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Objective: To describe a protocol for corneal ulcer monitoring utilizing daily fluorescein staining and evaluation of owner‐acquired anterior segment images. Animal studied: Nine client‐owned small animal patients (eight dogs, one cat) diagnosed with superficial corneal ulcers at the University of Georgia Veterinary Capitalize Hospital. Procedure(s): In addition to routine ulcer therapy, patients were discharged with supplies to perform daily fluorescein staining including a Quikvue® cobalt blue light camera adapter. Fluorescein staining was performed daily, photographs and/or videos were acquired at home by the patient's owner(s), and images were analyzed daily by trained personnel. In‐house examinations were performed weekly and within 24 h after the ulcer had appeared healed on photographs. Results: All (9/9) owners were able to take interpretable photographs. The majority (6/9) of patients had images successfully detailing their ulcer healing progress. One (1/9) patient appeared healed on images, but on subsequent examination had persistent ulceration covered by third eyelid elevation. Two (2/9) patients had persistent ulceration, consistent on both images and examination, but exited the study prematurely prior to ulcer healing. Conclusions: Remote fluorescein staining and image evaluation can be considered as an adjunct for monitoring ulcer healing but should not be used alone or as a substitute for ophthalmic examinations. Ulcers under the third eyelid have potential to be missed on image evaluation alone. [ABSTRACT FROM AUTHOR]

Aims: Early dysfunction in Alzheimer's disease (AD) is characterised by alterations of synapse structure and function leading to dysmorphic neurites, decreased spine density, impaired synaptic plasticity and cognitive deficits. The class II member HDAC4, which recently emerged as a crucial factor in shaping synaptic plasticity and memory, was found to be altered in AD. We investigated how the modulation of HDAC4 may contribute to counteracting AD pathogenesis. Methods: Using a cytoplasmic HDAC4 mutant (HDAC4SD), we studied the recovery of synaptic function in hippocampal tissue and primary neurons from the triple-transgenic mouse model of AD (3_Tg-AD). Results: Here, we report that in wild-type mice, HDAC4 is localised at synapses and interacts with postsynaptic proteins, whereas in the 3_Tg-AD, it undergoes nuclear import, reducing its interaction with synaptic proteins. Of note, HDAC4 delocalisation was induced by both amyloid-β and tau accumulation. Overexpression of the HDAC4SD mutant in CA1 pyramidal neurons of organotypic hippocampal slices obtained from 3_Tg-AD mice increased dendritic length and promoted the enrichment of N-cadherin, GluA1, PSD95 and CaMKII proteins at the synaptic level compared with AD neurons transfected with the empty vector. Moreover, HDAC4 overexpression recovered the level of SUMO2/3ylation of PSD95 in AD hippocampal tissue, and in AD organotypic hippocampal slices, the HDAC4SD rescued spine density and synaptic transmission. Conclusions: These results highlight a new role of cytoplasmic HDAC4 in providing a structural and enzymatic regulation of postsynaptic proteins. Our findings suggest that controlling HDAC4 localisation may represent a promising strategy to rescue synaptic function in AD, potentially leading to memory improvement. [ABSTRACT FROM AUTHOR]

Simonsiella is a known oral commensal organism and has been identified as a part of the normal ocular microbiota in humans. This case series highlights three cases of canine ulcerative keratitis in which a mixed bacterial infection, including high numbers of Simonsiella spp. had been identified cytologically. All cases had episodes of oral contamination, either from licking the eye, licking the paws and rubbing the eye, or housemate(s) licking the eye. In two of three cases, ulcer resolution was observed within 3 weeks following initiation of broad‐spectrum topical antimicrobial therapy. [ABSTRACT FROM AUTHOR]

Aims: Several studies reported that astrocytes support neuronal communication by the release of gliotransmitters, including ATP and glutamate. Astrocytes also play a fundamental role in buffering extracellular glutamate in the synaptic cleft, thus limiting the risk of excitotoxicity in neurons. We previously demonstrated that extracellular tau oligomers (ex‐oTau), by specifically targeting astrocytes, affect glutamate‐dependent synaptic transmission via a reduction in gliotransmitter release. The aim of this work was to determine if ex‐oTau also impair the ability of astrocytes to uptake extracellular glutamate, thus further contributing to ex‐oTau‐dependent neuronal dysfunction. Methods: Primary cultures of astrocytes and organotypic brain slices were exposed to ex‐oTau (200 nM) for 1 h. Extracellular glutamate buffering by astrocytes was studied by: Na+ imaging; electrophysiological recordings; high‐performance liquid chromatography; Western blot and immunofluorescence. Experimental paradigms avoiding ex‐oTau internalisation (i.e. heparin pre‐treatment and amyloid precursor protein knockout astrocytes) were used to dissect intracellular vs extracellular effects of oTau. Results: Ex‐oTau uploading in astrocytes significantly affected glutamate‐transporter‐1 expression and function, thus impinging on glutamate buffering activity. Ex‐oTau also reduced Na‐K‐ATPase activity because of pump mislocalisation on the plasma membrane, with no significant changes in expression. This effect was independent of oTau internalisation and it caused Na+ overload and membrane depolarisation in ex‐oTau‐targeted astrocytes. Conclusions: Ex‐oTau exerted a complex action on astrocytes, at both intracellular and extracellular levels. The net effect was dysregulated glutamate signalling in terms of both release and uptake that relied on reduced expression of glutamate‐transporter‐1, altered function and localisation of NKA1A1, and NKA1A2. Consequently, Na+ gradients and all Na+‐dependent transports were affected. [ABSTRACT FROM AUTHOR]

Objective: Iridocorneal angle (ICA) narrowing is a known risk factor for primary glaucoma in multiple species, but has not been described in companion rabbits. This study aimed to develop an ICA grading scheme for companion rabbits to enable early glaucoma predisposition diagnosis. Animals studied: Twenty healthy rabbits of varying breeds and ages. Procedures: Rabbits received complete ophthalmic examinations, including gonioscopy, and imaging of the ICA using spectral‐domain optical coherence tomography (SD‐OCT), Scheimpflug imaging (Pentacam® HR), and high‐resolution ultrasound (HRUS). Angle opening distance (AOD) and angle recess area (ARA) of the ICA were measured and assessed for agreement using a Bland‐Altman analysis. A five‐stage gonioscopy grading scheme was created, and Spearman‐rank test assessed for correlation between gonioscopy grades and ICA measurements. Differences among age and sex were analyzed with a nonparametric ANOVA and Wilcoxon rank‐sum test, respectively. Results: Analysis revealed AOD medians of 0.28mm for SD‐OCT [95% CI: 0.24‐0.31], 0.20mm for Pentacam® HR [95% CI: 0.18‐0.21], and 0.25mm for HRUS [95% CI: 0.22‐0.28]. The median ARA was 0.14mm2 for SD‐OCT [95% CI: 0.117‐0.163], 0.09mm2 for Pentacam® HR [95% CI: 0.082‐0.100], and 0.06mm2 for HRUS [95% CI: 0.046‐0.054]. The association between gonioscopy grade and SD‐OCT ARA was significant (P < 0.05), and there was a significant difference (P < 0.001) between imaging modalities for both ARA and AOD. Conclusions: Gonioscopy grade correlated well with SD‐OCT ARA. Therefore, SD‐OCT is recommended as a noncontact method for evaluating companion rabbit ICA. Each imaging device should not be used interchangeably for ICA evaluation. [ABSTRACT FROM AUTHOR]

The present study aimed to describe the use of systemic mycophenolate as a steroid‐sparing therapy for immune‐mediated ophthalmic disease. Records for canine patients with suspected or confirmed immune‐mediated ophthalmic disease were retrospectively reviewed for patient signalment, diagnoses, mycophenolate dose, concurrent medications, reported side effects, and long‐term outcome while receiving systemic mycophenolate. Patient diagnoses included: anterior uveitis, panuveitis, presumed immune‐mediated retinopathy, retinal detachment, chorioretinitis, optic neuritis, and/or uveodermatologic syndrome. Overall, 18 of 23 (78%) patients had either a complete or partial response to therapy. Only six of 18 (33%) patients with a complete or partial response to therapy continued to require adjunct systemic immunosuppressive/anti‐inflammatory therapy. Gastrointestinal side effects were reported in five of 23 (22%) patients; one of these cases resolved with a 50% mycophenolate dose decrease while maintaining good control of intraocular inflammation. In conclusion, systemic mycophenolate may be considered as an adjunct or sole therapy for medical management of canine immune‐mediated ophthalmic disease. [ABSTRACT FROM AUTHOR]

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline. [ABSTRACT FROM AUTHOR]

Antineoplastic therapy has been associated with pain syndrome development characterized by acute and chronic pain. The chemotherapeutic agent dacarbazine, used mainly to treat metastatic melanoma, is reported to cause painful symptoms, compromising patient quality of life. Evidence has proposed that transient receptor potential ankyrin 1 (TRPA1) plays a critical role in chemotherapy‐induced pain syndrome. Here, we investigated whether dacarbazine causes painful hypersensitivity in naive or melanoma‐bearing mice and the involvement of TRPA1 in these models. Mouse dorsal root ganglion (DRG) neurons and human TRPA1‐transfected HEK293 (hTRPA1‐HEK293) cells were used to evaluate the TRPA1‐mediated calcium response evoked by dacarbazine. Mechanical and cold allodynia were evaluated after acute or repeated dacarbazine administration in naive mice or after inoculation of B16‐F10 melanoma cells in C57BL/6 mice. TRPA1 involvement was investigated by using pharmacological and genetic tools (selective antagonist or antisense oligonucleotide treatment and Trpa1 knockout mice). Dacarbazine directly activated TRPA1 in hTRPA1‐HEK293 cells and mouse DRG neurons and appears to sensitize TRPA1 indirectly by generating oxidative stress products. Moreover, dacarbazine caused mechanical and cold allodynia in naive but not Trpa1 knockout mice. Also, dacarbazine‐induced nociception was reduced by the pharmacological TRPA1 blockade (antagonism), antioxidants, and by ablation of TRPA1 expression. TRPA1 pharmacological blockade also reduced dacarbazine‐induced nociception in a tumor‐associated pain model. Thus, dacarbazine causes nociception by TRPA1 activation, indicating that this receptor may represent a pharmacological target for treating chemotherapy‐induced pain syndrome in cancer patients submitted to antineoplastic treatment with dacarbazine. What's new? Acute and chronic pain syndromes, such as chemotherapy‐induced peripheral neuropathy, are extremely common among cancer patients, and can limit the use of chemotherapy. Several studies have indicated that the nerve receptor TRPA1 may be involved in this kind of pain. In this study, the authors used antisense, knockout, and pharmacological methods to conclude that the antineoplastic drug dacarbazine does induce pain signals via TRPA1 activation. This receptor may thus represent a valuable therapeutic target for treating chemotherapy‐induced pain. [ABSTRACT FROM AUTHOR]

Safranal, contained in Crocus sativus L., exerts anti‐inflammatory and analgesic effects. However, the underlying mechanisms for such effects are poorly understood. We explored whether safranal targets the transient receptor potential ankyrin 1 (TRPA1) channel, which in nociceptors mediates pain signals. Safranal by binding to specific cysteine/lysine residues, stimulates TRPA1, but not the TRP vanilloid 1 and 4 channels (TRPV1 and TRPV4), evoking calcium responses and currents in human cells and rat and mouse dorsal root ganglion (DRG) neurons. Genetic deletion or pharmacological blockade of TRPA1 attenuated safranal‐evoked release of calcitonin gene‐related peptide (CGRP) from rat and mouse dorsal spinal cord, and acute nociception in mice. Safranal contracted rat urinary bladder isolated strips in a TRPA1‐dependent manner, behaving as a partial agonist. After exposure to safranal the ability of allyl isothiocyanate (TRPA1 agonist), but not that of capsaicin (TRPV1 agonist) or GSK1016790A (TRPV4 agonist), to evoke currents in DRG neurons, contraction of urinary bladder strips and CGRP release from spinal cord slices in rats, and acute nociception in mice underwent desensitization. As previously shown for other herbal extracts, including petasites or parthenolide, safranal might exert analgesic properties by partial agonism and selective desensitization of the TRPA1 channel. [ABSTRACT FROM AUTHOR]

Background and Purpose: The mechanism of the anti-migraine action of extracts of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major constituent of these extracts, to specifically target TRPA1 channel and to affect functional responses relevant to migraine.Experimental Approach: Single-cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in rodent isolated urinary bladder, release of CGRP from mouse spinal cord in vitro and facial rubbing in mice and meningeal blood flow in rats were examined.Key Results: Isopetasin induced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of rat isolated urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by genetic deletion or pharmacological antagonism of TRPA1 channels. Pre-exposure to isopetasin produced marked desensitization of allyl isothiocyanate (AITC, TRPA1 channel agonist)- or capsaicin (TRPV1 channel agonist)-evoked currents in rat TG neurons, contractions of rat or mouse bladder and CGRP release from mouse central terminals of primary sensory neurons. Repeated intragastric administration of isopetasin attenuated mouse facial rubbing, evoked by local AITC or capsaicin, and dilation of rat meningeal arteries by acrolein or ethanol (TRPA1 and TRPV1 channel agonists respectively).Conclusion and Implications: Activation of TRPA1 channels by isopetasin results in excitation of neuropeptide-containing nociceptors, followed by marked heterologous neuronal desensitization. Such atten uation in pain and neurogenic inflammation may account for the anti-migraine action of butterbur. [ABSTRACT FROM AUTHOR]

ABSTRACT It has long been established that UVC light is a very effective method for inactivating pathogens in a fluid, yet the application of UVC irradiation to modern biotechnological processes is limited by the intrinsic short penetration distance of UVC light in optically dense protein solutions. This experimental and numerical study establishes that irradiating a fluid flowing continuously in a microfluidic capillary system, in which the diameter of the capillary is tuned to the depth of penetration of UVC light, uniquely treats the whole volume of the fluid to UVC light, resulting in fast and effective inactivation of pathogens, with particular focus to virus particles. This was demonstrated by inactivating human herpes simplex virus type-1 (HSV-1, a large enveloped virus) on a dense 10% fetal calf serum solution in a range of fluoropolymer capillary systems, including a 0.75 mm and 1.50 mm internal diameter capillaries and a high-throughput MicroCapillary Film with mean hydraulic diameter of 206 μm. Up to 99.96% of HSV-1 virus particles were effectively inactivated with a mean exposure time of up to 10 s, with undetectable collateral damage to solution proteins. The kinetics of virus inactivation matched well the results from a new mathematical model that considers the parabolic flow profile in the capillaries, and showed the methodology is fully predictable and scalable and avoids both the side effect of UVC light to proteins and the dilution of the fluid in current tubular UVC inactivation systems. This is expected to speed up the industrial adoption of non-invasive UVC virus inactivation in clinical biotechnology and biomanufacturing of therapeutic molecules. Biotechnol. Bioeng. 2016;113: 1481-1492. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In recent years, much effort has been devoted to identifying stimuli capable of enhancing adult neurogenesis, a process that generates new neurons throughout life, and that appears to be dysfunctional in the senescent brain and in several neuropsychiatric and neurodegenerative diseases. We previously reported that in vivo exposure to extremely low-frequency electromagnetic fields ( ELFEFs) promotes the proliferation and neuronal differentiation of hippocampal neural stem cells ( NSCs) that functionally integrate in the dentate gyrus. Here, we extended our studies to specifically assess the influence of ELFEFs on hippocampal newborn cell survival, which is a very critical issue in adult neurogenesis regulation. Mice were injected with 5-bromo-2′-deoxyuridine (BrdU) to label newborn cells, and were exposed to ELFEFs 9 days later, when the most dramatic decrease in the number of newly generated neurons occurs. The results showed that ELFEF exposure (3.5 h/day for 6 days) enhanced newborn neuron survival as documented by double staining for BrdU and doublecortin, to identify immature neurons, or NeuN labeling of mature neurons. The effects of ELFEFs were associated with enhanced spatial learning and memory. In an in vitro model of hippocampal NSCs, ELFEFs exerted their pro-survival action by rescuing differentiating neurons from apoptotic cell death. Western immunoblot assay revealed reduced expression of the pro-apoptotic protein Bax, and increased levels of the anti-apoptotic protein Bcl-2, in the hippocampi of ELFEF-exposed mice as well as in ELFEF-exposed NSC cultures, as compared with their sham-exposed counterparts. Our results may have clinical implications for the treatment of impaired neurogenesis associated with brain aging and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The global neoliberal economic and political order impregnated the emergence of democracy in South Africa. One of the hallmarks of this order is that the capacity of the state to transform society is constrained, particularly in the rural hinterlands. The incapacity of the state to extend its grip, both economically and politically, has provided traditional leaders with an opportunity to both recast themselves as intermediaries between state and society and elevate themselves to decision makers on behalf of large communities. The article examines the way in which traditional leaders have repositioned themselves in the new democracy, what their source of support is, and why the African National Congress government has come to support these efforts. [ABSTRACT FROM AUTHOR]

The tools for optimal design of photocatalytic air purifiers are still being established. In this article, the optimal design of monolith photocatalytic reactors irradiated by cylindrical UV lamps was investigated. The radiative transfer equation in dimensionless monoliths was solved by the Monte-Carlo method to yield the radiation field in the reactor. The effect of the dimensionless design parameters, monolith aspect ratio, geometric ratios, catalyst reflectivity and number of lamps were investigated and correlated in terms of photon absorption efficiency (φ), uniformity of radiation distribution (η), and overall monolith photonic efficiency (Φ = η φ. Optimal design is achieved for aspect ratios of 2.5 and monolith-to-lamp-length ratios in the range from 1 to 1.1. The largest number of lamps compatible with uniform air distribution over the monoliths should always be used. The optimal monolith-to-lamp-distance ratio, βoptimum; was correlated as: [βoptimum; = 1.698 (n + 1) - 0.279], where n is the number of lamps. [ABSTRACT FROM AUTHOR]

Cover Legend This figure shows an artistic representation of UVC inactivation of virus particles in a plastic fluoropolymer microcapillary film. The plastic microcapillary film has a refractive index similar to water and is very transparent to UVC light, consisting of a number of parallel microcapillaries embedded in a flat film. The inner diameter of the microcapillaries is tuned for rapid efficient UVC inactivation of virus particles in continuous flows. The cover image, by Nuno Miguel Reis et al., is based on the Article Photo inactivation of virus particles in microfluidic capillary systems, DOI: 10.1002/bit.25912. [ABSTRACT FROM AUTHOR]