Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Long-Term Morphological Changes of Symptomatic Lacunar Infarcts and Surrounding White Matter on Structural Magnetic Resonance Imaging.

BACKGROUND AND PURPOSE: Insights into evolution of cerebral small vessel disease on neuroimaging might advance knowledge of the natural disease course. Data on evolution of sporadic symptomatic lacunar infarcts are limited. We investigated long-term changes of symptomatic lacunar infarcts and surrounding white matter on structural magnetic resonance imaging. METHODS: From 2 nonoverlapping, single-center, prospective observational stroke studies, we selected patients presenting with lacunar stroke symptoms with a recent small subcortical (lacunar) infarct on baseline structural magnetic resonance imaging and with follow-up magnetic resonance imaging available at 1 to 5 years. We assessed changes in imaging characteristics of symptomatic lacunar infarcts and surrounding white matter. RESULTS: We included 79 patients of whom 32 (41%) had complete and 40 (51%) had partial cavitation of the index lesion at median follow-up of 403 (range, 315-1781) days. In 42 of 79 (53%) patients, we observed a new white matter hyperintensity adjacent to the index infarct, either superior (white matter hyperintensity cap, n=17), inferior (white matter hyperintensity track, n=13), or both (n=12). CONCLUSIONS: Half of the sporadic symptomatic lacunar infarcts developed secondary changes in superior and inferior white matter. These white matter hyperintensity caps and tracks may reflect another aspect of cerebral small vessel-related disease progression. The clinical and prognostic values remain to be determined.

Impact of ergot alkaloid and steroidal implant on whole-body protein turnover and expression of mTOR pathway proteins in muscle of cattle.

Introduction: Holstein steers (n = 32) were used to determine if the ergot analog, bromocriptine decreases muscle protein synthesis through inhibitory action on the mTOR pathway via a direct effect on signal proteins, and if these negative effects can be alleviated with anabolic agents. Methods: Steers were treated with intramuscular administration of bromocriptine (vehicle or 0.1 mg/kg BW) and a subdermal commercial steroidal implant containing trenbolone acetate (TBA) and estradiol 17ß (with or without), in a 2×2 factorial design. During the 35 day experiment, intake was restricted to 1.5 times maintenance energy requirement. On days 27 through 32, steers were moved to metabolism stalls for urine collection, and whole-body protein turnover was determined using a single pulse dose of [15N] glycine into the jugular vein on day 28. On day 35, skeletal muscle samples were collected before (basal state) and 60 min after (stimulated state) an i.v. glucose challenge (0.25 g glucose/kg). Blood samples were collected at regular intervals before and after glucose infusion for determination of circulating concentrations of glucose and insulin. Results: Bromocriptine reduced insulin and glucose clearance following the glucose challenge, indicating decreased insulin sensitivity and possible disruption of glucose uptake and metabolism in the skeletal muscle. Conversely, analysis of whole-body protein turnover demonstrated that bromocriptine does not appear to affect protein synthesis or urea excretion. Western immunoblot analysis of skeletal muscle showed that it did not affect abundance of S6K1 or 4E-BP1, so bromocriptine does not appear to inhibit activation of the mTOR pathway or protein synthesis. Estradiol/TBA implant decreased urea excretion and protein turnover but had no effect on protein synthesis, suggesting that steroidal implants promote protein accretion through unchanged rates of synthesis and decreased degradation, even in the presence of bromocriptine, resulting in improved daily gains. Implanted steers likely experienced increased IGF-1 signaling, but downstream activation of mTOR, S6K and 4E-BP1, and thus increased protein synthesis did not occur as expected. Conclusions: Overall, this data suggests that bromocriptine does not have a negative impact on muscle protein synthetic pathways independent of DMI.

Cavitation of deep lacunar infarcts in patients with first-ever lacunar stroke: a 2-year follow-up study with MR.

BACKGROUND AND PURPOSE: Studies in patients with lacunar stroke often assess the number of lacunes. However, data on how many symptomatic lacunar infarcts cavitate into a lacune are limited. We assessed the evolution of symptomatic lacunar infarcts over 2-year follow-up. METHODS: In 82 patients with first-ever lacunar stroke with a lacunar infarct in the deep brain regions (excluding the centrum semiovale), we performed a brain MR at presentation and 2 years later. We classified cavitation of lacunar infarcts at baseline and on follow-up MR as absent, incomplete, or complete. We recorded time to imaging, infarct size, and vascular risk factors. RESULTS: On baseline MR, 38 (46%) index infarcts showed complete or incomplete cavitation. Median time to imaging was 8 (0-73) days in noncavitated and 63 (1-184) days in cavitated lesions (P<0.05). On follow-up imaging, 94% of the lacunar infarcts were completely or incompletely cavitated, most had reduced in diameter, and 5 (6%) had disappeared. Vascular risk factors were not associated with cavitation. CONCLUSION: Cavitation and lesion shrinkage were seen in almost all symptomatic lacunar infarcts in the deep brain regions over 2-year follow-up. Counting lacunes in these specific regions at a random moment might slightly, however not substantially, underestimate the burden of deep lacunar infarction.

Effects of Bromocriptine on Glucose and Insulin Dynamics in Normal and Insulin Dysregulated Horses.

The objectives of the study were to study the effects of the synthetic ergot alkaloid (EA), bromocriptine, on glucose and lipid metabolism in insulin dysregulated (ID, n = 7) and non-ID (n = 8) mares. Horses were individually housed and fed timothy grass hay and two daily concentrate meals so that the total diet provided 120% of daily DE requirements for maintenance. All horses were given intramuscular bromocriptine injections (0.1 mg/kg BW) every 3 days for 14 days. Before and after 14 days of treatment horses underwent a combined glucose-insulin tolerance test (CGIT) to assess insulin sensitivity and a feed challenge (1 g starch/kg BW from whole oats) to evaluate postprandial glycemic and insulinemic responses. ID horses had higher basal plasma concentrations of insulin (P = 0.01) and triglycerides (P = 0.02), and lower concentrations of adiponectin (P = 0.05) compared with non-ID horses. The CGIT response curve showed that ID horses had slower glucose clearance rates (P = 0.02) resulting in a longer time in positive phase (P = 0.03) and had higher insulin concentrations at 75 min (P = 0.0002) compared with non-ID horses. Glucose (P = 0.02) and insulin (P = 0.04) responses to the feeding challenge were lower in non-ID compared to ID horses. Regardless of insulin status, bromocriptine administration increased hay intake (P = 0.03) and decreased grain (P < 0.0001) and total DE (P = 0.0002) intake. Bromocriptine treatment decreased plasma prolactin (P = 0.0002) and cholesterol (P = 0.10) and increased (P = 0.02) adiponectin concentrations in all horses. Moreover, in both groups of horses, bromocriptine decreased glucose clearance rates (P = 0.02), increased time in positive phase (P = 0.04) of the CGIT and increased insulin concentrations at 75 min (P = 0.001). The postprandial glycemic (P = 0.01) and insulinemic (P = 0.001) response following the oats meal was lower after bromocriptine treatment in all horses. In conclusion, in contrast to data in humans and rodents, bromocriptine treatment reduced insulin sensitivity in all horses, regardless of their insulin status. These results indicate that the physiological effects of EA might be different in horses compared to other species. Moreover, because bromocriptine shares a high degree of homology with natural EA, further investigation is warranted in horses grazing endophyte-infected grasses.

Differential effect of two dietary protein sources on time course response of muscle anabolic signaling pathways in normal and insulin dysregulated horses.

The objective of the study was to characterize the temporal changes of phosphorylation patterns of mTOR signaling proteins in response to two dietary protein sources in insulin dysregulated (ID, n = 8) and non-ID (n = 8) horses. Horses were individually housed and fed timothy grass hay and 2 daily concentrate meals so that protein was the first limiting nutrient and the total diet provided 120% of daily DE requirements for maintenance. On sample days, horses randomly received 0.25 g CP/kg BW of a pelleted alfalfa (AP) or commercial protein supplement (PS). Blood samples were collected before and 30, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 min post feeding and analyzed for plasma glucose, insulin and amino acid (AA) concentrations. Gluteus Medius muscle samples were obtained before and 90, 180, and 300 min after feeding and analyzed for relative abundance of phosphorylated mTOR pathway components using western immunoblot analysis. There was no effect of protein source on postprandial glucose and insulin responses (P ≥ 0.14) but consumption of PS elicited a 2 times larger AUC for essential AA (EAA), greater peak concentrations of EAA and a shorter time to reach peak EAA concentrations compared to AP. Abundance of phosphorylated mTOR (P = 0.08) and rpS6 (P = 0.10) tended to be ~1.5-fold greater after consumption of PS at 90 min compared to AP. Dephosphorylation patterns differed between protein sources and was slower for AP compared to PS. ID horses had a 2 times greater (P = 0.009) AUC and 3 times higher postprandial peak concentrations (P < 0.0001) for insulin compared to non-ID horses after consumption of both treatment pellets, but EAA responses were similar between groups (P = 0.53). Insulin status did not affect rpS6 or mTOR phosphorylation after consumption of either protein source (P ≥ 0.35), but phosphorylated rpS6 abundance was twice as high in ID compared to non-ID horses (P = 0.007). These results suggest that the consumption of higher quality protein sources may result in greater postprandial activation of the mTOR pathway compared to equal amounts of a forage-based protein source. Moreover, ID does not impair postprandial activation of mTOR and rpS6 proteins in horses following a protein-rich meal.

Pathways regulating equine skeletal muscle protein synthesis respond in a dose-dependent manner to graded levels of protein intake.

Activation of the mechanistic target of rapamycin (mTOR)-controlled anabolic signaling pathways in skeletal muscle of rodents and humans is responsive to the level of dietary protein supply, with maximal activation and rates of protein synthesis achieved with 0.2 to 0.4 g protein/kg body weight (BW). In horses, few data are available on the required level of dietary protein to maximize protein synthesis for maintenance and growth of skeletal muscle. To evaluate the effect of dietary protein level on muscle mTOR pathway activation, five mares received different amounts of a protein supplement that provided 0, 0.06, 0.125, 0.25, or 0.5 g of crude protein (CP)/kg BW per meal in a 5 × 5 Latin square design. On each sample day, horses were fasted overnight and were fed only their protein meal the following morning. A preprandial (0 min) and postprandial (90 min) blood sample was collected and a gluteus medius muscle sample was obtained 90 min after feeding the protein meal. Blood samples were analyzed for glucose, insulin, and amino acid concentrations. Activation of mTOR pathway components (mTOR and ribosomal protein S6 [rpS6]) in the muscle samples was measured by Western immunoblot analysis. Postprandial plasma glucose (P = 0.007) and insulin (P = 0.09) showed a quadratic increase, while total essential amino acid (P < 0.0001) concentrations increased linearly with the graded intake of the protein supplement. Activation of mTOR (P = 0.02) and its downstream target, rpS6 (P = 0.0008), increased quadratically and linearly in relation to the level of protein intake, respectively. Comparisons of individual doses showed no differences (P > 0.05) between the 0.25 and 0.5 g of protein intake for either mTOR or rpS6 activation, indicating that protein synthesis may have reached near maximal capacity around 0.25 g CP/kg BW. This is the first study to show that the activation of muscle protein synthetic pathways in horses is dose-dependent on the level of protein intake. Consumption of a moderate dose of high-quality protein resulted in near maximal muscle mTOR pathway activation in mature, sedentary horses.

Herpes Encephalitis: A Mortal Complication in a Patient Treated with Immunosuppressive Drugs because of Immune-Related Adverse Events after Ipilimumab Treatment.

Until a few years ago, metastatic melanoma had a poor prognosis with limited treatment options. These therapeutics options and thereby median survival have increased obviously over 5 years with the arrival of immunotherapeutic drugs like ipilimumab, nivolumab, and pembrolizumab. Nowadays, ipilimumab is often used in patients with metastatic melanoma. In this paper, we report a case of a 68-year-old man who developed, and eventually died of, herpes encephalitis after introducing ipilimumab as treatment for metastatic melanoma. To our knowledge, this is the first report in which herpes encephalitis as a complication after ipilimumab and infliximab treatment is described and we would like to make physicians aware of this possible serious neurological complication, especially when a patient has a history of herpes simplex infection.

Association between Perivascular Spaces and Progression of White Matter Hyperintensities in Lacunar Stroke Patients.

OBJECTIVES: Perivascular spaces are associated with MRI markers of cerebral small vessel disease, including white matter hyperintensities. Although perivascular spaces are considered to be an early MRI marker of cerebral small vessel disease, it is unknown whether they are associated with further progression of MRI markers, especially white matter hyperintensities. We determined the association between perivascular spaces and progression of white matter hyperintensities after 2-year follow-up in lacunar stroke patients. METHODS: In 118 lacunar stroke patients we obtained brain MRI and 24-hour ambulatory blood pressure measurements at baseline, and a follow-up brain MRI 2 years later. We visually graded perivascular spaces and white matter hyperintensities at baseline. Progression of white matter hyperintensities was assessed using a visual white matter hyperintensity change scale. Associations with white matter hyperintensity progression were tested with binary logistic regression analysis. RESULTS: Extensive basal ganglia perivascular spaces were associated with progression of white matter hyperintensities (OR 4.29; 95% CI: 1.28-14.32; p<0.05), after adjustment for age, gender, 24-hour blood pressure and vascular risk factors. This association lost significance after additional adjustment for baseline white matter hyperintensities. Centrum semiovale perivascular spaces were not associated with progression of white matter hyperintensities. CONCLUSIONS: Our study shows that extensive basal ganglia perivascular spaces are associated with progression of white matter hyperintensities in cerebral small vessel disease. However, this association was not independent of baseline white matter hyperintensities. Therefore, presence of white matter hyperintensities at baseline remains an important determinant of further progression of white matter hyperintensities in cerebral small vessel disease.