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Evaluation of treatment with a combination of mycophenolate mofetil and prednisolone in dogs with meningoencephalomyelitis of unknown etiology: a retrospective study of 86 cases (2009–2017)
Joong-Hyun Song1,
Do-Hyeon Yu1,
Hee-Chun Lee1,
Tae-Sung Hwang1,
Young Joo Kim2,
Su-Jin An1 &
Dong-In Jung ORCID: orcid.org/0000-0002-5116-60061
Combination therapy with glucocorticoids and adjunctive immunomodulating drugs has been generally accepted as a standard treatment regimen for meningoencephalomyelitis of unknown etiology (MUE). We hypothesized that treatment with MMF as an adjunctive agent along with glucocorticoids would be effective and well-tolerated protocol in dogs with MUE. Eighty-six dogs with MUE between May 2009 and June 2017 were included (59 females and 27 males; mean age of 5.93 years; mean body weight of 3.83 kg). The medical records of dogs with MUE treated with prednisolone and MMF were retrospectively evaluated to determine the therapeutic response, survival time, and treatment-related adverse effects.
A partial or complete response (CR) was recorded for 75 dogs. The overall median survival time from the initiation of treatment was 558 days. Dogs that showed CR with no relapse over the treatment period (from diagnosis to death) had significantly longer median survival times. A significantly higher mortality hazard ratio of 4.546 was recorded in dogs that failed to achieve CR. The interval between the onset of clinical signs and the clinical presentation was not significantly associated with CR, relapse rate, and survival time. Adverse effects included gastrointestinal upsets in 26 dogs (30.23%), sporadic infections in 17 dogs (19.77%), and pancreatitis in seven dogs (8.14%).
The results suggest that adjunctive MMF treatment for MUE is safe and comparable to other immunosuppressive protocols. The treatment should focus on the achievement of CR and preventing relapse for successful management.
Non-infectious inflammatory disorders of the central nervous system (CNS) can be divided into several subtypes based on the characteristics of the affected animal and the specific histopathological features. Among these disorders, granulomatous meningoencephalomyelitis (GME), necrotizing meningoencephalitis (NME), and necrotizing leukoencephalitis (NLE) have been frequently reported [1]. The umbrella term meningoencephalomyelitis of unknown etiology (MUE) has been introduced to describe dogs with non-infectious CNS inflammatory disorders without a histopathological diagnosis [2].
MUE has long been assumed to have an autoimmune and genetic pathogenesis, and it seems to involve aberrant immune responses directed against CNS constituents [3]. Many glucocorticoid-based protocols have been investigated for the treatment of MUE. Glucocorticoid monotherapy may adequately control the clinical signs initially, but the long-term response is variable, and immunosuppressive doses of glucocorticoids may cause adverse systemic effects in some patients [4, 5]. For these reasons, combination therapy with glucocorticoids and one or more immunomodulating drugs, or monotherapy with immunomodulating drugs has been generally accepted as the standard treatment regimen [1].
Mycophenolate mofetil (MMF) is the pro-drug of mycophenolic acid, an inhibitor of the enzyme inosine monophosphate dehydrogenase (IMPDH) [6]. It has multiple immunosuppressive effects, which are exerted mostly through activated lymphocytes. Lymphocytes are completely dependent on de novo purine biosynthesis, and the de novo synthesis of guanosine monophosphate for purines requires IMPDH. Therefore, inhibition of IMPDH by MMF leads to purine depletion specifically within lymphocytes and ultimately results in inhibited DNA production and cytostatic activity on both activated B- and T lymphocytes [7].
MMF has been used in veterinary medicine as an immunosuppressant to prevent allograft rejection and for various immune-mediated diseases [8,9,10,11,12,13]. It has also recently been considered a comparable alternative to other published immunosuppressive agents in the treatment of MUE [14,15,16,17]. The most commonly reported adverse effects of MMF are gastrointestinal upsets; however, these adverse effects were infrequent, transient, and non-life threatening in most cases [10, 12, 14, 17]. The purported advantages of using MMF over other adjunct immunosuppressive drugs include its rapid onset of action, availability in oral and parenteral formulations, and lack of myelotoxicity or hepatotoxicity [12, 18].
The purpose of this retrospective study was to describe the use of MMF as an adjunctive immunosuppressive agent administered with glucocorticoids in client-owned dogs with MUE. We hypothesized that treatment using MMF as an adjunctive agent with glucocorticoids would be effective and well-tolerated protocol in dogs with MUE. Furthermore, we aimed to report any adverse effects of long-term MMF therapy and risk factors associated with the clinical outcomes in dogs with MUE. In addition, we also tried to improve our understanding of MUE treatment through various analyzes with more strict medication control and large-scale filed than in previous studies.
One-hundred and eight dogs were included on the basis of the initial collection criteria. After assessments, 22 dogs were excluded for the following reasons: discontinuation of the MMF treatment (n = 8); receiving additional immunosuppressants (n = 4); lack of cerebrospinal fluid (CSF) evaluation data (n = 4); and lack of follow-up data (n = 6). Finally, 86 dogs were included in the study.
Signalments, clinical signs and treatment variations
Affected breeds included the Maltese (n = 36), Shih Tzu (n = 9), Yorkshire Terrier (n = 9), Chihuahua (n = 6), Pomeranian (n = 6), mixed-breed (n = 5), Toy Poodle (n = 3), Miniature Pinscher (n = 3), Pekinese (n = 3), and Miniature Dachshund (n = 2), and one each of Papillon, Shetland Sheepdog, Miniature Schnauzer, and French Bulldog. There were 59 females (13 spayed and 46 sexually intact) and 27 males (16 castrated and 11 sexually intact). Age at initial diagnosis ranged from 7 months to 15 years (median, 6 years; mean, 5.93 years). Body weight ranged from 1.45 to 11.7 kg (median, 3.125 kg; mean, 3.83 kg). The median interval from the onset of neurologic dysfunction to initial presentation was 14 days (range, 0–1080 days). Fifty-seven dogs (66.28%) belonged to the acute group and 29 dogs (33.72%) belonged to the chronic group.
At presentation, all dogs had clinical signs of neurologic dysfunction. Signs included seizure (n = 38), ataxia (n = 22), circling (n = 11), vestibular dysfunction (n = 11), hemiparesis (n = 10), tetraparesis (n = 9), paraparesis (n = 8), changes in mental status (e.g., dullness, restless or aggression) or altered behavior (n = 7), blindness (n = 7), head turn (n = 6), kyphosis (n = 2), painful reaction (n = 2), and cerebellar ataxia (n = 1).
Anti-epileptic drugs were initially administered to all dogs that presented with serial seizure episodes (23/86, 26.74%), 13 of which were prescribed phenobarbital (2 to 2.5 mg/kg PO every 12 h), 6 of which were prescribed potassium bromide (40 mg/kg PO every 24 h) and 4 of which were prescribed zonisamide (5 mg/kg PO every 12 h). Cefixime (5 mg/kg PO every 12 h) and metronidazole (10 mg/kg PO every 12 h) were also initially administered to 3 dogs (3/86, 3.45%) suspected infectious meniningoencephalomyelitis, and was immediately ceased when negative PCR results were identified.
Diagnostic imaging findings
Abnormal findings on diagnostic imaging (computed tomography [CT], n = 41; magnetic resonance imaging [MRI], n = 45) were detected in all dogs. Forty-five dogs (52.33%) showed a focal lesion and 41 dogs (47.67%) showed multifocal lesions. The affected neuroanatomic sites included the prosencephalon (n = 72), brainstem (n = 23), spinal cord (n = 2), and cerebellum (n = 1). Eleven (12.8%) of the dogs had both prosencephalon and brainstem lesions and only one (1.16%) dog had both prosencephalon and cerebellum lesions.
CSF analysis findings
The CSF was analyzed in all 86 dogs. Pleocytosis was detected in 79 of 86 dogs (91.86%) at the initial diagnosis. The median total nucleated cell count (TNCC) was 12 cells/μl (mean, 31.09 cells/μl; range, 1–372 cells/μl). All abnormal samples predominantly showed mononuclear cell (with predominance of either lymphocytes or macrophages) pleocytosis. Total protein (TP) concentration in the CSF was elevated in 52 of 86 dogs (60.47%), and the median TP concentration was 30 mg/dl (mean, 32.17 mg/dl; range, 0–300 mg/dl). Infectious disease testing using a real-time PCR assay of the CSF was performed in 15 of 86 dogs. The results for the PCR tests were negative in all 15 samples. All CSF samples were also examined microscopically and were all negative for infectious agents.
Response to therapy and survival time
Complete response (CR) after treatment initiation was recorded in 57 dogs (66.28%), whereas 18 dogs (20.93%) showed partial response (PR) and 11 dogs (12.79%) were unresponsive (no response [NR]) to therapy. CR within a month of treatment initiation was recorded in 49 dogs (56.98%). There was no statistically significant difference in CR rates between the acute group and the chronic group (P = 0.596). In a univariate multiple data analysis used to identify the risk factors for CR probability (Table 1), a significantly higher odds ratio was recorded in dogs that showed neurological dysfunctions other than only seizure history before presentation, relative to those that had only seizure history (odds ratio of 3.701; P = 0.013; 95% confidence interval, 1.311–10.488). Of the 75 responders (both CR and PR), 34 dogs (45.33%) showed a relapse after achieving a treatment response. The relapsed dogs were managed successfully with an increased dose of prednisolone or MMF, and some patients needed additional treatment with anticonvulsants (16/34, 47.06%). Of the 34 relapsed dogs, only five dogs (14.7%) failed to achieve re-remission of the relapsed clinical signs. There were no significant (P = 0.302) differences in relapse rates between the acute group and the chronic group.
Table 1 Results of univariate multiple logistic analysis of potential risk factors for failed CR among dogs treated with a combined MMF-prednisolone therapy
The median survival time (MST) for all dogs was 558 days (range, 3–2634 days) (Fig. 1). Fifteen dogs (17.44%) were censored from the survival analysis; 13 dogs were still alive at the end of the study, one dog died from concurrent heart disease, and the other dog died from concurrent pancreatitis. The MST for dogs in the acute group was 401 days (range, 3–2502 days) and that for dogs in the chronic group was 807 days (range, 3–2634 days). There was no statistical difference (P = 0.125) in survival time between the acute and chronic groups. There were significant (CRs compared with PRs, P < 0.001; CRs compared with NRs, P < 0.001; PRs compared with NRs, P < 0.001) differences in the MST for dogs that showed a CR to treatment during the study period (877 days; range, 35–2634 days), compared with the MST for dogs that showed a PR (122 days; range, 21–879 days) or NR (30 days; range, 3–221 days) (Fig. 2). Furthermore, the MST of the dogs that showed CR within a month (877 days; range, 35–2634 days) was significantly (P = 0.004) longer than that of the dogs that did not (111 days; range, 3–2502 days). The MST was also significantly (P = 0.011) longer for dogs that did not show relapse (993 days; 35–2634 days) than for dogs that did show relapse (410 days; range, 21–2021 days) (Fig. 3).
Kaplan-Meier survival curve for 71 dogs treated with MMF and prednisolone for MUE. The MST was 558 days (range, 3–2634 days)
Kaplan-Meier survival curve for 71 dogs treated with MMF and prednisolone for MUE in the CR (n = 45), PR (n = 15), and NR (n = 11) groups. Survival times differed significantly between the groups
Kaplan-Meier survival curves for 60 dogs treated with MMF and prednisolone for MUE. Dogs that did not show relapse within the study period (n = 31) were compared with those that did show relapse (n = 29). There was a significant difference between both groups (P = 0.011)
The MST was significantly (P = 0.01) longer for dogs that had a focal lesion (690 days; range, 4–2634 days) than for dogs that had multifocal lesions (401 days; range, 3–1834 days) (Fig. 4). The MST for dogs with brainstem involvement was 244 days (range, 3–2634 days) and that for dogs that did not have brainstem involvement was 609 days (range, 3–2502 days). There was no statistical difference in MST between the two groups (P = 0.057) (Fig. 5).
Kaplan-Meier survival curves for 71 dogs treated with MMF and prednisolone for MUE. Dogs that showed a focal lesion (n = 34) were compared with those showing multifocal lesions (n = 37). There was a significant difference between both groups (P = 0.01)
Kaplan-Meier survival curves for 71 dogs treated with MMF and prednisolone for MUE. Dogs that showed brainstem involvement (n = 24) were compared with dogs that did not show brainstem involvement (n = 47). There was no statistical difference in MST between both groups (P = 0.057)
Univariate multiple Cox regression analysis with 10 variables showed that the CR and TNCC at diagnosis were significant factors in predicting mortality (Table 2). The dogs that failed to achieve CR (both NR and PR) over the study period had a 4.546-fold higher relative hazard ratio of mortality than those who achieved CR (P < 0.001; 95% confidence interval, 2.596–7.960). The TNCC at the diagnosis increased the relative hazard ratio for mortality by 1.004-fold with an increase in cell count (P = 0.032; 95% confidence interval, 1.000–1.008). Age, sex, body weight, the presence of seizure history, the duration of clinical signs before treatment, lesional distribution, brainstem involvement, and TP had no impact on mortality.
Table 2 Univariate multiple Cox regression analysis showed the CR and TNCC at diagnosis were significant factors in predicting mortality
Treatment-related adverse effects
Treatment-related adverse effects were reported in 39 of 86 (45.35%) dogs. Of these 39 cases, 14 dogs had two or more concurrent adverse effects. The most common adverse effect was gastrointestinal problems (n = 26 dogs, 26/86, 30.23%); we censored any patients with gastrointestinal manifestations associated with extra-gastrointestinal diseases (e.g., infectious diseases) and pancreatitis; these included diarrhea (n = 16, 3 of 16 dogs had hemorrhagic diarrhea), vomiting (n = 11, 1 of 11 dogs had hemorrhagic vomiting), anorexia (n = 3), and constipation (n = 1). Most of these dogs showed gastrointestinal signs within a month after the initial treatment. Some dogs required supportive therapy, but most symptoms were resolved with a reduced dose of MMF. The dose of MMF was reduced by 50% from that of the pervious dose and slowly increased up to the maximum tolerated dose over one month. The others required no treatment and resolved themselves within a few days. The second most common adverse effect was sporadic infections (n = 17 dogs, 17/86, 19.77%); these included pyometra (n = 4), otitis externa (n = 3), bacterial dermatitis (n = 2), fungal dermatitis (n = 2), demodicosis (n = 2), bacterial rhinitis (n = 2), urinary tract infection (n = 2), and one each of bronchopneumonia, vaginitis, and mastitis. Infectious diseases were treated with an appropriate therapy for each infectious agent and pyometra was resolved with surgical intervention. Pancreatitis was reported in seven dogs (7/86, 8.14%), and one of these dogs had concurrent pancreatic abscess. Pancreatitis was resolved in most patients with supportive therapy, and the dog that had a pancreatic abscess underwent surgical treatment. One of these dogs was euthanized by the owner due to the recurrent chronic pancreatitis. Adverse effects attributable to prednisolone therapy were not recorded in this study and improved during tapering.
Hematologic abnormalities were identified in 49 dogs (49/86, 56.98%). Abnormal results of CBC were found in 26 of 86 (30.23%). Abnormal results of biochemistry were found in 34 of 86 (39.53%). Of these, 16 dogs had two or more concurrent hematologic abnormalities. These included elevated liver enzyme activity levels (n = 27), leukocytosis (n = 17), thrombocytosis (n = 10), anemia (n = 8), hypertriglyceridemia (n = 6), elevated lipase activity (n = 3), hypercholesterolemia (n = 3), hyperglycemia (n = 3), and hypocalcemia (n = 1). Most of the adverse effects might have been related to the concurrent administration of glucocorticoids. The issue was mostly resolved with prednisolone tapering, and none of the patients had clinical signs of these hematologic abnormalities. Anemia was mild and transient in all eight dogs. Seven of the dogs had concurrent gastrointestinal bleeding or one of the inflammatory diseases mentioned above, such as hemorrhagic diarrhea, pancreatitis, infectious skin disease, and pyometra. The anemia of the other dog was non-specific and resolved on the next follow-up visit. The patient with hypocalcemia had a medical history of concurrent acute pancreatitis, and hypocalcemia resolved during the recovery of pancreatitis.
The results of this study suggest that the administration of MMF in combination with prednisolone could serve as an immunosuppressive protocol for the initial therapy of MUE that was comparable to the other reported protocols. Most dogs responded to the MMF and prednisolone protocol, with 66.28% of dogs showing a CR. The overall MST after initiating the treatment was 558 days, and 13 dogs (15.12%) that were still alive at the end of the study had a relatively long follow-up time (median, 914 days from treatment; range, 449–2595 days).
The survival times for dogs in this study were similar to those in the previous studies of dogs treated with several immunosuppressive protocols for MUE. In two retrospective studies investigating the use of MMF in combination with corticosteroids, the MSTs were reported to be 250 days (n = 20; range, 6–1679 days) [5] and 731 days (n = 25; range, 582–1672 days) [17]. In studies of treatment protocols using corticosteroids in combination with other immunosuppressive drugs, the MSTs ranged from 26 to 1834 days (median, 531 days). The MSTs of dogs treated with corticosteroids in conjunction with cytosine arabinoside were 531, 26, and 735 days [7, 19, 20], while the MSTs of those treated with lomustine were 457 (GME) and 329 (necrotizing encephalomyelitis) days [21], and those of dogs treated with cyclosporine were 930 and 620 days [22, 23]. The dogs treated with azathioprine in combination with prednisone had an MST of 1834 days [24], and the dogs treated with procarbazine and prednisone had an MST of 425 days [25]. Some of the studies that showed a large gap in the MSTs against the others showed an obvious difference in study design. In one study of cytosine arabinoside [19], 33% of the enrolled cases died within zero to three days of diagnosis. This suggests that the cases enrolled in this study were unlikely to have a long survival time regardless of the treatment protocol. In the study with azathioprine that showed an MST of 1834 days [24], azathioprine therapy was delayed until after ruling out the possibility of infectious CNS disease. Some dogs that did not survive the intermediate period before obtaining the results for the infectious disease titer were excluded from this study. In one study of MMF therapy [17], additional immunosuppressive drugs were added during the study period and the MST was calculated before the initiation of MMF treatment. Thus, it was concluded that the immunosuppressive protocols reported so far have similar prognoses and the establishment of a gold standard protocol is difficult as of now. Therefore, an individual-based protocol considering the patient's state, drug availability, affordability, and adverse effects might be the best treatment option for dogs with MUE.
The MST was significantly longer for the dogs that showed a CR compared with the dogs that showed a PR and NR, and most of the patients who showed a CR achieved their responses within a month. In addition, a significantly higher mortality hazard ratio of 4.546 was recorded in dogs that failed to achieve a CR, relative to those that showed a CR over the study period. Thus, these results combined with the results of two other previous studies of MUE [14, 24] suggest that the achievement of CR and improvement within a month were crucial for predicting the prognosis, and clinicians should do their best to achieve CR. Moreover, the presence of neurological dysfunctions other than only seizure history can be used as a good predictor of the failure to achieve a CR in the clinical setting, according to the logistic analysis. The dogs in this study were divided into two groups according to the acuteness of the disease course, based on the current literature [15]. The acuteness had no significant effect on the MST and the CR rates in this study, contrary to the authors' expectation and a previous study that performed a similar comparison [14]. Although it was not statistically significant, the relatively short MST of the acute group compared to the chronic group indicated that the acute group might have a more severe disease course and may need a more aggressive treatment protocol for a favorable prognosis. However, obvious limitations are evident in this comparison due to the fact that these subgroups were characterized in only a time-dependent manner; further studies based on the severity of the neurological dysfunctions before treatment will be needed.
One previous study of MUE treated with a combined prednisone-azathioprine therapy showed that the MST (472 days) was significantly (P < 0.001) shorter for dogs that did relapse than for dogs that did not relapse (1961 days) [24], in agreement with the results of this study. It was thus verified that dogs that did not relapse during treatment had a more favorable long-term outcome. Furthermore, most of the relapsed dogs in both studies showed a favorable response as the dose of corticosteroids was re-increased. This may mean that corticosteroid therapy is one factor contributing to the maintenance of clinical responses and prevention of relapse. Therefore, it seems that tapering of the corticosteroids should be done more cautiously and slowly, but proper drug dosing adjustments in patients with MUE that had shown remission remain elusive.
Signalment data were recorded to evaluate the association of signalment with MUE. Female dogs were over-represented (68.6%), which is comparable to former large-scale, multi-purpose retrospective MUE studies, and the predominance of female patients is considered to be similar to the findings for other immune-mediated diseases [1, 3, 26,27,28]. Most cases in this study were small breeds and only two of the 86 dogs were medium-sized breed dogs, which was consistent with the results of previous surveys [3, 29]. The Maltese dog (41.86%) was the most commonly affected breed in this study. Additional commonly affected breeds were the Shih Tzu (10.47%) and Yorkshire Terrier (10.47%). Given the fact that the Maltese is one of the most numerous dogs in South Korea [30], MUE might be a prevalent neurological disease in South Korea.
In addition to the MMF-prednisolone therapy, 23 dogs in our study were received anti-epileptic medication as an initial therapy. Most of them received anti-epileptic medication throughout the entire study period. While, the initial administration of anti-epileptic medication with the MMF-prednisolone therapy did not significantly affect patient survival (P > 0.05). This result suggests that the anti-epileptic medication does not seem to affect the treatment of MUE itself. Because anti-epileptic drugs frequently used with immunosuppressive treatment in dogs with MUE, however, further well-controlled studies will be needed to clarify the effects of anti-epileptic medication on MUE.
Gastrointestinal problems are well-known MMF-related adverse effects, which are comparatively benign and reversible. Gastrointestinal problems were found in 30.23% of the dogs in this study, and most of them occurred within the first month of treatment. The MMF-prednisolone protocol used in this study was relatively safe with proper management, and there was no need to stop this treatment due to the gastrointestinal upsets. The previous two studies of MUE treated with a combined MMF-prednisone protocol also documented treatment-related gastrointestinal problems. The results from one study showed a 20% rate of gastrointestinal side effects, which was similar to that in our study [14]. Another study showed a relatively low gastrointestinal side effect rate of 8% with similar patient survival as compared with the results of our study [17]. Although there was a difference in the enrolled population, the biggest difference between the studies was the initial dose of MMF. The initial dose of MMF in our study was 20 mg/kg every 12 h based on the previous literature [15], but the other study chose an initial dose of 10 mg/kg every 12 h. This suggests that MMF has dose-dependent gastrointestinal adverse effects, and the dose of 20 mg/kg every 12 h might be high in some patients. Individualized dose-titration or preliminary gastrointestinal protection thus might be required for dogs that need high doses of MMF, especially in the early phase of treatment. In addition, the starting dosage of MMF does not seem to have an overt effect on survival time. This impression is supported by data from the human study of MMF that reported that the adverse gastrointestinal effects of MMF are mainly related to its peak serum concentration [31].
Sporadic infections were not an uncommon adverse effect of long-term MMF therapy in this study. Opportunistic infections are important adverse effects related to the long-term immunosuppressive therapy used in immune-mediated diseases. They are commonly managed by appropriate therapy, but when they are not treated in a timely manner, they can cause a fatal illness. Given the relatively high incidence of sporadic infections in this study, regular check-up examinations and the maintenance of a high level of sanitation should be pursued for the long-term management of dogs treated with MMF.
Corticosteroids have long been considered to be a risk factor for canine pancreatitis [32, 33]. However, this belief has not been proven and is now largely dismissed by recent works [34]. While pancreatitis was recorded in 8% of the dogs in this study, no previous reports have documented the incidence of pancreatitis after MMF treatment in veterinary medicine. Two previous studies of human patients have suggested the possibility of MMF-induced pancreatitis [35, 36]. The mechanism underlying MMF-induced pancreatitis remains unknown, but an allergic response to pancreas was proposed, like azathioprine, which has a similar mechanism of immunosuppressive action to that induced by MMF [37, 38]. Thus, this long-term study has suggested pancreatitis as a new adverse event of MMF treatment in canine patients, and further investigation will be needed to confirm the association of pancreatitis with the combined MMF-corticosteroids therapy.
There are several limitations in this study. First, histopathological confirmation of the diagnosis was not performed in most cases. Although the cases that strictly met the inclusion criteria were included in this study, it may be possible that some dogs that had several different CNS disorders were included, such as dogs with infectious diseases and neoplastic diseases. However, the results of diagnostic imaging were highly suggestive of an inflammatory conditions in the CNS and CSF findings did not provide any evidence to suspect infectious or neoplastic CNS diseases. Furthermore, infectious CNS diseases are uncommon in our region, and most of the cases in this study showed relevant improvement with immunosuppressive therapy. The histopathological classification of GME, NME, and NLE was also impossible, and their incidences could not be predicted. Moreover, the study population was somewhat biased toward the specific breeds (e.g., Maltese, Yorkshire Terrier, and Chihuahua) that are most commonly affected by necrotizing encephalitis [15, 39, 40]. The efficacy of MMF in different histopathological types of MUE may differ, thereby affecting the results of this study, but this is beyond the scope of the present study.
Other innate limitations of this study are its retrospective nature and the lack of a control population. A placebo control group is needed to establish the accurate efficacy of combined MMF-corticosteroid treatment in MUE, but it has serious ethical problems. Therefore, a prospective, randomized, double-blinded, matched-controlled study comparing the efficacy of MMF-corticosteroid combined therapy with a corticosteroid monotherapy is considered the best option and is warranted to clarify the beneficial effects of additional MMF in MUE. The variations in therapeutic regimen among the patients due to the study's retrospective nature might have impacted the results of this study. This includes the initial doses and timings of both MMF and prednisolone, tapering of drugs, treatment changes in relapsed patients, and doses and types of additional anticonvulsants used in some patients. Since these variances during the treatment period were inevitable, only those patients who received controlled therapy within a restricted standard were included in the study. Finally, the patients that responded well to the therapy but were still alive at the end of the study were censored from the survival data. This could probably affect the results of this study, which were analyzed with survival times. Thus, a further larger-scale study with a long-term follow-up period is warranted to substantiate these initial results.
In summary, the overall findings help us extend our understanding of the MMF treatment for MUE. MMF appears to be safe and comparable to other immunosuppressive drugs for dogs with MUE. The dogs that showed a CR and did not relapse over the treatment period had significantly longer MST, suggesting that treatment should focus on the achievement of a CR and preventing a relapse for the successful management of MUE. Attention to the adverse effects including gastrointestinal upsets and sporadic infections was warranted, particularly in patients treated with high-dose, long-term MMF. However, further prospective, randomized, large-scale, controlled studies will be needed to fully understand the efficacy of MMF as an adjunctive immunosuppressive drug in dogs with MUE.
Case selection and data collection
The medical records of dogs diagnosed with MUE and treated with MMF and prednisolone at our hospital between May 2009 and June 2017 were retrospectively reviewed. The study included dogs with focal or multifocal CNS abnormalities, CT and/or MRI findings compatible with the focal or multifocal CNS disease most consistent with the non-infectious inflammatory change, and complete medical records containing at least one month of follow-up information after initiating MMF therapy, and meeting one of the following two criteria: (1) abnormal CSF findings consistent with inflammation without evidence of infectious or neoplastic etiology and (2) negative test results from CSF analysis for local infectious etiological agents. The dogs were excluded the following reasons: presence of concurrent systemic diseases at initial diagnosis; significant changes in treatment protocol during the study period; death associated with unknown cause during the study period.
The data collected from the medical records included information regarding signalment, body weight, the presentation of clinical signs, the interval between clinical sign onset and initial presentation, neuroanatomical lesion localization, hematology and biochemistry values, MRI and CT imaging findings, CSF analysis, treatment protocol, response, survival from the initiation of MMF therapy, and drug-related adverse events.
All dogs underwent a CT and/or MRI scan. MRI was performed under general anesthesia with an APERTO 0.4 Tesla scanner (Hitachi Medical Corporation, Tokyo, Japan). The standard MRI sequences for this study included T1- and T2-weighted images in the sagittal and transverse planes, fluid-attenuated inversion recovery images in the transverse plane, and T1-weighted images after the administration of intravenous gadolinium ethylenediaminetetraacetic acid injection (Omniscan; GE-Healthcare, Little Chalfont, United Kingdom) at a dosage of 0.20 mmol/kg bodyweight in the transverse planes. CT was performed under general anesthesia with a Somatom Emotion Duo scan system (Siemens medical systems, Munich, Germany). Pre-contrast and post-contrast contiguous 3-mm-thick transverse images were obtained. All post-contrast images were obtained following the injection of intravenous iohexol (Omnipaque 300; GE-Healthcare, Little Chalfont, United Kingdom) at a dosage of 0.9 g I/kg bodyweight.
Samples of CSF were collected from cisterna magna puncture during the same anesthetic session following CT or MRI scanning. The CSF samples were analyzed on the same day as sampling, and the analyses included measurement of the TNCC, measurement of TP concentration, and cytologic analysis. The results of the CSF analysis were considered abnormal if the TNCC was above 5 cells/μl and the TP was above 25 mg/dl. Cytologic CSF analysis was performed on modified Romanowsky-Giemsa-stained (Diff-Quik) cyto-centrifuged slides. Infectious disease testing for Bartonella spp., Borrelia burgdorferi sensu lato, Blastomyces dermatitidis, Canine distemper virus, Coccidioides spp., Cryptococcus spp. Histoplasma capsulatum, Neospora spp., Toxoplasma gondii, and West Nile virus were performed using real-time PCR assay (Neurologic RealPCR™; IDEXX Laboratories, Westbrook, ME, USA) on CSF in some of the cases.
Treatment protocol
All patients began therapy with both MMF (CellCept®, Roche Laboratories, Nutley, NJ, USA) and prednisolone (Solondo tab, Yuhan Pharmacy, Seoul, Korea) on the day of diagnosis. Treatment was individually tailored to the basis of each patient's clinical state; however, the following treatment protocols were strictly applied in all cases. Prednisolone was initially administered at a mean dose of 0.93 mg/kg (median, 1 mg/kg; range, 0.5–1 mg/kg) PO every 12 h. Prednisolone was continued at the initial dose for a total of four to eight weeks. After assuming a successful response, the prednisolone dose was gradually tapered to the lowest effective dose required to maintain clinical remission (reducing the dose by a quarter or half every month). The mean initial dose of MMF was 19.25 mg/kg (median, 20 mg/kg; range, 10–20 mg/kg) PO every 12 h. The MMF dose was slowly tapered to 10–15 mg/kg every 12 h after a period of CR in some cases. Drug tapering was based on the neurologic state and adverse drug effects at follow-up.
Assessment designs
Outpatient follow-up neurological examinations and telephone communication with referring veterinarians and clients were conducted in all cases, when available, two weeks, four weeks, three months, and six months after the initiation of therapy and every six months thereafter. The neurological examinations were recorded and compared with the previous results. Complete blood counts and serum biochemistry analyses were performed at the time of initial presentation and at four to six weeks and six to twelve months following the initiation of therapy. Information regarding adverse events potentially associated with MMF treatment were collected from follow-up examinations and communication logs.
Response to therapy was defined as evidence of clinical improvement of neurologic signs at the follow-up examination and divided into three categories: (1) CR (total resolution of neurological signs); (2) PR (improvement with partially resolved neurological signs); and (3) NR (no improvement or progression of neurological signs). Relapse was defined as worsening of neurologic symptoms after an initial response had been obtained.
Response and survival-specific data for each dog were analyzed by statistical tests. All cases were divided into the "CR" and "failed CR" groups to evaluate the association of CR with survival time, and the possible risk factors for failed CR were analyzed. Furthermore, survival analysis of the dogs that showed CR within a month, the results of which would influence decision-making on treatment changes, was performed. All patients were also divided into two groups according to the interval between clinical sign onset and initial presentation, which was defined as the acuteness of the disease, and the therapeutic responses of these two groups were compared. Patients presenting with a disease course of two weeks or less after onset were defined as the "acute" group, and those presenting with a disease course of more than two weeks after onset were defined as the "chronic" group. Additionally, a paired survival assay was performed to compare dogs with a focal lesion with those showing multifocal lesions, dogs with brainstem involvement with those that did not show brainstem involvement, and dogs showing a relapse with dogs that did not.
Pearson's chi-squared statistic was used to test for an association between the acuteness of the disease and some response-related factors, including the occurrence of CR and relapse. Logistic regression analysis was used to test for the relationships of various risk factors to CR probability.
Kaplan-Meier survival curves for survival analysis were obtained to calculate the MST for all cases. Patients still living at the end of the study period and those who stopped the therapy during the study period and died from unrelated causes were censored from the analysis for the Kaplan-Meier curve. A log-rank statistic was used to compare various factors for survival probability. Cox's proportional hazards regression analysis was applied to assess for the relationships of various risk factors for mortality.
Values of P < 0.05 were considered statistically significant. Analyses were performed with the use of SPSS software statistics (SPSS 19.0.0 for windows, IBM, Armonk, NY, USA).
CBC:
Complete blood counts,
CNS:
Cerebrospinal fluid
Complete response
GME:
Granulomatous meningoencephalomyelitis
IMPDH:
Inosine monophosphate dehydrogenase
MMF:
Median survival time
MUE:
Meningoencephalomyelitis of unknown etiology
NLE:
Necrotizing leukoencephalitis
NME:
Necrotizing meningoencephalitis
Partial response
TNCC:
Total nucleated cell count
Total protein
Granger N, Smith PM, Jeffery ND. Clinical findings and treatment of non-infectious meningoencephalomyelitis in dogs: a systematic review of 457 published cases from 1962 to 2008. Vet J. 2010;184:290–7.
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Talarico LR, Schatzberg SJ. Idiopathic granulomatous and necrotising inflammatory disorders of the canine central nervous system: a review and future perspectives. J Small Anim Pract. 2010;51:138–49.
Jung DI, Kang BT, Park C, Yoo JH, Gu SH, Jeon HW, et al. A comparison of combination therapy (cyclosporine plus prednisolone) with sole prednisolone therapy in 7 dogs with necrotizing meningoencephalitis. J Vet Med Sci. 2007;69:1303–6.
Mercier M, Barnes Heller HL. Efficacy of glucocorticoid monotherapy for treatment of canine meningoencephalomyelitis of unknown etiology: a prospective study in 16 dogs. Vet Med Sci. 2015;1:16–22.
Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacol. 2000;47:85–118.
Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther. 2007;20:229–38.
Ackermann AL, May ER, Frank LA. Use of mycophenolate mofetil to treat immune-mediated skin disease in 14 dogs - a retrospective evaluation. Vet Dermatol. 2017;28:195–e44.
Broaddus KD, Tillson DM, Lenz SD, Niemeyer GP, Brawner WR, Welch JA, et al. Renal allograft histopathology in dog leukocyte antigen mismatched dogs after renal transplantation. Vet Surg. 2006;35:125–35.
Dewey CW, Cerda-Gonzalez S, Fletcher DJ, Harb-Hauser MF, Levine JM, Badgley BL, et al. Mycophenolate mofetil treatment in dogs with serologically diagnosed acquired myasthenia gravis: 27 cases (1999-2008). J Am Vet Med Assoc. 2010;236:664–8.
Segev G, Cowgill LD, Heiene R, Labato MA, Polzin DJ. Consensus recommendations for immunosuppressive treatment of dogs with glomerular disease based on established pathology. J Vet Intern Med. 2013;27:S44–54.
Wang A, Smith JR, Creevy KE. Treatment of canine idiopathic immune-mediated haemolytic anaemia with mycophenolate mofetil and glucocorticoids: 30 cases (2007 to 2011). J Small Anim Pract. 2013;54:399–404.
Yau VK, Bianco D. Treatment of five haemodynamically stable dogs with immune-mediated thrombocytopenia using mycophenolate mofetil as single agent. J Small Anim Pract. 2014;55:330–3.
Barnoon I, Shamir MH, Aroch I, Bdolah-Abram T, Srugo I, Konstantin L, et al. Retrospective evaluation of combined mycophenolate mofetil and prednisone treatment for meningoencephalomyelitis of unknown etiology in dogs: 25 cases (2005-2011). J Vet Emerg Crit Care. 2016;26:116–24.
Dewey CW. Encephalopathies: disorders of the brain. In: Dewey CW, da Costa RC, editors. Practical guide to canine and feline neurology. 3rd ed. New Jersey: Wiley; 2015. p. 141–236.
Song JH, Moon JH, Kim HS, Sur JC, Park C, So KM, et al. Acute progress of necrotizing meningoencephalitis in a dog. J Vet Clin. 2016;33:290–4.
Woolcock AD, Wang A, Haley A, Kent M, Creevy KE, Platt SR. Treatment of canine meningoencephalomyelitis of unknown aetiology with mycophenolate mofetil and corticosteroids: 25 cases (2007–2012). Vet Med Sci. 2016;2:125–35.
Abelson AL, Shelton GD, Whelan MF, Cornejo L, Shaw S, O'Toole TE. Use of mycophenolate mofetil as a rescue agent in the treatment of severe generalized myasthenia gravis in three dogs. J Vet Emerg Crit Care. 2009;19:369–74.
Lowrie M, Smith PM, Garosi L. Meningoencephalitis of unknown origin: investigation of prognostic factors and outcome using a standard treatment protocol. Vet Rec. 2013;172:527.
Smith PM, Stalin CE, Shaw D, Granger N, Jeffery ND. Comparison of two regimens for the treatment of meningoencephalomyelitis of unknown etiology. J Vet Intern Med. 2009;23:520–6.
Flegel T, Boettcher IC, Matiasek K, Oevermann A, Doherr MG, Oechtering G, et al. Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs. J Am Vet Med Assoc. 2011;238:337–45.
Adamo P, Rylander H, Adams WM. Ciclosporin use in multi-drug therapy for meningoencephalomyelitis of unknown aetiology in dogs. J Small Anim Pract. 2007;48:486–96.
Pakozdy A, Leschnik M, Kneissl S, Gumpenberger M, Gruber A, Tichy A, et al. Improved survival time in dogs with suspected GME treated with ciclosporin. Vet Rec. 2009;164:89–90.
Wong MA, Hopkins AL, Meeks JC, Clarke JD. Evaluation of treatment with a combination of azathioprine and prednisone in dogs with meningoencephalomyelitis of undetermined etiology: 40 cases (2000-2007). J Am Vet Med Assoc. 2010;237:929–35.
Coates JR, Barone G, Dewey CW, Vitale CL, Holloway-Azene NM, Sessions JK. Procarbazine as adjunctive therapy for treatment of dogs with presumptive antemortem diagnosis of granulomatous meningoencephalomyelitis: 21 cases (1998-2004). J Vet Intern Med. 2007;21:100–6.
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Muñana KR, Luttgen PJ. Prognostic factors for dogs with granulomatous meningoencephalomyelitis: 42 cases (1982-1996). J Am Vet Med Assoc. 1998;212:1902–6.
Kim E, Choe C, Yoo JG, Oh SI, Jung Y, Cho A, et al. Major medical causes by breed and life stage for dogs presented at veterinary clinics in the Republic of Korea: a survey of electronic medical records. PeerJ. 2018;6:e5161.
Behrend M. Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management. Drug Saf. 2001;24:645–63.
Cook AK, Breitschwerdt EB, Levine JF, Bunch SE, Linn LO. Risk factors associated with acute pancreatitis in dogs: 101 cases (1985-1990). J Am Vet Med Assoc. 1993;203:673–9.
Simpson K, Lamb C. Acute pancreatitis in the dog. In Pract. 1995;17:328.
Mansfield C. Acute pancreatitis in dogs: advances in understanding, diagnostics, and treatment. Top Companion Anim Med. 2012;27:123–32.
Dooley MA, Cosio FG, Nachman PH, Falkenhain ME, Hogan SL, Falk RJ, et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J Am Soc Nephrol. 1999;10:833–9.
Einollahi B, Dolatimehr F. Acute pancreatitis induced by mycophenolate mofetil in a kidney transplant patient. J Nephropharmacol. 2015;4:72–4.
Houston DM, Taylor JA. Acute pancreatitis and bone marrow suppression in a dog given azathioprine. Can Vet J. 1991;32:496–7.
Kawanishi H, Rudolph E, Bull FE. Azathioprine-induced acute pancreatitis. N Engl J Med. 1973;289:357.
Higgins RJ, Dickinson PJ, Kube SA, Moore PF, Couto SS, Vernau KM, et al. Necrotizing meningoencephalitis in five Chihuahua dogs. Vet Pathol. 2008;45:336–46.
Stalis IH, Chadwick B, Dayrell-Hart B, Summers BA, Van Winkle TJ. Necrotizing meningoencephalitis of Maltese dogs. Vet Pathol. 1995;32:230–5.
This research was presented as a poster at the American College of Veterinary Internal Medicine (ACVIM) Forum 2019, Phoenix, Arizona, U.S.A., 06.06-06.08., 2019.
No funding sources to declare.
Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, 52828, South Korea
Joong-Hyun Song, Do-Hyeon Yu, Hee-Chun Lee, Tae-Sung Hwang, Su-Jin An & Dong-In Jung
College of Veterinary Medicine, Western University of Health Sciences, Pomona, California, 91766-1854, USA
Young Joo Kim
Joong-Hyun Song
Do-Hyeon Yu
Hee-Chun Lee
Tae-Sung Hwang
Su-Jin An
Dong-In Jung
JHS and DIJ collected the clinical and laboratory data, performed the statistical analysis and drafted the manuscript. DHY and SJA participated in the collection of the clinical and laboratory data, the design and the statistical analysis of the study. HCL and TSH participated in the collection of the clinical and diagnostic imaging data and the design of the study. YJK performed the statistical analysis and participated in the design of the manuscript. All authors read and approved the final manuscript.
Correspondence to Dong-In Jung.
Not applicable. Retrospective medical record review; hospital approval not required for clinicians to access medical record system at their respective institutions.
Song, JH., Yu, DH., Lee, HC. et al. Evaluation of treatment with a combination of mycophenolate mofetil and prednisolone in dogs with meningoencephalomyelitis of unknown etiology: a retrospective study of 86 cases (2009–2017). BMC Vet Res 16, 192 (2020). https://doi.org/10.1186/s12917-020-02414-3
Granulomatous meningoencephalitis (GME)
Meningoencephalomyelitis of unknown etiology (MUE)
Mycophenolate mofetil (MMF)
Necrotizing meningoencephalitis (NME)
Neurology and neuroscience


The 2014 Riverstone Chardonnay has a youthful, brassy yellow color of medium depth. The aromas are fresh and reminiscent of ripe nectarine, apple and strawberry combined with honey, grilled hazelnuts and toasty oak from the barrel fermentation and sur lie aging. The palate weight is plump and rich, with flavors echoing the aromas with a delicate balance of acidity, buttery length and sophisticated elegance.
The 2014 vintage was the warmest in the last seventeen years. The total growing degree days (GDD) for the season were a warm 2,774 - a mid-Region II - well above the 2,365 GDD Region I average for the Arroyo Seco AVA. This atypical growing season began with a very warm, dry spring, which initiated early bud break and flowering. Summer, however, was cool and windy, which slowed the ripening for Chardonnay and preserved the fresh acidity that is a hallmark of Arroyo Seco fruit. Harvest began about one week earlier than normal on September 17th with the harvest of Dijon clones in blocks 2 and 4 of our Greenfield home ranch and finished on October 20th. Our Riverstone Chardonnay is now comprised of nine Chardonnay clones - 4, 5, 17, 76, 95, 96, 548, 809 and Hyde-Wente - which bring a complexity of flavors, textures and acidities.
The vines for our J. Lohr Estates Riverstone Chardonnay are grown primarily on Elder loam soils underlain by "riverstones" deposited over thousands of years by the Arroyo Seco River. These stones limit soil depth from one to four feet, although roots are found at greater depths. This unique combination of sandy loam and cobblestone soil keeps the vines' vegetative growth and fruit in balance, while the cool climate and winds of the Salinas Valley extend the growing season - retaining the natural grape acids and intense varietal character of Chardonnay.
Excellent paired with Sicilian chicken with roasted lemons, capers and olives, moules marinières or a simple Thomas Keller roast chicken.


text:
Reškovci je naselje u Republici Hrvatskoj, u sastavu općine Kapela, Bjelovarsko-bilogorska županija.

Stanovništvo

Prema popisu stanovništva iz 2001. godine, naselje je imalo 45 stanovnika te 12 obiteljskih kućanstava.
Prema popisu stanovništva 2011. godine naselje je imalo 34 stanovnika.

Izvori

Naselja u sastavu Općine Kapela

redpajama_set_name: RedPajamaWikipedia


Another way to really captivate learners is to provide them with staggered stories. Giving them a portion at a time evokes their intrigue enough for them to continue with the course to find out how the story ends. This could be told by an animated character or tutor who acts as a familiar face to guide them through the process. Short but regular contact is key.
To further enhance engagement in eLearning, visuals are a must. These may take the form of photos, illustrations, videos, charts or anything else that presents information in a clear and concise format. Not only is this visually appealing, it also enhances learners' ability to recall information and, eradicates chunks of texts and the misconception that learning simply equals reading.
It is essential that content is relevant to learners and that they know each module's purpose. Providing students with an interactive platform for certain tasks enhances this relevance and places learners in the driving seat of their own eLearning experience; able to control multiple outcomes. Interactions may come in the form of tab interactions, which allow learners to choose content relevant to them, interactive scenarios as well as quizzes and questions. Combining all this with a conversational, personable tone makes learning content even more relatable and engaging.
Appealing to auditory and visual senses, a multisensory experience can be achieved most effectively by implementing an array of videos to captivate the audience, particularly when the content is genuinely of interest. It's important that videos are relevant, of high quality and suit the target audience; an added bonus if they contain interactive options as well.
Fun is possibly the number one source of engagement and games will almost definitely achieve this. Bringing a competitive, challenging element to learning breaks up the monotony of being fed facts and instead, tests learners' knowledge as well as their decision-making abilities.
It's evident that there are various ways to improve the quality of learners engagement in eLearning, and although it is not essential to utilise all above strategies at once, it could be a case of trial and error to decipher what works best for your organisation. Remember to always encourage feedback from learners so you can constantly update and amplify your eLearning programme according to their experiences, needs and preferences.


The Consumer Financial Protection Bureau ("CFPB") recently issued a new mortgage disclosure rule that combines mortgage disclosures established by the Truth-in-Lending Act ("TILA") and the Real Estate Settlement Procedures Act ("RESPA") into a single rule known as TILA-RESPA Integrated Disclosure ("TRID") rule. The TRID rule has been in effect since October 3, 2015.
The goal of the TRID rule is to promote clarity during the loan process by providing borrowers with accurate and consistent information in connection with different loan and settlement cost options offered by their lenders.
The TRID rule applies to most closed-end consumer credit transactions secured by real property (e.g., all lenders making mortgage loans, including community banks), but does not apply to chattel-dwelling loans (e.g., loans secured by a mobile home or by a dwelling not attached to real property).
The LE, issued by the lender, contains the loan amount, loan term, interest rate, and monthly payment, and states whether any of these terms can change and whether a prepayment penalty or a balloon payment is applicable to the loan. Additionally, the total closing costs (e.g., the lender origination fees, taxes, governmental fees, any deposits and down payments, and seller credits) are specified to reflect the amount of money due at closing. The LE must be received by the borrower within three business days of the receipt of the borrower's loan application or placed in the mail no later than the seventh business day before closing. Other than a reasonable credit report fee, lenders cannot charge any fees until the LE has been provided to a borrower who has been advised that the application can proceed.
The CD, issued by the lender or its settlement agent, reiterates the LE information and specifies the settlement costs. For example, the CD contains a table comparing the estimated closing costs on the LE to the final costs contained on the CD. This allows the borrower to review the fees, terms and any changes and to question the lender about them. The CD must be provided to the borrower at least three business days prior to closing. Certain changes, such as an APR increase of more than 1/8 of a percentage point for fixed rate loans or 1/4 of a point for adjustable rate loans, will trigger a new CD form to be prepared and a new three-day waiting period to begin prior to closing. The same is true if a pre-payment penalty is added to the loan or if there is a change to the loan product, for example, a change from a variable to a fixed rate mortgage. For any other changes, a new CD will be required, but no new waiting period is triggered, and the CD can be provided at closing. If there are changes after closing which result in a change to the amount actually paid by the borrower from the amount disclosed in the final CD, a new CD may be required.
The TRID rule provides that the borrower can waive the seven-business-day waiting period after receiving the LE and the three-day waiting period after receiving the CD if the borrower has a "bona fide personal financial emergency," which requires closing the transaction before the end of these waiting periods. While this term is not defined, the CFPB's example sets a high bar, as it involves a borrower facing an imminent foreclosure sale of his or her home unless loan proceeds are available to the borrower during the respective waiting periods.
It is important to note that the TRID rule imposes significant liabilities on lenders and does not allow for much leeway or flexibility. Because lenders face substantial penalties for violating the TRID disclosure requirements (e.g., from $5,000 per day for a violation to $1 million per day for known violations) and also may be required to refund the excess payment when the borrower's costs involved in obtaining the loan exceed certain parameters for the costs specified in the LE, lenders will need to exercise extreme caution in complying with the TRID rule by scrutinizing any variations between the LE and the CD. Therefore, borrowers should be prepared for delays, as any variation may have the potential to cause lenders to delay closing rather than incur any violation.
In order to expedite the closing process, a borrower must maintain communication with his or her lender during the loan process and should provide all documentation and closing information, including homeowner's insurance, as early in the process as possible. For example, in order for the lender to meet the timeline for providing the LE, all documents and charges that are related to the transaction should be submitted to the lender at least 10 days prior to closing. Furthermore, to avoid last minute delays in connection with the issuance of the CD, which must be finalized within three-day period to prior to closing, the borrower should promptly notify the lender of any changes to the transaction, so that the lender has sufficient time to determine their impact on the terms of the loan and to update the CD.
To speak to a real estate transaction attorney about the TRID rule or other concerns regarding residential and commercial transactions, please contact Irina Shteynberg at Solomon Blum Heymann LLP. Our corporate and transactional lawyers are experienced in providing counsel to clients in the US, offshore, and abroad.


Medical Advisory services and Offshore Medicals.
medicine and remote health care.
US, Brazil, Africa and the Middle East.
ROC Health Services currently manage clients both at international and local level from our offices in London and Scotland. Our occupational and medical services, combined with our technological infrastructure, allows clients to efficiently manage the planning and delivery of occupational health within their company.


text:
Ingvil Smines Tybring-Gjedde, née en 1965 à Oslo, est une femme politique norvégienne, membre du Parti du progrès (populiste). Elle est ministre de la Sécurité sociale de Norvège du  jusqu'en janvier 2020.

Biographie
En 2018, elle est listée parmi les femmes les plus puissantes de Norvège par le magazine Kapital, à la  place.

Avant d'être nommée ministre, elle fut conseillère principale au Ministère des Affaires étrangères en 2011 puis Secrétaire d'État au Ministère du Pétrole et de l'Énergie.

Elle est nommée Ministre de la Sécurité sociale de Norvège le  dans le Gouvernement Solberg, et le reste jusqu'en janvier 2020, lorsque le Parti du progrès quitte la coalition gouvernementale pour protester du rapatriement en Norvège d'une femme de djihadiste.

Durant le procès de Laila Anita Bertheussen, compagne d'un autre membre du parti et autre ministre du gouvernement Solberg , Ingvil Smines Tybring-Gjedde a été présentée comme ayant aidée l'accusée à rédiger une tribune mensongère la présentant comme victime d'actes antiracistes, actes que Bertheussen avait inventé ou accompli elle-même.

Ingvil Smines Tybring-Gjedde est mariée à , député du Parti du progrès au Parlement norvégien depuis 2005.

Références

Femme politique norvégienne
Ministre norvégienne
Naissance en juillet 1965
Naissance à Oslo


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text:
Q: computability and geometry Hello,
I am looking for a discussion on computability and algorithms in relation to geometric constructions.
Does anyone know if the subject has  been treated from the viewpoint of elementary euclidean geometry (ex. ruler and compass constructibility)?
Thank you
Davide

A: I personally like this elegant but somewhat obscure (relatively) recent paper by Alekhnovich and Belov (MR1866477; Russian version is downloadable; it was written while Misha was still in Moscow).  Enjoy!

A: Tarski's theorem on real-closed fields shows that there is a decision procedure to compute the truth or falsity of any first-order statement in the real closed field $\langle\mathbb{R},+,\cdot,\lt,0,1\rangle$, which includes via Cartesian geometry  many of the usual concepts of Euclidean geometry and more. For example, this language is expressive enough to speak of circles, lines, paraboloids, and so on, real algebraic equations in any finite dimension, the $n$-dimensional metric, concepts of bounded or unbounded solution sets and so on. Tarski's algorithm provably determines the truth of any statement expressible in this language, even when these statements involve complex alternations of quantifiers (for every circle, there are three lines such that for every parabola of a certain kind and so on...), which in other contexts often cause undecidability.
Unfortunately, the set of integers is not definable in this language (since this would immediate refute decidability by allowing the halting problem to be expressed), and it follows that Tarski's theorem does not apply very well to questions about algorithms, which is the main focus of your question, since one seems to need the integers to express concepts of iterating a procedure, a central consideration with algorithms.

A: You might want to look at George Stiny's Shape: Talking about Seeing and Doing (MIT Press, 2006) and Dominic Widdows's Geometry and Meaning (CSLI Publications, 2004).

redpajama_set_name: RedPajamaStackExchange


A product listing for a sanding belt that contains Schema, shown with the code that made it. The product rating, highlighted in blue, comes from the "ratingValue" item property. The number of votes, highlighted in red, comes from the "ratingCount" item property. And the product cost, highlighted in green, comes from the "price" item property.
You might have heard about Schema but dismissed it as more computer jargon that you don't fully understand, and don't care about. You've got a site that looks nice, what more do you need?
Well, to stand out from the competition, there is a lot going on behind-the-scenes of a website. A lot more than most people realise. When searching for a chocolate brownie recipe, how does Google (or whichever search engine you are using) decide which websites to show you first? There are thousands of food blogs and recipe sites out there, all competing for attention. There are many things that go into each Google, Bing, Yahoo! etc. ranking (also known as Search Engine Optimization – SEO), from keyword content usage, site structure, quality of pictures on the site, site speed, number of links – the list goes on and on. Having Schema on a website is one way for search engines to attractively display a site, which can benefit any genre, from real estate, e-commerce, home services, and beyond.
The dictionary definition of Schema is "an underlying organizational pattern or structure; conceptual framework." And that is exactly what it does on the Internet: it is a framework for websites to display more efficiently and attractively on search engines. In this article, "Schema" will refer specifically to the structured data markup schema that schema.org created, which is a joint effort by Google, Yandex, Yahoo!, and Bing, with the goal to standardize Microdata markups used on websites.
In the most basic term, Schema is a specific vocabulary of tags that is added to a website's HTML to improve the way the site is represented in search engine results. Basically, a code that is added to your website to give search engines more information, to relay better results to the users.
For example, see this search result for the Arkells, the two circled results have Schema, which gives the user the information in a clear manner.
Schema also helps Google and other search engines understand the data on a website. Search engines like structured information, and Schema is a consistent and standard structured data markup that is supported by them. Essentially, it provides a consistent way for computers to understand the data on a page, and helps search engines display information usefully in search results. Schema tells the search engines what your data means, not just what it says.
It should be noted that it is fine to mark up only some properties of an item as Schema is not an all-or-nothing choice. However, marking up as much content as possible helps search engines use your information to present your page to users in the most useful way.
If people only ever go to your site directly, as opposed to searching for a product or service you offer on a search engine, then sure, Schema does not affect the actual site, so having it is not crucial. However, it is not likely that potential clients will find your website this way. In your monthly Google Analytics Reports* not only can you tell how many people reached your website, but you can see how they arrived on your site, be it by entering the domain name directly, as a link on another site, or if they searched for your product or service in a search engine and your site came up and they clicked on the link to your site.
Since searches are done multiple times a day for products and services, and people do not usually scroll through many, if any, of Google's pages to find what they want, it is important to be on that first page of results. There are paid ways to be at the top (AdWords – which we offer, get in touch to find out more) but Schema is more organic as it is simply helping the search engines by giving them clear information, thus the site is more favourably ranked. Schema is also known as "rich snippets," and because more information is provided to users from the search engines, there is increased traffic, sharing, and click through to a site. Since the purpose of most websites is to get people going to them, these are desired improvements!
Now of course there is no magic formula to guarantee being #1. We at Radar Hill are not going to make you overzealous unattainable promises about your website's ranking. We believe in doing things ethically and honestly, so it should be noted that having Schema is not going to suddenly shoot up your ranking to the top. However, it will incrementally increase the likelihood of a click through to your website from the search engines. Schema is but one of dozens of additional things that you can do to your site to maximize its performance, resulting in a positive ranking in the search engines.
*The Google Analytics reports are invaluable for all kinds of information on visitors to your site. Feel free to ask us about your reports, or view them yourself to see where most people are coming from to your site – it will likely be from search engines.
Schema is programmed right into the HTML code, the core building blocks of your website. From there, it references Schema.org to determine how to parse the information correctly.
Three search results for brownie recipes with Schema, displayed above two search results without (circled in red).
Schema makes it easier for search engines to go through web pages more effectively and display relevant results to users based on their search queries. Now it can be noted that Schema works best visually for those products or services that have reviews. However, it should also be noted that just because you can't always see the product or service nice and clear like it should be displayed, does not mean that Schema isn't working. The search engines still pick up on it and present it to the searcher favourably.
It is difficult to explain something that is so abstract and is essentially invisible on the surface most of the time. However, there are no difficult steps that you personally have to take to include Schema onto your website. Nothing new for you to do or learn, other than knowing it will help with search engine results. We will customize the underlying coding of your website to use Schema and take care of everything on your behalf.
Eating Well" result does not have Schema. Notice how there is not a lot information on it, there is no picture, no rating, and it doesn't give a snippet of the recipe, unlike the others. The Paula Deen Chicken Stir-Fry Recipe, while there is no picture, still has Schema. You will notice that there is the enticing star rating, how many reviews, and cooking time etc.
Next time you search for something see if you can tell which links are using Schema, and think why you decided to click on a certain link. Is it because there was a picture? Reviews? Price? People don't want to have to click through a whole site to find what they are looking for. Make things easier for them by succinctly having as much information as possible in their search engine results, which is possible with Schema.
I Want Schema – Now What?
If Google likes your website, then it will get ranked higher in the search results. It is as simple as that. However, getting Google to like your website, isn't so simple – there is a lot that goes into it. There are a lot of behind-the-scenes invisible aspects to optimizing a website, and that is why we have Kendra, our Google certified specialist, who ensures that our websites are as pleasing to Google and other search engines as possible. Schema is simply another feature that works in conjunction with many other tools that your website has, to optimize it for the search engines.
If this article has illuminated the benefit of implementing Schema on your website, please get in touch! It is an easy process for you, just say the word and we will implement all the necessary code. We are always happy to help optimize your web presence to make you stand out from the competition. Let us know if you would like Schema added to your website and we will get it done.
This entry was posted in At Radar Hill, Business Website Tips, E-Commerce & Retail, Graphic Design, Products & Services, SEO & Marketing, SEO & Marketing, Technology, Web Design and tagged Business, Google, HTML, images, Optimize, programming, Schema, SEO, SERP, Then and Now, tips, website. Bookmark the permalink.


Firm membership is available to firms that practice Structural Engineering in the State of Minnesota and have a practice either completely devoted to the practice of structural engineering or have a department or individuals who are engaged to be practicing structural engineering as a Professional Engineer, registered in the State of Minnesota. The cost of the firm membership is $150.00 and covers the firm membership from July 1 of the first year to June 30 of the following year and is renewable annually. Each member firm is allowed to have two voting members, who may be called upon throughout the year to vote on various items such as new officers, by-law changes and new policies. Please include the names of 2 voting members when submitting firm membership application.
Associate membership is open to individual structural engineers employed by organizations that are not eligible for firm membership. With the exception of serving as an officer of the coalition, associate members may participate on committees, attend meetings and participate in all other MNSEA activities.
Sebesta Blomberg & Associates, Inc.


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Workers Occupy Legislature After Bill to Ban Replacement Workers Defeated
Queen's Park - Union members and their supporters are refusing to leave the legislature following the Ontario government's defeat of legislation to ban the use of replacement workers during strikes and lockouts.
The workers and their supporters say they won't leave until they can meet with Premier Dalton McGuinty.
"Dalton McGuinty's failure to ensure second-reading passage of Bill 45 means lengthy labour disputes in this province are doomed to continue as companies refuse to negotiate and continue to operate by using contracted replacement workers," says United Steelworkers' Ontario Director Wayne Fraser, who is leading the sit-in at Queen's Park.
Bill 45, sponsored by MPP France Gélinas (NDP Nickel Belt), would ban the growing practice of hiring replacement workers to avoid collective bargaining.
"The very nature of labour relations is altered by this well-planned and financed practice, and workers and communities suffer as a result," said Fraser. He pointed to the year-long strike against Brazilian mining giant Vale and several multi-year disputes in Toronto, Nanticoke and Brantford, to name a few.
"McGuinty is saying to all of Ontario that workers' right to free and fair collective bargaining is no longer valid. He has set the stage for a Wisconsin-style attack against every unionized worker in Ontario. He needs to tell us why he has chosen insecurity over community-building, and therefore what is he prepared to do to solve these terrible and unnecessary strikes and lockouts.
Fraser said McGuinty is lying when he says his government has restored balance and fairness to Ontario labour relations.
"That is an absolute load of crap," said Fraser. "The truth is that current public policy does not protect citizens, and the state of labour relations in this province has instead forced people into bankruptcy, prompted family breakdown and worse.
"That is why we will not leave this place until there is an obvious and stated commitment to do the right thing."
Wayne Fraser, USW, 416-577-4045;
Pat Van Horne, USW, 613-859-1763.
USW.ca, Thurs Mar 31 2011

redpajama_set_name: RedPajamaCommonCrawl


It was something we heard several years ago.
With the advance of technology, we'll be able to get more done and yet also have more free time. Now that sounded great!
Well, CBS News had a report that said not so well.
According to the report about half of American workers skip lunch. That's right, not just shorten their lunch hour, they skip it all together. Why? Well, apparently technology has helped in getting more done, but the free time thing maybe hasn't materialized quite so much.
Reasons for skipping that usual lunch break include just too busy and pressure to perform. One professor of Human Resources Management at Temple University said we wear our 'busyness' as a badge of honor and like to be seen as that person working right by their computer.
Some experts say its all OK and helps workers stay focused. But on the negative side it can lead to burnout and mistakes.
So how about you? Do you enjoy a deserved hour long relaxing lunch? Or is it a candy bar by that keyboard at work?


PONTIAC LEMANS 1989 The Passenger's Side Front Wheel hub wears down and needs to be replaced, pe 91-101 .
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Home » psych • rawk • review » A Look Back at Pink Floyd's "Point Me at the Sky"
Posted in psych, rawk, review By Bill Kopp On December 18, 2013
A Look Back at Pink Floyd's "Point Me at the Sky"
Released 45 years ago yesterday (and recorded in a single day a mere six weeks earlier), Pink Floyd's "Point Me at the Sky" is characterized (by Wikipedia) as "the least readily available of all officially released Pink Floyd recordings. Though it was an a-side, its flip – "Careful With That Axe, Eugene" is infinitely more well-known.
Featuring a gentle-then-shouted lead vocal from guitarist David Gilmour, "Point Me at the Sky" is very much transitional Floyd. Sonically it is very much of the heavy psychedelic style popular in '68, and though its lyrics deal with space travel, it doesn't sound much at all like what would later be known as "Space Rock" (Pink Floyd's The Dark Side of the Moon being the exemplar of that genre).
Gilmour was still rather new to the band at this point; he had joined the previous December, ostensibly as a fifth member alongside then-leader Syd Barrett. Though the group did a small handful of live dates as a five-piece, by March 1968 Barrett was soon gone, and the group dynamic shifted greatly. The group's second LP (and first without Syd), A Saucerful of Secrets was released in June '68. But it's long suite-like pieces – a rough template for the style the group would later pursue – were certainly not radio fodder. In those days – in the UK, at least – singles were often wholly separate from albums, and aimed at a different audience. "Point Me at the Sky," then, could in some ways be considered a commercial effort for the fledgling Barrett-less Floyd. That said, it completely failed to chart. It would be the last non-LP single Pink Floyd ever released.
Though the song was composed with bassist Roger Waters, it's Gilmour's decidedly more tuneful vocal that fronts the track. Starting off gentle, elegiac, almost like a nursery rhyme, it initially charts a musical path not unlike the more childlike-wonder style Barrett used on Piper at the Gates of Dawn. But suddenly it blasts into a heavy, stomping section – unlike anything the Floyd had committed to tape previously, save perhaps the riffier sections of "Interstellar Overdrive" – before a massed chorus of voices proclaims the title lyrics.
The song has never appeared officially on a vinyl LP, and to date its only CD presence is as part of the bonus CD titled The Early Singles, included as part of the now-deleted 1992 Shine On box set. My own first exposure to this obscurity was via its inclusion on a bootleg/pirate LP I acquired many decades ago, the punningly-titled compilation Dark Side of the Moo.
But through the miracle of YouTube, I present to you Pink Floyd's promo clip for "Point Me at the Sky" in all its glory. (Better audio copies exist, but this clip has the advantage of showing our boys mugging for video.)
You may also enjoy the career-spanning Pink Floyd essay I wrote many years ago for Trouser Press.
Tags:pink floyd


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