Equine uveitis: Outcome and adverse effects after one or two intravitreal low-dose gentamicin injections.

BACKGROUND: Uveitis is common in horses, potentially turning chronic (persistent or recurrent) resulting in impaired vision or blindness. All mainstay therapeutics aims at controlling inflammation, but long-term or lifelong treatment is often needed with possibly severe side effects. Therefore, intravitreal injections with low-dose gentamicin (IVGI) have been used in attempt to give a long-lasting result with potentially less side effects. OBJECTIVES: To retrospectively assess outcome and long-term complications following one or two low-dose IVGI in Swedish horses with chronic uveitis. STUDY DESIGN: Retrospective case series. METHODS: Medical records of horses diagnosed with uveitis examined at the Equine Clinic of the University Animal Hospital of Sweden between 2016 and 2021 were reviewed. Inclusion criteria were horses with a diagnosis of chronic uveitis that were treated with 4 mg IVGI. After injection, tapering doses of anti-inflammatory medications were administered. Due to persistence or recurrence of uveitis despite IVGI, some horses received a second injection. A positive outcome was defined as controlled uveitis, despite no or minimal anti-inflammatory medication. RESULTS: 32 eyes (29 horses) were included. Based on clinical evaluation, uveitis was classified as anterior (91%) or panuveitis (9%). 10 eyes were treated with IVGI twice. A positive outcome was observed in 13/32 eyes (41%). Inflammation in 9/32 eyes was controlled after the first, and in 4/10 eyes after the second IVGI treatment. Long-term complications included retinal degeneration in seven eyes, and mature cataracts in five eyes. Enucleations were performed in 14/32 eyes, due to lack of favourable response of IVGI, or due to complications, that is, glaucoma, corneal ulceration, and/or corneal mineralisation. One horse was euthanised due to painful bouts of inflammation in both eyes despite treatment. MAIN LIMITATIONS: Small sample size, retrospective design with no control group, no histopathology performed, infrequent sampling for Leptospira and no standardised treatment protocol after the IVGI. CONCLUSIONS: In this group of Swedish horses, predominantly diagnosed clinically with anterior uveitis, a positive outcome was observed in 41% of eyes following one or two low-dose IVGI. Retinal degeneration in the visual streak was observed in 22% of eyes, which is a higher proportion of this complication than previously described.

Towards multimodal boosting of motivation for fall-preventive physical activity in seniors: An iterative development evaluation study.

Background: Many seniors need to increase their physical activity (PA) and participation in fall prevention exercise. Therefore, digital systems have been developed to support fall-preventive PA. Most of them lack video coaching and PA monitoring, two functionalities that may be relevant for increasing PA. Objective: To develop a prototype of a system to support seniors' fall-preventive PA, which includes also video coaching and PA monitoring, and to evaluate its feasibility and user experience. Methods: A system prototype was conceived by integrating applications for step-monitoring, behavioural change support, personal calendar, video-coaching and a cloud service for data management and co-ordination. Its feasibility and user experience were evaluated in three consecutive test periods combined with technical development. In total, 11 seniors tested the system at home for four weeks with video coaching from health care professionals. Results: Initially, the system's feasibility was non-satisfactory due to insufficient stability and usability. However, most problems could be addressed and amended. In the third (last) test period, both seniors and coaches experienced the system prototype to be fun, flexible and awareness-raising. Interestingly, the video coaching which made the system unique compared to similar systems was highly appreciated. Nonetheless, even the users in the last test period highlighted issues due to insufficient usability, stability and flexibility. Further improvements in these areas are needed. Conclusions: Video coaching in fall-preventive PA can be valuable for both seniors and health care professionals. High reliability, usability and flexibility of systems supporting seniors are essential.

Topical ophthalmic atropine in horses, pharmacokinetics and effect on intestinal motility.

BACKGROUND: Topical ophthalmic atropine sulfate is an important part of the treatment protocol in equine uveitis. Frequent administration of topical atropine may cause decreased intestinal motility and colic in horses due to systemic exposure. Atropine pharmacokinetics are unknown in horses and this knowledge gap could impede the use of atropine because of the presumed risk of unwanted effects. Additional information could therefore increase safety in atropine treatment. RESULTS: Atropine sulfate (1 mg) was administered in two experiments: In part I, atropine sulfate was administered intravenously and topically (manually as eye drops and through a subpalpebral lavage system) to six horses to document atropine disposition. Blood-samples were collected regularly and plasma was analyzed for atropine using UHPLC-MS/MS. Atropine plasma concentration was below lower limit of quantification (0.05 µg/L) within five hours, after both topical and IV administration. Atropine data were analyzed by means of population compartmental modeling and pharmacokinetic parameters estimated. The typical value was 1.7 L/kg for the steady-state volume of distribution. Total plasma clearance was 1.9 L/h‧kg. The bioavailability after administration of an ophthalmic preparation as an eye drop or topical infusion were 69 and 68%, respectively. The terminal half-life was short (0.8 h). In part II, topical ophthalmic atropine sulfate and control treatment was administered to four horses in two dosing regimens to assess the effect on gastro-intestinal motility. Borborygmi-frequency monitored by auscultation was used for estimation of gut motility. A statistically significant decrease in intestinal motility was observed after administration of 1 mg topical ophthalmic atropine sulfate every three hours compared to control, but not after administration every six hours. Clinical signs of colic were not observed under any of the treatment protocols. CONCLUSIONS: Taking the plasma exposure after topical administration into consideration, data and simulations indicate that eye drops administrated at a one and three hour interval will lead to atropine accumulation in plasma over 24 h but that a six hour interval allows total washout of atropine between two topical administrations. If constant corneal and conjunctival atropine exposure is required, a topical constant rate infusion at 5 µg/kg/24 h offers a safe alternative.

COVID-19 recovery: tackling the 2-week wait colorectal pathway backlog by optimising CT colonography utilisation.

AIM: To review the indications for computed tomography colonography (CTC) performed on patients referred via the 2-week wait colorectal pathway (2WWCP). MATERIALS AND METHODS: A retrospective study was performed on all patients referred through the 2WWCP between October 2018 and September 2019. The referrals were audited against the National Institute for Health and Care Excellence (NICE) NG12/DG30 guidelines for referral to the 2WWCP, and against the Royal College of Radiologists (RCR) 2017 guidelines for CTC. RESULTS: Over the study period, there were 1,707 2WWCP referrals, and 362 (21.2%) of these patients underwent CTC. The median age was 66 years, and 55% were female. Forty-six patients did not meet the NICE NG12/DG30 guidelines for referral to the 2WWCP, and a further 268, although meeting the NICE guidelines, did not meet the RCR 2017 guidelines for CTC. In total, only 13% of CTCs performed complied with both guidelines. CONCLUSION: This audit demonstrated a significant opportunity to reallocate CTC resources in the recovery stage of the COVID-19 pandemic. To improve outcomes for colorectal cancer (CRC) in the UK, establishing a selective straight-to-test CTC 2WWCP should be considered. Documented consent detailing the risks and benefits of CTC versus colonoscopy should take place in order to assist the patient in making an informed choice.

Effect of the 2018 European drought on methane and carbon dioxide exchange of northern mire ecosystems.

We analysed the effect of the 2018 European drought on greenhouse gas (GHG) exchange of five North European mire ecosystems. The low precipitation and high summer temperatures in Fennoscandia led to a lowered water table in the majority of these mires. This lowered both carbon dioxide (CO2) uptake and methane (CH4) emission during 2018, turning three out of the five mires from CO2 sinks to sources. The calculated radiative forcing showed that the drought-induced changes in GHG fluxes first resulted in a cooling effect lasting 15-50 years, due to the lowered CH4 emission, which was followed by warming due to the lower CO2 uptake. This article is part of the theme issue 'Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale'.

Variability, repeatability and test-retest reliability of equine flash visual evoked potentials (FVEPs).

BACKGROUND: Visual evoked potentials (VEPs) are electrical potentials generated by neurons in the central nervous system in response to visual stimuli. A series of positive and negative wavelets in response to flash-stimuli (flash-VEP; FVEP) or reversing, iso-luminant patterns (pattern-VEP; PVEP) are recorded. Pathological conditions affecting the post-retinal pathways can alter overall waveform morphology, and also affect wavelet peak times and amplitudes. FVEPs have recently been described in horses, but more data on the variability within and between subjects is required, to adequately interpret results from clinical equine patients. Therefore, the purpose of this study was to describe the variability, repeatability and test-retest reliability of equine FVEPs in normal, adult horses. RESULTS: Equine FVEPs were recorded from one randomly selected eye in 17 horses, from both eyes in eight of these horses, and also at two separate recording sessions in six horses. N1, P2, N2 and P4 wavelets were present in 100% of the recordings in all horses, while P1, N2a, P3 and P5 were only present in some recordings. Coefficients of variation (CVs) were low for P2, N2 and P4 peak times, but higher for all amplitudes. There were no statistically significant differences comparing peak times and amplitudes between eyes or between sessions. Coefficients of repeatability (CRs) are reported for P2, N2 and P4 peak times between eyes (P2; 5 ms, N2; 18 ms, P4; 18 ms) and also between sessions (P2; 5 ms, N2; 16 ms, P4; 39 ms). Intraclass correlation coefficients (ICCs), as an estimate of test-retest reliability, was assessed to be fair to excellent for most parameters. CONCLUSIONS: This study provides important data on variability, repeatability and test-retest reliability of FVEPs in normal, adult horses. We conclude that P2, N2 and P4 peak times should be included in the evaluation of equine FVEPs. The large inherent variability of FVEP amplitudes is likely to make them less suitable and useful for establishing a diagnosis on their own in most clinical patients, but they may occasionally provide support to a clinical diagnosis.

Visual evoked potentials in the horse.

BACKGROUND: Electrical potentials generated in the central nervous system in response to brief visual stimuli, flash visual evoked potentials (FVEPs), can be recorded non-invasively over the occipital cortex. FVEPs are used clinically in human medicine and also experimentally in a number of animal species, but the method has not yet been evaluated in the horse. The method would potentially allow the ophthalmologist and equine clinician to evaluate visual impairment caused by disorders affecting post-retinal visual pathways. The aim was to establish a method for recording of FVEPs in horses in a clinical setting and to evaluate the waveform morphology in the normal horse. METHODS: Ten horses were sedated with a continuous detomidine infusion. Responses were recorded from electrodes placed on the scalp. Several positions were evaluated to determine suitable electrode placement. Flash electroretinograms (FERGs) were recorded simultaneously. To evaluate potential contamination of the FVEP from retinal potentials, a retrobulbar nerve block was performed in two horses and transection of the optic nerve was performed in one horse as a terminal procedure. RESULTS: A series of positive (P) and negative (N) peaks in response to light stimuli was recorded in all horses. Reproducible wavelets with mean times-to-peaks of 26 (N1), 55 (P2), 141 (N2) and 216 ms (P4) were seen in all horses in all recordings. Reproducible results were obtained when the active electrode was placed in the midline rostral to the nuchal crest. Recording at lateral positions gave more variable results, possibly due to ear muscle artifacts. Averaging ≥100 responses reduced the impact of noise and artifacts. FVEPs were reproducible in the same horse during the same recording session and between sessions, but were more variable between horses. Retrobulbar nerve block caused a transient loss of the VEP whereas transection of the optic nerve caused an irreversible loss. CONCLUSIONS: We describe the waveform of the equine FVEP and our results show that it is possible to record FVEPs in sedated horses in a clinical setting. The potentials recorded were shown to be of post-retinal origin. Further studies are needed to provide normative data and assess potential clinical use.

Localisation of the SMC loading complex Nipbl/Mau2 during mammalian meiotic prophase I.

Evidence from lower eukaryotes suggests that the chromosomal associations of all the structural maintenance of chromosome (SMC) complexes, cohesin, condensin and Smc5/6, are influenced by the Nipbl/Mau2 heterodimer. Whether this function is conserved in mammals is currently not known. During mammalian meiosis, very different localisation patterns have been reported for the SMC complexes, and the localisation of Nipbl/Mau2 has just recently started to be investigated. Here, we show that Nipbl/Mau2 binds on chromosomal axes from zygotene to mid-pachytene in germ cells of both sexes. In spermatocytes, Nipbl/Mau2 then relocalises to chromocenters, whereas in oocytes it remains bound to chromosomal axes throughout prophase to dictyate arrest. The localisation pattern of Nipbl/Mau2, together with those seen for cohesin, condensin and Smc5/6 subunits, is consistent with a role as a loading factor for cohesin and condensin I, but not for Smc5/6. We also demonstrate that Nipbl/Mau2 localises next to Rad51 and γH2AX foci. NIPBL gene deficiencies are associated with the Cornelia de Lange syndrome in humans, and we find that haploinsufficiency of the orthologous mouse gene results in an altered distribution of double-strand breaks marked by γH2AX during prophase I. However, this is insufficient to result in major meiotic malfunctions, and the chromosomal associations of the synaptonemal complex proteins and the three SMC complexes appear cytologically indistinguishable in wild-type and Nipbl (+/-) spermatocytes.

Lake secondary production fueled by rapid transfer of low molecular weight organic carbon from terrestrial sources to aquatic consumers.

Carbon of terrestrial origin often makes up a significant share of consumer biomass in unproductive lake ecosystems. However, the mechanisms for terrestrial support of lake secondary production are largely unclear. By using a modelling approach, we show that terrestrial export of dissolved labile low molecular weight carbon (LMWC) compounds supported 80% (34-95%), 54% (19-90%) and 23% (7-45%) of the secondary production by bacteria, protozoa and metazoa, respectively, in a 7-km(2) boreal lake (conservative to liberal estimates in brackets). Bacterial growth on LMWC was of similar magnitude as that of primary production (PP), and grazing on bacteria effectively channelled the LMWC carbon to higher trophic levels. We suggest that rapid turnover of forest LMWC pools enables continuous export of fresh photosynthates and other labile metabolites to aquatic systems, and that substantial transfer of LMWC from terrestrial sources to lake consumers can occur within a few days. Sequestration of LMWC of terrestrial origin, thus, helps explain high shares of terrestrial carbon in lake organisms and implies that lake food webs can be closely dependent on recent terrestrial PP.

A catchment-scale carbon and greenhouse gas budget of a subarctic landscape.

This is the first attempt to budget average current annual carbon (C) and associated greenhouse gas (GHG) exchanges and transfers in a subarctic landscape, the Lake Torneträsk catchment in northern Sweden. This is a heterogeneous area consisting of almost 4000 km2 of mixed heath, birch and pine forest, and mires, lakes and alpine ecosystems. The magnitudes of atmospheric exchange of carbon in the form of the GHGs, CO2 and CH4 in these various ecosystems differ significantly, ranging from little or no flux in barren ecosystems over a small CO2 sink function and low rates of CH4 exchange in the heaths to significant CO2 uptake in the forests and also large emissions of CH4 from the mires and small lakes. The overall catchment budget, given the size distribution of the individual ecosystem types and a first approximation of run-off as dissolved organic carbon, reveals a landscape currently with a significant sink capacity for atmospheric CO2. This sink capacity is, however, extremely sensitive to environmental changes, particularly those that affect the birch forest ecosystem. Climatic drying or wetting and episodic events such as insect outbreaks may cause significant changes in the sink function. Changes in the sources of CH4 through increased permafrost melting may also easily change the sign of the current radiative forcing, due to the stronger impact per gram of CH4 relative to CO2. Hence, to access impacts on climate, the atmospheric C balance alone has to be weighed in a radiative forcing perspective. When considering the emissions of CH4 from the mires and lakes as CO2 equivalents, the Torneträsk catchment is currently a smaller sink of radiative forcing, but it can still be estimated as representing the equivalent of approximately 14000 average Swedish inhabitants' emissions of CO2. This can be compared with the carbon emissions of less than 200 people who live permanently in the catchment, although this comparison disregards substantial emissions from the non-Swedish tourism and transportation activities.

A controlled trial of self-help treatment of recurrent headache conducted via the Internet.

The Internet can reach a large number of people at a low cost and offers the opportunity for 2-way communication. The present study was designed to evaluate the effects of applied relaxation and problem solving in the treatment of recurrent headache when implemented via the Internet and E-mail. A group of 102 headache sufferers were randomized to 2 conditions: a 6-week treatment condition or a waiting-list control. The dropout was proportionately large (56%), and at the end of the study there were 20 participants in the treatment condition and 25 participants in the control condition. Results showed statistically significant reductions in headache for the treated participants. In 50% of these, the reduction was clinically significant. The Internet has the potential to serve as a complement in the treatment of recurrent headache and deserves further study.

Characterization of CD40-dependent immunoglobulin class switching.

Previous studies have shown that signalling via CD40 together with cytokines stimulates immunoglobulin (Ig) class switching in B cells. This process includes induction of germline (GL) transcripts and switch recombination. Using an agonistic rat anti-mouse CD40 monoclonal antibody (MoAb), we investigated the role of CD40 signalling in these molecular events. We found that stimulation of murine B cells induced high steady-state levels of germline gamma1, gamma2b and low levels of epsilon transcripts. No detectable gamma2a or alphaRNA were found and the level of gamma3 transcripts was high both in stimulated and unstimulated cells. Although cells treated with anti-CD40 MoAb had high levels of GL gamma1 and gamma3 transcripts, we failed to detect switching to IgG1 or IgG3. However, anti-CD40 MoAb-stimulated cells increased expression of IgG2b. Interestingly, anti-CD40 plus interleukin (IL)-5 induced switching to IgG1. Previous work has demonstrated that CD40 signalling, but not lipopolysaccharide (LPS), induces the gamma1 promoter and that NF-kappaB motifs are important. We show here that both LPS and anti-CD40 activated NF-kappaB proteins binding to the gamma1 promoter. The bound NF-kappaB complexes were different with regard to total concentration and subunit composition. In the light of our data, the mechanism of CD40-mediated Ig class switching is discussed.

CD40 signaling induces interleukin-4-independent IgE switching in vivo.

T cell-deficient T cell receptor (TCR) beta-/- x TCR delta-/- knockout mice lack circulating IgE and fail to produce antigen-specific IgE in response to stimulation with T cell-dependent antigens. We show here that these animals are able to produce significant levels of circulating polyclonal IgE when injected with an agonistic anti-mouse CD40 monoclonal antibody. CD40-mediated induction of circulating polyclonal IgE in T cell-deficient mice was only partially reduced when the animals were co-treated with neutralizing anti-interleukin-4 (IL-4) antibody. The IL-4 independence of this response was further supported by experiments showing that anti-CD40 antibodies induced circulating IgE when injected into IL-4 knockout mice, and sterile RNA epsilon transcript production when cultured with purified B cells from the same mice. These data strongly suggest that CD40 signaling causes IL-4-independent IgE switching in mice.

Cell cycle regulation of immunoglobulin class switch recombination and germ-line transcription: potential role of Ets family members.

Previous studies have indicated that transcription of germ-line (GL) CH genes is necessary to obtain immunoglobulin (Ig) class switching. We report here a correlation between proliferation, switching and GL transcripts. Smu-S gamma 1 switch recombination in lipopolysaccharide (LPS) + interleukin-4 (IL-4)-activated mouse B cells was assayed by a digestion-circularization polymerase chain reaction. Switching to gamma 1 is reduced upon inhibition of DNA synthesis with hydroxy-urea (HU) or aphidicholin (AC). Incubation of activated B cells with HU severely reduces steady-state levels of GL gamma 1 and epsilon RNA. By utilizing elutriation to synchronize B cell blasts in different phases of the cell cycle, it was found that GL gamma 1 transcripts are mainly expressed in G1 and S phases, but not in G0. Using the electrophoretic mobility shift assay, we characterized two major LPS-induced complexes, which bind to the GL gamma 1 promoter and are expressed at levels which correlate with the amount of LPS-induced DNA synthesis. Furthermore, the intensity of the complexes is reduced when cells are arrested with the DNA synthesis inhibitors HU or AC. Elutriation experiments revealed that the complexes are expressed in G1 and S, but not in G0. They bind to an Ets consensus element near the major initiation sites used in proliferating cells. The possible implications of these findings for Ig isotype switching are discussed.

Differing organic Acid exudation pattern explains calcifuge and acidifuge behaviour of plants.

Many vascular plant species are unable to colonize calcareous sites. Thus, the floristic composition of adjacent limestone and acid silicate soils differs greatly. The inability of calcifuge plants to establish in limestone sites seems related to a low capacity of such plants to solubilize and absorb Fe or phosphate from these soils. Until now, mechanisms regulating this differing ability of plants to colonize limestone sites have not been elucidated. We propose that contrasting exudation of low-molecular organic acids is a major mechanism involved and show that germinating seeds and young seedlings of limestone plants exude considerably more di- and tricarboxylic acids than calcifuges, which mainly exude monocarboxylic acids. The tricarboxylic citric acid is a powerful extractor of Fe, and the dicarboxylic oxalic acid a very effective extractor of phosphate from limestone soils. Monocarboxylic acids are very weak in these respects. The study is based on ten species from limestone soils and ten species from acid silicate soils.