-finalists will undergo a four month virtual accelerator before attending AdvaMed 2016. There, four finalists will be selected to present and compete for $250,000 in cash prizes, with the winner being selected by audience vote.  In addition, throughout the year there will be additional awards given in three areas: Value, Execution, and Momentum. During every round of MedTech Innovator we go over each company, in alphabetical order, to give our readers some insight into what makes these technologies so exciting. Here we go…

Adhesys Medical: Surgical sealants can be used in a variety of situations. Materials-wise there are two major players at the moment: cyanoacrylate derivatives (similar to superglue), are most commonly used to close skin wounds, while fibrin glues are used for a variety of situations within the body such as dural tears during spinal surgery. Both of these compounds have some disadvantages. Adhesys is looking to disrupt the current market with a novel, patented synthetic bioabsorbable poly-urethane based adhesive. Their solution is reportedly stronger, works better in wet environments, and lasts 20 days.

Adient Medical: Pulmonary embolism is a concerningly common, potentially fatal condition in which a clot travels from the systemic vasculature through the inferior vena cava where it can then lodge into the pulmonary vasculature. Patients at risk can be identified. These at risk patients are treated with chemical thromboprophylaxis and sometimes even with the implantation of an IVC filter, a physical net that catches clots as they float by before they can make it to the lungs. While IVC filters can be effective they also have some drawbacks. Over time they can actually be a source of thrombi themselves, pieces can fragment off, or they can occlude bloodflow. For this reason they are often retrieved after a period of time, which in itself carries some risk and cost. Adient Medical looks to address this problem by developing an absorbable IVC filter. This would allow the benefits of temporary thrombus filtration and then avoid the need for costly and risky retrieval procedures.

Augmedics LTD: This company is developing an augmented reality headset dubbed "The ViZOR" that, when combined with 3D reconstructed cross sectional imaging such as a CT scan combined with surgical navigation techniques, can project images of the patient's anatomy, such as the spine, in such a way that it appears that the surgeon is "seeing through" the patient. Furthermore, the system can make suggestions such as where and at what angle to place implants such as pedicle screws.  The company has ambitious goals for its technology to include deep learning elements in addition to some robotics applications.

C-SATS, Inc.:  Recently there has been increasing interest in objectively evaluating surgical performance. No one had ever even really examined whether improved technical skill in the operating room leads to improved patient outcomes until a study in 2013 which confirmed this intuitive hypothesis.  Unfortunately there is no way currently other than by word of mouth for patients to know how able their surgeon is.  Furthermore once surgeons are out of training there is really very little objective feedback for their performance. C-SATS seeks to provide a low cost and highly innovative solution to this problem. They crowd-source a multitude of "qualified reviewers," who may not necessarily have medical backgrounds, to review surgical video feeds and grade them objectively. This creative thinking actually was proven scientifically in a pilot study using Amazon's Mechanical Turk which can be read here (http://ift.tt/29OA8ld)

Catalia Health: Mabu is a personal healthcare companion/robot being developed by Catalia Health that is the basis of their patient engagement platform. Mabu has voice recognition capabilities, and also has a tablet which can be used for display and input. The platform also integrates with your smartphone to provide alerts such as medication reminders.

Cor: Using a patented vibration spectroscopy method Cor has created a home blood chemistry system marketed as a personal wellness product. In this fashion they hope to bypass FDA regulatory requirements for their initial offering. They have already raised in excess of $100k on their Indiegogo campaign. The interesting technology uses disposable cartridges to extract a drop of blood from the skin on the arm, which is described as painless. The cartridge is then inserted into a reusable reader which transfers the results to the platform. Over time the trends and patterns are recognized by the system and wellness recommendations are made such as specifics regarding diet and exercise.

Echo Labs:  Wrist mounted wellness trackers have been very popular lately, but their function remained somewhat limited with most only being able to detect steps, heart-rate and sometimes O2 level. Echo labs has created a revolutionary optical tracker that can detect heart-rate, blood pressure, O2 level, pH, and CO2. Their technology is made possible by a highly complex and proprietary algorithm. It will be exciting to see how they market the device and what use cases they develop.

Green Sun Medical: Green sun has an exciting, although somewhat mysterious, technology that may fundamentally alter the way we currently brace children with adolescent idiopathic scoliosis. While previously controversial it is now widely accepted and scientifically proven that compliant bracing can prevent the progression of scoliosis to the point of requiring a highly invasive and costly surgery. The braces, however, are time consuming to produce, can be uncomfortable for patients, and sometimes can cause problems such as pressure sores. Braces have improved through recent technological advances such as 3d scanning and sensors to confirm they are being worn. However, the braces are built around a single snapshot in time, and they are only checked and adjusted at typically 4 to 6 month intervals. Green Sun Medical seeks to completely change the way we brace scoliosis curve utilizing pressure sensors and dynamically adjustable braces. The brace can adjust itself on the fly or with manual input, theoretically leading to not only improved correction but proper fit for the entirety of the gap between follow-ups.  It can also decrease the frequency of complications such as pressure sores, and hopefully increase compliance by making the brace more comfortable. The technology has the backing of major names in the world of pediatric orthopaedics and is definitely something to keep an eye on.

Intensix:  Thanks to big data technology Intensix has created a predictive analytic system that can detect when a patient in an ICU setting begins to deteriorate in real-time. The system can reduce costs and can improve clinical outcomes. It is currently live at Tel Aviv Medical Center, Israel.

IntuiTap: Lumbar punctures are can be a technically challenging procedure, sometimes taking more than 2 hours when it should take about 30 minutes. Repeated taps and lengthy procedures can lead to serious complications such as bleeding, pain, infection or dural leak.  IntuiTap looks to streamline the entire process through multiple innovative and exciting ways. Currently most performers of LPs palpate bony landmarks with their fingers, which can be inaccurate in patients of certain body habitus or less skilled providers. Intuitap has developed a proprietary "palpation" system that can provide a digital representation of the bony anatomy of the patient's lumbar spine and in addition make recommendations for insertion location and angle. The system includes an in-line pressure transducer which makes measuring the opening pressure faster, more accurate and less prone to contamination. Finally the system has a patented fluid collection system which is easier to use and reportedly less prone to contamination.

Linear Health Sciences:  IV catheters are often accidentally snagged during day-to-day hospital activity, sometimes leading to painful unintentional removal of the catheter from the body. Much like the Apple MacBook's magnetic breakaway power connectors, linear health science has a similar concept in their OrchidValve. This device attaches to a standard IV luer lock connector in-line with standard IV tubing. If the cord is snagged the tubing will breakaway harmlessly, leaving the catheter in place. A new valve is then placed and the IV can be restarted without another catheter placement procedure, saving the hospital time and money and saves the patient from the discomfort of repeated IV attempts.

Madorra:  Vaginal dryness is a significant issue that affects post-menopausal women, breast cancer survivors and others. Madorra is a team out of Stanford's Biodesign program, and their solution is a non-hormonal, natural, physiologic lubrication device to combat this issue.

PreDxion Bio:  MicroKine is a point-of-care diagnostic system developed by PreDxion Bio that can measure plasma cytokines in 30 minutes from a single drop of blood. The system is designed for use in an ICU setting where rapid changes in management can be made for the most critically ill patients thanks to this technology.

SafeHeal:  Patients who require a resection of the colon often sometimes receive a diverting colostomy, where the proximal colon is brought up to the skin so that the colonic contents can exit the body through an ostomy, often collected in a pouch. In this way the anastomotic site, where the healthy colon ends were re-attached, is protected from fecal contents and allowed to heal. This procedure is uncomfortable for the patient, carries complications, and also has social stigma and emotional impact. SafeHeal has developed a device, dubbed ColoVac, that seeks to completely avoid the need for a diverting colostomy. Their device is a covered stent that is placed inside the colon at the anastomosis, protecting the area from excessive pressure and from exposure to fecal contents.

SilverCloud Health:  Silvercloud health is a comprehensive behavioral and mental health therapeutic platform. The platform has a multitude of features including having a supporter follow your progress and provide feedback, and social integration. In addition it also provides customized enterprise solutions. The specific programs offered include dealing with issues such as anxiety, depression, chronic illness, eating disorders and stress.

Sontina Medical, LLC: This company is creating a low-cost, fast, easy to use and high quality single-use breast biopsy device.

Tueo Health:  In pediatrics, chronic asthma is a costly and potentially deadly condition that can be difficult to stay on top of. A large component of this cost, and risk, are acute asthma flares, which can be treated effectively by adjusting a patient's medications. The key problem is that it can be difficult to identify an acute flare early enough to prevent the need for hospitalization. Tueo medical has created an ingenious sensor that resides in a child's bedroom and can accurately detect an acute asthma flare at a very early stage. Using this information in conjunction with the patient's medical team medication adjustments can be made preventing the serious consequences associated with improperly treated flares. The minds behind Tueo are graduates of Stanford's Biodesign program.

V-Sense Medical Devices:  Recording vital signs in a nursing home setting is typically performed by scheduled vital sign checks by nursing staff a few times a day. Unfortunately in those hours in between checks there is a window where nurses could be alerted to trouble if they only had access to alarming changes in vitals. V-sense uses technology originally developed by NASA to wirelessly measure heart rate and respiratory rate using a small cubic sensor with no patient contact whatsoever. V-sense can give nurses real-time alerts to intervene before it's too late.

Vetex Medical: Venous thrombi can be a challenging clinical problem to treat, and can be a risk factor for pulmonary embolism. Vetex is creating a novel thrombectomy catheter device that is "more aggressive and effective." Details are not available at this time for this intriguing technology.

WestFace Medical Devices, Inc.: SingleStick is a technology being developed by WestFace which uses "needle-tip imaging" to insure vascular access everytime even for unskilled users.

The Value Award was recently announced and Adient Medical was selected as the winner with Green Sun Medical as a close second. Good luck to all the companies involved and we'll be back in October to report on the finalists and overall winner.

This post Medtech Innovator 2016 Semi-Finalists Announced appeared first on Medgadget.

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Synthesis of asymmetric zinc(II) phthalocyanines with two different functional groups & spectroscopic properties and photodynamic activity for photodynamic therapy

Publication date: Available online 5 July 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Meltem Göksel
Zinc(II) phthalocyanine containing [2-(tert-butoxycarbonyl)amino]ethoxy and iodine groups (A and B), as well as their deprotected mono-amino and tri-iodine zinc(II) phthalocyanine (2) were obtained. This structure surrounds by substituents with functional groups. From this perspective it can be used a starting material for many reactions and applications, such as sonogashira coupling, carbodiimide coupling. An example of a first diversification reaction of this compound was obtained with conjugation of a biotin. Asymmetrically biotin conjugated and heavy atom bearing zinc(II) phthalocyanine (3) were synthesized characterized for the first time and photophysical, photochemical and photobiological properties of these phthalocyanines were compared in this study.

Graphical abstract

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Atrial fibrillation after lung cancer surgery: incidence, severity, and risk factors

Abstract

Purpose

Atrial fibrillation (Af) is a common post-operative cardiac complication after lung cancer surgery; however, the type of lung cancer surgery being performed has evolved, remarkably, into minimally invasive surgical procedures. The purpose of this study was to quantify the incidence and severity of post-operative Af and to identify the risk factors for Af, using a recent cohort of lung cancer surgery patients.

Methods

We reviewed, retrospectively, the medical records of 593 patients, who underwent lung cancer surgery between 2011 and 2013, for the development of post-operative Af.

Results

The overall incidence of post-operative Af in our study was 6.4 % (38/593). Three (8 %) of these 38 patients, subsequently, suffered brain infarction. Multivariate analysis revealed that mediastinal lymph node dissection (OR ND-2/ND-0–1 = 3.06; 95 % CI 1.06–10.9) was associated with the development of post-operative Af.

Conclusion

Omission of mediastinal lymph dissection for patients with early stage lung cancer and a high risk of Af should be considered to prevent post-operative Af.

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PPARα and IL-17A responses associated with the intestinal immune response against the protozoan parasite Giardia muris

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Natural killer cells as key players in the vaccine-induced immune response against bovine GI nematodes

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Giardia muris infection in mice is associated with the intestinal activation of the Peroxisome Proliferator-Activated Receptor Alpha followed by a protective IL-17A response

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Mercy Named Most Wired for 13th Time

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By Mercy's Jennifer Harutunian

Finding quick answers among millions of patient records has been a challenge in health care. Today, Mercy's ability to pull together data from many sources, including its electronic health record (EHR), and provide immediate answers - for leaders needing business insight and care teams needing lifesaving, proven results - has once again earned Mercy distinguished honors.

For the 13th year, the American Hospital Association (AHA) Health Forum has named Mercy a Most Wired™ health system, and for the second time in three years since the AHA began handing out special honors, again placed Mercy in the "Advanced" category for exceeding core criteria along with only 19 others.

The AHA honors health systems that use technology in innovative ways to make improvements in clinical quality and safety, health care business and administrative management and to support the clinical integration of many different treatment settings.

"Today, we're much smarter with data, using it not just to tightly integrate care across locations and specialties, but also to quickly compare costs and results for the products and methods of care used across Mercy, instantly revealing the best, most cost-effective treatment for patients," said Gil Hoffman, Mercy's chief information officer.

Mercy's Most Wired™ Advanced designation comes on the heels of several awards for Mercy's IT organization, Mercy Technology Services, including InformationWeek's Elite 100 Innovator award, the CIO 100 award for IT Excellence and being named an "Analytics Wizard" by software giant, SAP.

Since its strategic decision to implement an integrated EHR in 2008, Mercy has been finding ways to improve patient care with data, and now provides EHR and analytics services to other hospitals and health systems looking to do the same.

"Mercy's shift from capturing data to delivering instant intelligence represents real transformation in health care - a change we continue to pursue for the patients and families whose lives are positively impacted thanks to lower costs and better care," Hoffman said.

Health care's Most Wired® survey, published annually by Health & Hospitals Networks (H&HN), is a leading industry barometer measuring information technology (IT) use and adoption among 680 participants, representing nearly 35 percent of all U.S. hospitals.

For a full list of winners, visit www.hhnmag.com. 

Show EMS Sitewide: 

Yes!

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Introduction of perfluoroalkyl chain into the esterifying moiety of bacteriochlorophyll c in the green sulfur photosynthetic bacterium Chlorobaculum tepidum by pigment biosynthesis

Publication date: Available online 5 July 2016
Source:Bioorganic & Medicinal Chemistry
Author(s): Yoshitaka Saga, Hayato Yamashita, Keiya Hirota
The green sulfur photosynthetic bacterium Chlorobaculum (Cba.) tepidum was grown in liquid cultures containing perfluoro-1-decanol, 1H,1H,2H,2H-heptadecafluoro-1-decanol [CF3(CF2)7(CH2)2OH] or 1H,1H-nonadecafluoro-1-decanol [CF3(CF2)8CH2OH], to introduce rigid and fluorophilic chains into the esterifying moiety of light-harvesting bacteriochlorophyll (BChl) c. Exogenous 1H,1H,2H,2H-heptadecafluoro-1-decanol was successfully attached to the 17²-carboxy group of bacteriochlorophyllide (BChlide) c in vivo: the relative ratio of the unnatural BChl c esterified with this perfluoroalcohol over the total BChl c were 10.3 %. Heat treatment of the liquid medium containing1H,1H,2H,2H-heptadecafluoro-1-decanol with β-cyclodextrin before inoculation increased the relative ratio of the BChl c derivative esterified with this alcohol in the total BChl c in Cba. tepidum. In a while, 1H,1H-nonadecafluoro-1-decanol was not attached to BChlide c in Cba. tepidum, which was grown by its supplementation. These results suggest that the rigidity close to the hydroxy group of the esterifying alcohol is not suitable for the recognition by the BChl c synthase called BchK in Cba. tepidum. The unnatural BChl c esterified with 1H,1H,2H,2H-heptadecafluoro-1-decanol participated in BChl c self-aggregates in chlorosomes.

Graphical abstract

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Site-Specific Neutrophil Migration and CXCL2 Expression in Periodontal Tissue

The oral microbial community is the best-characterized bacterial ecosystem in the human host. It has been shown in the mouse that oral commensal bacteria significantly contribute to clinically healthy periodontal homeostasis by influencing the number of neutrophils that migrate from the vasculature to the junctional epithelium. Furthermore, in clinically healthy tissue, the neutrophil response to oral commensal bacteria is associated with the select expression of the neutrophil chemokine CXCL2 but not CXCL1. This preliminary study examined the contribution of commensal bacteria on neutrophil location across the tooth/gingival interface. Tissue sections from the root associated mesial (anterior) of the second molar to the root associated distal (posterior) of the second molar were examined for neutrophils and the expression of the neutrophil chemokine ligands CXCL1 and CXCL2. It was found that both the number of neutrophils as well as the expression of CXCL2 but not CXCL1 was significantly increased in tissue sections close to the interdental region, consistent with the notion of select tissue expression patterns for neutrophil chemokine expression and subsequent neutrophil location. Furthermore, mice gavaged with either oral Streptococcus or Lactobacillus sp. bacteria induced a location pattern of neutrophils and CXCL2 expression similar to the normal oral flora. These data indicate for the first time select neutrophil location and chemokine expression patterns associated with clinically healthy tissue. The results reveal an increased inflammatory load upon approaching the interproximal region, which is consistent with the observation that the interproximal region often reveals early clinical signs of periodontal disease.

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Pulp Fibroblasts Control Nerve Regeneration through Complement Activation

Dentin-pulp regeneration is closely linked to the presence of nerve fibers in the pulp and to the healing mechanism by sprouting of the nerve fiber's terminal branches beneath the carious injury site. However, little is known about the initial mechanisms regulating this process in carious teeth. It has been recently demonstrated that the complement system activation, which is one of the first immune responses, contributes to tissue regeneration through the local production of anaphylatoxins such as C5a. While few pulp fibroblasts in intact teeth and in untreated fibroblast cultures express the C5a receptor (C5aR), here we show that all dental pulp fibroblasts, localized beneath the carious injury site, do express this receptor. This observation is consistent with our in vitro results, which showed expression of C5aR in lipoteichoic acid–stimulated pulp fibroblasts. The interaction of C5a, produced after complement synthesis and activation from pulp fibroblasts, with the C5aR of these cells mediated the local brain-derived neurotropic factor (BDNF) secretion. Overall, this activation guided the neuronal growth toward the lipoteichoic acid–stimulated fibroblasts. Thus, our findings highlight a new mechanism in one of the initial steps of the dentin-pulp regeneration process, linking pulp fibroblasts to the nerve sprouting through the complement system activation. This may provide a useful future therapeutic tool in targeting the fibroblasts in the dentin-pulp regeneration process.

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Craniosynostosis and Resynostosis: Models, Imaging, and Dental Implications

Craniosynostosis occurs in approximately 1 in 2,000 children and results from the premature fusion of ≥1 cranial sutures. If left untreated, craniosynostosis can cause numerous complications as related to an increase in intracranial pressure or as a direct result from cranial deformities, or both. More than 100 known mutations may cause syndromic craniosynostosis, but the majority of cases are nonsyndromic, occurring as isolated defects. Most cases of craniosynostosis require complex cranial vault reconstruction that is associated with a high risk of morbidity. While the first operation typically has few complications, bone rapidly regrows in up to 40% of children who undergo it. This resynostosis typically requires additional surgical intervention, which can be associated with a high incidence of life-threatening complications. This article reviews work related to the dental and maxillofacial implications of craniosynostosis and discusses clinically relevant animal models related to craniosynostosis and resynostosis. In addition, information is provided on the imaging modalities used to study cranial defects in animals and humans.

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Corrigendum

Alikhani M, Lopez JA, Alabdullah H, Vongthongleur T, Sangsuwon C, Alikhani M, Alansari S, Oliveira SM, Nervina JM, Teixeira CC. 2016. High-frequency acceleration: therapeutic tool to preserve bone following tooth extractions. J Dent Res. 95(3):311–318. (Original DOI: 10.1177/0022034515621495)

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Directed Acyclic Graphs for Oral Disease Research

Directed acyclic graphs (DAGs) are nonparametric graphical tools used to depict causal relations in the epidemiologic assessment of exposure-outcome associations. Although their use in dental research was first advocated in 2002, DAGs have yet to be widely adopted in this field. DAGs help identify threats to causal inference such as confounders, bias due to subject selection, and inappropriate handling of missing data. DAGs can also inform the data analysis strategy based on relations among variables depicted on it. This article uses the example of a study of temporomandibular disorders (TMDs), investigating causal effects of facial injury on subsequent risk of TMD. We illustrate how DAGs can be used to identify 1) potential confounders, 2) mediators and the consequences of attempt to estimate direct causal effects, 3) colliders and the consequences of conditioning on colliders, and 4) variables that are simultaneously mediators and confounders and the consequences of adjustment for such variables. For example, one DAG shows that statistical adjustment for the pressure pain threshold would necessarily bias the causal relation between facial injury and TMD. Finally, we discuss the usefulness of DAGs during study design, subject selection, and choosing variables to be measured in a study.

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Distinct Oral Neutrophil Subsets Define Health and Periodontal Disease States

Neutrophils exit the vasculature and swarm to sites of inflammation and infection. However, these cells are abundant in the healthy, inflammation-free human oral environment, suggesting a unique immune surveillance role within the periodontium. We hypothesize that neutrophils in the healthy oral cavity occur in an intermediary parainflammatory state that allows them to interact with and contain the oral microflora without eliciting a marked inflammatory response. Based on a high-throughput screen of neutrophil CD (cluster of differentiation) marker expression and a thorough literature review, we developed multicolor flow cytometry panels to determine the surface marker signatures of oral neutrophil subsets in periodontal health and disease. We define here 3 distinct neutrophil subsets: resting/naive circulatory neutrophils, parainflammatory neutrophils found in the healthy oral cavity, and proinflammatory neutrophils found in the oral cavity during chronic periodontal disease. Furthermore, parainflammatory neutrophils manifest as 2 distinct subpopulations—based on size, granularity, and expression of specific CD markers—and exhibit intermediate levels of activation as compared with the proinflammatory oral neutrophils. These intermediately activated parainflammatory populations occur in equal proportions in the healthy oral cavity, with a shift to one highly activated proinflammatory neutrophil population in chronic periodontal disease. This work is the first to identify and characterize oral parainflammatory neutrophils that interact with commensal biofilms without inducing an inflammatory response, thereby demonstrating that not all neutrophils trafficking through periodontal tissues are fully activated. In addition to establishing possible diagnostic and treatment monitoring biomarkers, this oral neutrophil phenotype model builds on existing literature suggesting that the healthy periodontium may be in a parainflammatory state.

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Clinical Significance and Roles in Angiogenesis of Circulating Microparticles in Oral Cancer

Our recent study established the increased circulating microparticles (MPs) and their procoagulant activity in oral squamous cell carcinoma (OSCC). In the present study, we further evaluated different phenotypes of circulating MPs in OSCC patients and explored their clinical significance and effects on angiogenesis (a critical event in tumor progression). To conduct the study, circulating MPs in 45 OSCC patients and 18 healthy volunteers were characterized and quantified by transmission electron microscopy and flow cytometry. Correlations between circulating MPs and clinicopathologic data, microvessel density, and proangiogenic factor levels in patients with OSCC were analyzed by immunohistochemistry and Spearman rank correlation test. Additionally, the in vitro studies were performed with use of human umbilical vein endothelial cells. Our results showed that the levels of circulating MPs as well as the subsets of platelet-derived, endothelium-derived, and pan-leukocyte MPs in stages III to IV OSCC were significantly higher than stages I to II and healthy subjects. Moreover, these increased circulating MPs were significantly correlated with tumor size, TNM stages, microvessel density, and expression levels of vascular endothelial growth factor (VEGF) and matrix metallopeptidase 9 (MMP9) in OSCC patients. The in vitro studies revealed that circulating MPs isolated from OSCC patients could be effectively taken up by human umbilical vein endothelial cells and could promote the proliferation, migration, invasion, and tube formation of recipient endothelial cells, accompanied by increased expression of proangiogenic factors. In summary, circulating MPs play important roles in angiogenesis and local tumor progression of OSCC. Our results shed new light on the progression of OSCC and might be helpful to explore novel treatment strategies targeting tumor angiogenesis.

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Response to Letter to the Editor, "Dentin Bonding Testing Using a Mini-interfacial Fracture Toughness Approach"

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Access to Fluoridated Water and Adult Dental Caries: A Natural Experiment

Systematic reviews have found no evidence to support a benefit of water fluoridation (WF) to prevent dental caries in adult populations. The aim of this natural experiment was to investigate whether lifetime access to fluoridated water is associated with dental caries experience among adults from Florianópolis, Brazil. The data originated from a population-based cohort study (EpiFloripa Adult) initiated in 2009 (n = 1,720) when participants were aged 20 to 59 years. The second wave was carried out in 2012 (n = 1,140) and included a dental examination and a face-to-face questionnaire. Participants residing at the same address since the age of 7 y or before were included in the primary analyses. Sensitivity analyses were also performed. WF was implemented in the city in 2 different periods of time: 1982 (60% of the population) and 1996. Dental caries was assessed by the decayed, missing, and filled teeth (DMFT) index. A combination of residential status, participant's age, and year of implementation of WF permitted the creation of participants' lifetime access to fluoridated water: >75%, 50% to 75%, and <50% of a participant's lifetime. Covariates included sex, age, socioeconomic mobility, educational attainment, income, pattern of dental attendance, and smoking. Participants who accessed fluoridate water <50% of their lifetime presented a higher mean rate ratio of DMFT (1.39; 95% CI, 1.05–1.84) compared with those living >75% of their lifetime with residential access to fluoridated water. Participants living between 50% and 75% and <50% of their lives in fluoridated areas presented a decayed and filled teeth mean ratio of 1.34 (95% CI, 1.02–1.75) and 1.47 (95% CI, 1.05–2.04) higher than those with residential access to fluoridated water >75% of their lifetime, respectively. Longer residential lifetime access to fluoridated water was associated with less dental caries even in a context of multiple exposures to fluoride.

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Mentoring and Role Modeling: The Gifts That Keep On Giving

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Lack of Buffering by Composites Promotes Shift to More Cariogenic Bacteria

Secondary caries (SC) remains a very important problem with composite restorations. The objectives of this study were to test the acid-buffering ability of several restorative materials and to evaluate whether buffering of the restorative material has an impact on the microbial composition of the biofilm. Disk-shaped specimens of conventional composite, composite with surface prereacted glass-ionomer filler particles (so-called giomer), glass-ionomer cement (GIC), amalgam, and hydroxyapatite (HAp) (control) were exposed to aqueous solutions with pH 4, 5, 6, and 7 and to the medium containing bacteria-produced acids, and pH changes were recorded over several days. Next, material specimens were immersed in bacterial growth medium with pH adjusted to 5. After a 24-h incubation, the extracts were collected and inoculated with a cariogenic (Streptococcus mutans) and a noncariogenic (Streptococcus sanguinis) species. The bacterial growth was monitored both in a single-species model by spectrophotometry and in a dual-species model by viability quantitative polymerase chain reaction. Amalgam and HAp showed the strongest acid-buffering ability, followed by the GIC and the giomer, while the conventional composite did not exhibit any buffering capacity. Furthermore, due to the lack of acid-buffering abilities, composite was not able to increase the pH of the medium (pH 5), which, in the absence of antibacterial properties, allowed the growth of S. mutans, while the growth of S. sanguinis, a less aciduric species, was completely inhibited. A similar effect was observed when bacteria were cultured together: there was a higher percentage of S. mutans and lower percentage of S. sanguinis with the conventional composite than with other materials and HAp. In conclusion, conventional composites lack the ability to increase the local pH, which leads to the outgrowth of more acidogenic/aciduric bacteria and higher cariogenicity of the biofilm. Together with lack of antibacterial properties, lack of buffering may account for the higher susceptibility of composites to SC.

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The Grooved Rodent Incisor Recapitulates Rudimentary Teeth Characteristics of Ancestral Mammals

It is known from the paleontology studies of eutherian mammals that incisor numbers were reduced during evolution. The evolutionary lost incisors may remain as vestigial structures at embryonic stages. The recapitulation of the incisor patterns among mammalian species will potentially uncover the mechanisms underlying the phenotypic transition of incisors during evolution. Here, we showed that a minute tooth formed in the presumptive groove region of the gerbil upper incisor at the early developmental stages, during which multiple epithelial swellings and Shh transcription domains spatiotemporally appeared in the dental epithelium, suggests the existence of vestigial dental primordia. Interestingly, when we trimmed the surrounding mesenchyme from incisor tooth germs at or before the bud stage prior to ex vivo culture, the explants developed different incisor phenotypes ranging from triplicated incisors, duplicated incisors, to Lagomorpha-like incisors, corresponding to the incisor patterns in the eutherian mammals. These results imply that the phenotypic transition of incisors during evolution, as well as the achievement of ultimate incisors in adults, arose from differential integrations of primordia. However, when the incisor tooth germ was trimmed at the cap stage, a grooved incisor developed similar to the normal condition. Furthermore, the incisor tooth germ developed a small but smooth incisor after the additional removal of the minute tooth and a lateral rudiment. These results suggest that multiple dental primordia integrated before the cap stage, with the labial primordia contributing to the labial face of the functional incisor. The minute tooth that occupied the boundary of the 2 labial primordia might be implicated in the groove formation. This study sheds light on how rudiments incorporate into functional organs and aids the understanding of incisor evolution.

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