Clarifying dairy calf mortality phenotypes through postmortem analysis.

Health problems can be thought of as phenotypic expressions of the complex relationships between genes, environments, and phenomes as a whole. Detailed evaluations of phenotypic expressions of illness are required to characterize important biological outcomes. We hypothesized that classifying dairy calf mortality phenotypes via a systematic postmortem analysis would identify different cause-of-death diagnoses than those derived from treatments alone. This cross-sectional study was carried out on a dairy calf ranch in the northwestern United States from June to September 2017 and focused on calves ≤90 d of age. Comparisons were made between causes of death based on 3 levels of information: on-farm treatment records alone, necropsy-based postmortem analyses in addition to treatment records, and Washington Animal Disease Diagnostic Laboratory (WADDL) results in addition to all other information. A total of 210 dairy calves were necropsied during this study, of which 122 cases were submitted to WADDL. Necropsy- and WADDL-derived mortality phenotypes were in almost perfect agreement (Cohen's κ = 0.86) when broadly categorized as diarrhea, respiratory, diarrhea and respiratory combined, or other causes. The level of agreement between on-farm treatment records and postmortem-derived results was low and varied by the level of diagnostic detail provided. There was just fair agreement (κ = 0.22) between treatment-based and necropsy-based phenotypes without WADDL input and only slight agreement (κ = 0.13) between treatment-based and corresponding necropsy-based phenotypes with WADDL input. Even for those cases in which causes of death aligned along a comparable pathologic spectrum, the lack of detail inherent to standard treatment-based causes of death failed to identify meaningful target areas for intervention. This was especially apparent for numerous cases of necrotizing enteritis and typhlitis (cecal inflammation) that were variously categorized as diarrhea and pneumonia by treatment-based diagnoses. The specificity of these lesions stood in stark contrast to the otherwise generic cause of death diagnoses derived from treatments. The findings from this study supported the hypothesis and highlighted the value of on-farm necropsies and laboratory-based diagnostics to (1) detect antemortem disease misclassifications, (2) provide detail regarding disease processes and mortality phenotypes, and (3) direct disease mitigation strategies.

Loss of oligophrenin1 leads to uncontrolled Rho activation and increased thrombus formation in mice.

BACKGROUND: Platelet cytoskeletal reorganization is essential for platelet adhesion and thrombus formation in hemostasis and thrombosis. The Rho GTPases RhoA, Rac1 and Cdc42 are the main players in cytoskeletal dynamics of platelets and induce filopodia and lamellipodia formation and actin polymerization to strongly increase the platelet surface upon activation. Moreover, they are important for platelet secretion, integrin activation and arterial thrombus formation. OBJECTIVES: Rho GTPases are regulated by GTPase-activating proteins (GAPs) that stimulate their GTPase activity to terminate Rho signaling. The regulation of Rho GTPase activity in platelets is not well defined. Recently, we identified oligophrenin1 (OPHN1), a RhoGAP in platelets that exhibits strong GTPase-stimulating activity towards RhoA, Cdc42 and Rac1. RESULTS: In the present study we show for the first time, that deficiency of OPHN1 led to abnormal Rho activation and increased platelet cytoskeletal reorganization, including cell adhesion and lamellipodia formation on fibrinogen. Furthermore, platelets from ophn1(-/-) mice showed enhanced susceptibility to platelet activation with alterations in actin distribution and early release of granules. Platelet activation was enhanced following GPVI and PAR4 stimulation. This translated into elevated platelet thrombus formation and promoted arterial thrombosis under low shear conditions with altered hemostasis, as detected by tail bleeding time. CONCLUSIONS: The results of the present study identified OPHN1 as an important regulator of platelet cytoskeletal reorganization and demonstrate that abnormal regulation of Rho proteins leads to increased platelet adhesion and thrombus formation under low shear conditions in vitro and in vivo, suggesting a prothrombotic phenotype of mice critical for acute thrombotic occlusions.

Selective retina therapy for acute central serous chorioretinopathy.

AIMS: To evaluate selective retina therapy (SRT) as a treatment of acute central serous chorioretinopathy. METHODS: 30 eyes of 30 patients with central serous chorioretinopathy of at least a 3 months' duration were recruited. 14 eyes were randomised to an SRT group (Q-switched neodymium-doped yttrium lithium fluoride (Nd:YLF) laser, wavelength 527 nm, t=1.7 µs, energy 100-370 µJ, spot diameter 200 µm, pulse repetition rate 100 Hz,) and 16 eyes to a control group. After 3 months of follow-up, patients in the control group with persistence of subretinal fluid (SRF) were allocated to a cross-over group, treated with SRT and followed up for further 3 months. The main outcome measures were change of best-corrected Early Treatment Diabetic Retinopathy Study visual acuity (BCVA) and SRF. RESULTS: At 3 months of follow-up, the mean (SD) improvement of BCVA was significantly greater after SRT than in the control group: 12.7 (7.2) versus 6.3 (8.9) letters (p=0.04). SRF had decreased significantly more after SRT as compared with that the control group: 203 (136) µm versus 41 (150) µm (p=0.005). In eight eyes allocated to the cross-over group, the mean BCVA had increased during 3 months of follow up before SRT by 1.4 (5.2) letters and continued to increase during 3 months following SRT by 7.4 (6.3) letters, while SRF increased by 39.5 (160.2) µm before SRT and decreased by 151.5 (204.9) µm after SRT. In six of the eight eyes, SRF had completely resolved 3 months after SRT. CONCLUSIONS: SRT appears to expedite functional recovery and the re-absorption of SRF as compared with that in untreated controls. A larger prospective, randomised phase 3 confirmative patient study is warranted. TRIAL REGISTRATION NUMBER: NCT00987077.

[Central serous chorioretinopathy (CSC)]. / Chorioretinopathia centralis serosa (CCS).

In the acute stage central serous chorioretinopathy (CSC) is characterized by serous retinal detachment. Monofocal or multifocal structural changes of the pigment epithelium layer are common. Unilateral blurred vision is the major clinical symptom. The pathogenesis is unclear but corticosteroids and stress may trigger the disease. Normal vision often returns spontaneously within a few months. Therapeutic options are at a low evidence level. Carbonic anhydrase, mild laser photocoagulation, selective retinal therapy, photodynamic therapy and the intravitreal injection of bevacizumab have been reported. The authors suggest a treatment strategy on the basis of the available data.

Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage.

AIM: To evaluate the efficacy and safety of pars plana vitrectomy (ppV) with subretinal coapplication of recombinant tissue plasminogen activator (rtPA) and bevacizumab, and fluid-gas exchange for neovascular age-related macular degeneration (AMD) with submacular haemorrhage (SMH). METHODS: Consecutive interventional case series of 12 patients with neovascular AMD with SMH with a maximum history of 14 days. All patients underwent ppV with subretinal coapplication of rtPA and bevacizumab, and fluid-gas (20% SF6) exchange. Phakic patients underwent concomitant cataract surgery. Additional injections of bevacizumab were applied intravitreally 4 and 8 weeks postop. RESULTS: Complete displacement of SMH from the fovea was achieved in 9 of 12 patients. The mean best-corrected visual acuity (BCVA) improved significantly from preop logMAR 1.9 (range 3.0 to 0.7) to logMAR 1.2 (range 3.0 to 0.3) at 4 weeks postop (p = 0.01) and to logMAR 0.9 (range 1.6 to 0.2) at 12 weeks postop (p = 0.006). The mean improvement of BCVA 4 weeks postop as compared with preop was logMAR 0.7 (range -0.2 to 2.3). The mean improvement of BCVA 12 weeks postop as compared with preop was logMAR 0.96 (range -0.3 to 2.8). Overall, at 12 weeks postop, BCVA had improved in 10 patients, remained unchanged in one patient and worsened in one patient. CONCLUSION: PpV with subretinal coapplication of rtPA and bevacizumab, and fluid-gas exchange effectively displaces SMH and improves visual acuity in most patients.

[Retrospective case analysis of ophthalmological and systemic risk factors in patients with retinal vascular occlusion]. / Retrospektive Fallanalyse zum ophthalmologischen und internistischen Risikoprofil von retinalen Gefässverschlüssen.

OBJECTIVE: The aim was to determine systemic risk factors for acute central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) and to evaluate the usefulness of systemic diagnostics in CRAO and CRVO. METHODS: The study consisted of a retrospective chart review including 80 patients (CRAO 38, CRVO 42). All patients underwent systemic diagnostics including blood pressure measurement, blood cholesterol level, carotid Doppler imaging, transthoracic echocardiography (TTE), intraocular pressure measurement, glaucoma history and presence of thrombophilic factors. A systemic medical history was obtained. RESULTS: Systemic hypertension was found in 76.3% CRAO and 75.6% CRVO patients. Abnormal cardiac findings were detected in 61% (CRAO) and 22% (CRVO). Abnormal carotid findings were detected in 44.1% for CRAO and 9.5% for CRVO. Pathological thrombophilic factors were found in both groups for approximately 15%. CONCLUSIONS: TTE and carotid Doppler are important tools in the diagnosis of sources of emboli in patients with CRAO, while for CRVO abnormal findings are revealed by TTE and carotid Doppler less often. Thrombophilia should be ruled out in the absence of common risk factors, especially in younger patients and systemic hypertension should be adequately controlled.

[Autologous RPE-choroid translocation in exudative AMD. A case series of 10 consecutive patients]. / Autologe RPE-Chorioidea-Translokation bei exsudativer AMD. Eine Falldemonstration 10 konsekutiver Patienten.

BACKGROUND: To evaluate the retinal sensitivity and fixation pattern after removal of choroidal neovascularisation (CNV) and autologous retinal pigment epithelium (RPE)-choroid translocation in patients with exudative age-related macular degeneration (AMD). METHODS: The functional and morphologic results of 10 consecutive patients (nine with exudative AMD, one with geographic atrophy) were analysed. The mean follow-up was 16.8 (14-20) months. Functional evaluation was performed with the MP1 microperimeter. RESULTS: Preoperative visual acuity ranged from hand motion to 0.2 (decimal), and postoperative visual acuity ranged from hand motion to 0.4. Fixation on the graft was shown in four patients. Microperimetry proved light increment sensitivity over the graft in five patients. Light increment sensitivity could be kept on a constant level in four of these patients. Postoperative complications included retinal detachment (three), proliferative vitreoretinopathy (one), and development of CNV (one). CONCLUSION: Autologous RPE-choroid sheet translocation is feasible and comparatively safe. Fixation and light perception on the graft proved to be possible. Light increment sensitivity can be kept on a constant level for at least 20 months.

[Diagnostics of metamorphopsia in retinal diseases of different origins]. / Diagnostik von Metamorphopsien bei Netzhauterkrankungen unterschiedlicher Genese.

We investigated the ability of preferential hyperacuity perimeter (PHP) and Amsler grid testing to detect metamorphosia in patients with macular hole (MH), central serous retinopathy (CSR), epiretinal membranes (EM), intermediate AMD (iAMD), classic and occult choroidal neovascularization (CNV) due to AMD, and compared the results. A total of 147 patients (n =153 eyes) with classic (35 eyes) and occult (38 eyes) CNV, iAMD (13 eyes), MF (23 eyes), RCS (11 eyes), EM (13 eyes) and control group (20 eyes) were involved. All of these patients underwent corrected visual acuity and eye examinations inclusive of the Amsler grid. The PHP test was performed after pupil dilation. In all patients, fundus photography and optical coherence tomography (OCT) (Humphrey/Zeiss OCT III) were performed. In patients with CNV and CSR a fluorescein angiography was also performed. Metamorphopsia detection rates by Amsler grid and PHP were compared statistically. The sensitivity of PHP vs Amsler grid in detecting metamorphosia was 69% vs 85% in patients with MH, for CSR 64% vs 73%, EM 77% vs 100%, iAMD 85% vs 100%, classic CNV 83% vs 94% and occult CNV 81% vs 71%. The results for patients with occult CNV were significant (P =0.046), using the chi(2)-test. The PHP-test showed high sensitivity for diagnosing CNV. In occult CNV, PHP was superior to the Amsler grid in detecting metamorphopsia. In the other diseases involving the macular (MH, EM, CSR, iAMD), the detection rate and sensitivity of the Amsler grid was superior to PHP.

[Selective retina therapy in central serous chorioretinopathy with detachment of the pigmentary epithelium]. / Selektive Retina-Therapie bei Retinopathia centralis serosa mit Pigmentepithelabhebung.

BACKGROUND: Selective Retina Therapy (SRT) is a new and innovative laser treatment modality that selectively treats the retinal pigmentary epithelium while sparing the photoreceptors. This therapeutic concept appears to be particularly suitable for treating patients with acute or chronic central serous chorioretinopathy (CSC). We present preliminary results obtained in five patients who had CSC associated with pigmentary epithelium detachment (PED) and serous subretinal fluid (SRF) and who were treated with SRT. METHODS: This case series was made up of five male patients (mean age 47 years) with chronic CSC and SRF resulting from PED. Examinations performed before and at 1 month and 3 months after the treatment were: BCVA, FLA, OCT (Zeiss OCT III). For SRT, confluent treatment of the PED (area of leakage) was carried out using a pulsed frequency-doubled, Q-switched Nd-YLF prototype laser (lambda=527 nm, t= 1.7 s, 100 Hz, energy = 150-250 J). RESULTS: Best corrected visual acuity at baseline was 0.53, while after 4 weeks it was 0.56 and after 12 weeks, 0.5. At baseline leakage was seen at the PED on fluorescein angiography in all patients. After 4 weeks leakage activity was no longer noted on angiography in 4 of 5 patients. OCT at baseline showed SRF at the edge of the PED in all patients, but in 4 of the 5 patients this was no longer detectable after 4 weeks. CONCLUSION: SRT is a safe and effective treatment for patients with CSC in which PED has caused SRF. Not a single case of rip syndrome was observed in this study, even though the PED was treated confluently. Since SRT spares the photoreceptors it is particularly suitable for the treatment of CSC, especially when the origin of leakage is located close to the fovea. The results indicate that SRT leads to reconstruction of the outer blood-retina barrier.

[Selective retina therapy in patients with diabetic maculopathy]. / Selektive Retina-Therapie bei Patienten mit diabetischer Makulopathie.

Selective Retina Therapy (SRT) is a new laser treatment that selectively targets the retinal pigmen epithelium (RPE). In this study, we treated 39 patients presenting with nonischemic, focal and focal-diffuse diabetic maculopathy with SRT. In the main. the results indicate that SRT had stabilizing effects on visual acuity, angiographic leakage, lipid exudation, and foveal retinal thickness. SRT is safe and is especially useful for treating pathologies that are located close to the fovea, which cannot be treated with conventional argon laser photocoagulation.

Selective retina therapy in patients with central serous chorioretinopathy.

BACKGROUND: Central serous chorioretinopathy (CSC) is a disease with a localized breakdown of the outer blood-retinal barrier located within the retinal pigment epithelium (RPE) causing subretinal fluid accumulation. Selective retina therapy (SRT) is a new, minimally invasive laser technology that has been designed to selectively target the RPE. SRT spares retinal tissue. METHODS: Twenty-seven eyes of 27 patients with active CSC were treated with SRT using a pulsed double-Q-switched Nd-YLF prototype laser (lambda=527 nm, t=1.7 micros). At baseline, best-corrected visual acuity was determined and fluorescein angiography and optical coherence tomography were performed. The patients were followed for up to 3 months. RESULTS: After 4 weeks 85.2% of patients showed complete resolution of subretinal fluid and in 96.3% there was no leakage visible on fluorescein angiography. After 3 months 100% of patients demonstrated no subretinal fluid and 100% of patients had no leakage activity on fluorescein angiography. Visual acuity, 20/40 at baseline, improved to 20/28 after 4 weeks and to 20/20 after 3 months. CONCLUSION: SRT is a safe and effective treatment for active CSC. Especially if the RPE leak is located close to the fovea, SRT is the favoured therapeutic option. We recommend earlier treatment of patients with acute CSC in order to prevent development of chronic changes due to CSC with irreversible anatomical and functional damage. SRT might be considered as a first-line treatment for active CSC.

Placebo controlled pilot trial to study the remyelinating potential of intravenous immunoglobulins in multiple sclerosis.

Currently there is no treatment available to improve a stable deficit in multiple sclerosis. It was shown in animal models that intravenous immunoglobulins (IVIg) can enhance central nervous remyelination, and the first open trials were promising. We therefore conducted a double blind, placebo controlled pilot study to evaluate the effect of IVIg treatment in patients with multiple sclerosis with a stable clinical deficit. The primary outcome parameter was the change in central motor conduction time as an indirect measure of central myelination. Secondary outcome parameters were neurological examinations including the expanded disability status scale (EDSS), neurological rating scale (NRS), and manual muscle testing (MMT). Ten patients were treated first with placebo and then with IVIg (0.4 g/kg body weight on 5 consecutive days), the two treatments being separated by an interval of 6 weeks. There was no difference in the central motor conduction times measured before and 6 weeks after each treatment. Clinically there was a small improvement after IVIg treatment, but there was no significant difference when compared with placebo. In conclusion, our data do not support a role for IVIg in the remyelination of stable multiple sclerosis lesions as measured by central conduction time. The importance of the small clinical benefit is currently not clear.

The value of magnetic resonance imaging in carpal tunnel syndrome.

We examined 62 patients (72 hands) with carpal tunnel syndrome (CTS) by magnetic resonance imaging (MRI) of the carpal tunnel and latency measurements of the median nerve. In 32 of 72 hands a probable causative lesion of the CTS was identified by MRI, for example tenosynovitis, a cyst-like structure, or an aberrant muscle. The MRI findings were confirmed by surgery in 16 of 24 hands, slightly corrected in 5, and not substantiated in 3. In 65 of 72 hands, MRI disclosed pathology of the median nerve, most prominently an enlargement of the nerve at the level of the os pisiforme, a finding not seen during surgery. Oedema of the nerve was found in 14 of 72 hands. The distal latencies were prolonged in 62 of 72 hands. The sensory latencies correlated significantly with the MRI-determined cross-sectional area of the nerve at the level of the distal radius. The lack of other correlations suggests that partly independent features of the nerve lesion are demonstrated in each method or that the sensitivity and specificity of both methods are limited. Further experience with MRI in CTS is desirable. At present, the practical use of MRI in CTS should be restricted to special diagnostic problems such as carpal tunnel syndromes which do not respond adequately to conservative or surgical treatment.