Paroxysmal atrial fibrillation occurs often in cryptogenic ischaemic stroke. Final results from the SURPRISE study.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) increases the risk of stroke fourfold and is associated with a poor clinical outcome. Despite work-up in compliance with guidelines, up to one-third of patients have cryptogenic stroke (CS). The prevalence of asymptomatic paroxysmal atrial fibrillation (PAF) in CS remains unknown. The SURPRISE project aimed at determining this rate using long-term cardiac monitoring. METHODS: Patients with CS after protocolled work-up including electrocardiography (ECG) and telemetry were included after informed consent. An implantable loop recorder (ILR) was implanted subcutaneously. PAF was defined by events of atrial arrhythmia >2 min with a correlating one-lead ECG confirming the diagnosis. RESULTS: Eighty-five patients were monitored for a mean of 569 days (SD ±310). PAF was documented in 18 patients (20.7%) during the study period and detected by ILR in 14 patients (16.1%). In three patients PAF was detected by other methods before or after monitoring and was undiscovered due to device sensitivity in one case. The first event of PAF was documented at a mean of 109 days (SD ±48) after stroke onset. PAF was asymptomatic in all cases and occurred in episodes lasting predominantly between 1 and 4 h. Four recurrent strokes were observed, three in patients with PAF; all three patients were on oral anticoagulation (OAC). CONCLUSIONS: One in five patients with CS had PAF, which occurred at low burden and long after stroke. Future studies should determine the role of implantable cardiac monitors after stroke and determine the potential therapeutic benefit of OAC treatment of patients with PAF.

Feasibility of endovascular and surface cooling strategies in acute stroke.

BACKGROUND: Therapeutic hypothermia (TH) is a promising treatment of stroke, but limited data are available regarding the safety and effectiveness of cooling methodology. We investigated the safety of TH and compared the cooling capacity of two widely used cooling strategies - endovascular and surface cooling. METHODS: COOLAID Oresund is a bicentre randomized trial in Copenhagen (Denmark) and Malmö (Sweden). Patients were randomized to either TH (33°C for 24 h) in a general intensive care unit (ICU) or standardized stroke unit care (control). Cooling was induced by a surface or endovascular-based strategy. RESULTS: Thirty-one patients were randomized. Seven were cooled using endovascular and 10 using surface-based cooling methods and 14 patients received standard care (controls). 14 (45%) patients received thrombolysis. Pneumonia was recorded in 6 (35%) TH patients and in 1 (7%) control. 4 TH patients and 1 control developed massive infarction. 1 TH patient and 2 control suffered asymptomatic haemorrhagic transformation. Mortality was comparable with 2 (12%) in the TH group and 1 (7%) among controls. Mean (SD) duration of hospital stay was 25.0 days (24, 9) in TH and 22.5 days (20.6) in control patients (P = 0.767). Mean (SD) induction period (cooling onset to target temperature) was 126.3 min (80.6) with endovascular cooling and 196.3 min (76.3) with surface cooling (P = 0.025). CONCLUSIONS: Therapeutic hypothermia with general anaesthesia is feasible in stroke patients. We noticed increased rates of pneumonia, while the length of hospital stay remained comparable. The endovascular cooling strategy provides a faster induction period than surface cooling.

Adrenocorticotropin and beta-lipotropin in the hypothalamus. Localization in the same arcuate neurons by sequential immunocytochemical procedures.

Adrenocorticotropin and beta-lipotropin (beta-LPH) have been localized by immunoperoxidase methods in nerve cells and fibers of the hypothalamus and brain stem of the ewe. 6-mum sections were immunostained first for either ACTH or beta-LPH. The reaction products and the antibody complexes were then eluted completely from the tissue, and the same section was immunostained for the second peptide. Absorption of the primary antisera with a variety of peptide fragments of ACTH and beta-LPH demonstrated, immunocytochemically as well as by radioimmunoassay, that the ACTH and beta-LPH antisera were directed to the COOH- and NH(2)-termini of the peptides, respectively. Neither antiserum recognized any portion of the heterologous peptide. In the sequential staining procedure on the same tissue section, preincubation of the antisera with the homologous peptide abolished the staining, whereas preincubation with the heterologous peptide did not affect it, regardless of the order followed. Every nerve cell in the arcuate nucleus that contained ACTH also contained beta-LPH, but beta-LPH cells appeared, probably falsely, to be twice as numerous as ACTH cells. beta-LPH-positive fibers in and beyond the hypothalamus were also more numerous and stained more intensively than ACTH fibers. The salient exception was fibers in the infundibular zona externa, where the opposite was true. Our observations establish that ACTH and beta-LPH are contained in the same nerve cells They stongly favor biosynthesis in brain, probably from a common precursor molecule, as has been demonstrated in the pituitary gland. The complexity of the cytologic distribution pattern described suggests that the two peptides are not processed in the same manner by the nerve cell.

Brain peptides: what, where, and why?

Within the past decade, a large number of peptides have been described within the vertebrate central nervous system. Some of these peptides were previously known to be present in nonneural vertebrate tissues, as well as in lower species, in which they may serve as primitive elements of intercellular communication prior to the development of neuronal or endocrine systems. In vertebrates, these peptides are thought to have neurotransmitter or neuromodulatory roles and appear to be involved in the regulation of a number of homeostatic systems, although the mechanisms of their actions are still unclear.

Circadian corticosteroid periodicity: critical period for abolition by neonatal injection of corticosteroid.

Circadian variation of corticosteroid concentrations in rat plasma is suppressed if corticosteroids are administered between days 2 to 4 of neonatal life, but not if they are given between days 12 to 14 of neonatal life. This indicates a critical period for the effect of corticosteroid administration on the central nervous system pathways regulating such periodicity. Circadian periodicity of corticosteroids is not affected by neonatal administration of testosterone or reserpine.

beta-Endorphin is not detectable in plasma from normal human subjects.

beta-Endorphin is not detectable in plasma from normal human subjects when measured under baseline conditions or after the subjects have received vasopressin, an agent that elevates beta-lipotropin and adrenocorticotropic hormone (ACTH). Significant amounts of beta-endorphin are present in plasma of patients with endocrine disorders associated with increased ACTH and beta-lipotropin production. Highly purified, natural beta-lipotropin is not peripherally converted to beta-endorphin in vivo in normal subjects.

Suprachiasmatic nuclear lesions do not abolish food-shifted circadian adrenal and temperature rhythmicity.

Daytime restriction of food and water availability in nocturnal animals phase shifts the circadian periodicity of plasma corticosteroid concentrations and body temperature. These shifted rhythms persist in animals with lesions of the suprachiasmatic nuclei who are arrhythmic under normal conditions. These findings suggest the existence of an additional "clock" that may be involved in the generation of the rhythm.

Circadian pattern of plasma 17-hydroxycorticosteroid: alteration by anticholinergic agents.

Atropine, administered to cats just prior to the time of the expected circadian rise in levels of 17-hydroxycorticosteroid in plasma, blocks this rise. Atropine does not alter this circadian pattern when administered at other times in the circadian cycle. Results similar to those obtained with atropine have been observed with short-acting barbiturates. Dibenzyline administered just prior to the time of the expected circadian rise is ineffective in blocking this rise. These findings support the hypothesis that the circadian pattern of plasma 17-hydroxycorticosteroid levels reflects activation, by the central nervous system, of the hypothalamicpituitary-adrenal axis during a "critical time period" in the circadian cycle.

Pituitary hormones in brain: where, how, and why?

Peptide and protein hormones usually considered as being of pituitary origin have been detected within the central nervous system by means of radioimmunoassay, bioassay, and immunocytochemical techniques. Intracerebral administration of some of these hormones or fragments thereof elicit behavioral responses, suggesting that they may have a physiological role similar to that described for other peptidergic neurotransmitter or neuromodulator substances. Evidence available for some of these hormones indicates that they are synthesized within the central nervous system and that their regulation may differ from that of their pituitary counterparts.

Induced expression of the glucocorticoid receptor in the rat intermediate pituitary lobe.

Synthesis and release of pro-opiomelanocortin-derived peptides are under differential regulation in the anterior and intermediate lobes of the pituitary. Glucocorticoids inhibit synthesis of pro-opiomelanocortin-related peptides in the anterior lobe but not in the intermediate lobe. These two lobes are also characterized by differences in neural innervation and blood flow, both of which may represent routes of access for regulatory factors (the intermediate lobe is avascular). Immunoreactive glucocorticoid receptor, which can be demonstrated in many tissues, is absent from the intermediate lobe. Immunocytochemistry was used to demonstrate the presence of immunoreactive glucocorticoid receptor in the intermediate lobe after pituitary stalk transection, neurointermediate lobe grafts to kidney capsule, or monolayer culture of neurointermediate pituitary cells. This appearance of the glucocorticoid receptor is presumably a consequence of removal of intermediate pituitary cells from neural influences that may be responsible for inhibiting their expression under normal conditions in vivo.

Characterization and localization of proopiomelanocortin messenger RNA in the adult rat testis.

Northern blot analysis of total RNA and polyadenylated RNA isolated from adult rat testes showed that a proopiomelanocortin (POMC)-like messenger RNA molecule is present in these extracts. The testicular POMC messenger RNA is comparable in length to amygdala and midbrain POMC messenger RNA and appears to be at least 200 nucleotides shorter than POMC messenger RNA found in the hypothalamus and anterior and intermediate lobes of the pituitary gland. Hybridization in situ showed that POMC messenger RNA is located in Leydig cells, which are the only testicular cells that contain immunostainable POMC-derived peptides. These results suggest that local synthesis of POMC occurs in the testis.

Pituitary intermediate lobe in dog: two cell types and high bioactive adrenocorticotropin content.

The pituitary intermediate lobe of most species is cytologically monotonous, but that of the dog is composed of two immunocytochemically distinct cell types. The predominant A cells are typical pars intermedia cells: they stain immunocytochemically for alpha-melanotropin and, more weakly, for adrenocorticotropin and beta-lipotropin. The B cells are like the corticotrophs of the anterior lobe: they stain intensely for adrenocorticotropin and beta-lipotropin but not for alpha-melanotropin. The B cells may account for the high concentration of bioactive adrenocorticotropin measured in the canine pars intermedia, and may explain why in dogs adenomas causing Cushing's disease through hypersecretion of adrenocorticotropin can arise from the intermediate as well as the anterior pituitary lobe.

Mating and pregnancy can occur in genetically hypogonadal mice with preoptic area brain grafts.

Adult female hypogonadal mice, in whom hypogonadism is secondary to a genetic deficiency in hypothalamic gonadotropin-releasing hormone (GnRH), are infertile. Mating, pregnancy, and delivery of healthy litters were achieved after transplantation of normal fetal preoptic area tissue, a major site of GnRH-containing cell bodies, into the third ventricle of adult female hypogonadal mice. Immunocytochemistry revealed GnRH-containing neurons in the grafts and GnRH-containing processes extending to the lateral median eminence of the host brains.

Assessment of the genotoxic and carcinogenic risks of p-nitrophenol when it is present as an impurity in a drug product.

According to the 2008 US FDA (draft) and 2006 EMEA guidance documents for genotoxic impurities, an impurity that is positive in an in vitro genotoxicity study, in the absence of in vivo genotoxicity or carcinogenicity data, should be treated as genotoxic and typically controlled to 1.5 microg/day for chronic use. For p-nitrophenol (PNP), existing study results (i.e., positive in vitro clastogenicity in mammalian cells, no information on its in vivo genotoxicity, and negative with respect to carcinogenicity in a dermal mouse study with no confirmation of systemic exposure) indicated that it should be considered genotoxic and exposure as a drug impurity limited. Therefore, to more completely characterize the genotoxic potential of PNP (consistent with the guidance documents), in vivo mouse micronucleus and dermal pharmacokinetic bridging studies were conducted. In the micronucleus study, PNP was negative, demonstrating that the reported in vitro clastogenicity is not present in vivo. In the pharmacokinetic study, PNP was well absorbed dermally, validating the negative dermal carcinogenicity assessment. These results indicate that PNP should be considered a non-genotoxic impurity and, as a drug impurity, a threshold limit of 4 mg/day would be set (per ICH Q3C). This threshold limit is higher than the EPA reference dose (listed in the 2006 Edition of the Drinking Water Standards and Health Advisories), so if present at such levels, the specification limits for PNP should be determined on a case-by-case basis, based on risk-benefit.

Thrombolysis and thrombectomy in patients treated with dabigatran with acute ischemic stroke: Expert opinion.

Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.

Mechanical Thrombectomy with the Embolus Retriever with Interlinked Cages in Acute Ischemic Stroke: ERIC, the New Boy in the Class.

BACKGROUND AND PURPOSE: The Embolus Retriever with Interlinked Cages (ERIC) device is a novel stent retriever for mechanical thrombectomy. It consists of interlinked cages and could improve procedural benchmarks and clinical outcome compared with classic stent retrievers. This study compares the rates of recanalization, favorable clinical outcome, procedural adverse events, and benchmarks between the ERIC device and classic stent retrievers. MATERIALS AND METHODS: From 545 patients treated with thrombectomy between 2012 and 2015, 316 patients were included. The mean age was 69 ±13 years, the mean baseline NIHSS score was 17 ± 5, and 174 (55%) were men. The ERIC was used as the primary thrombectomy device in 59 (19%) patients. In a propensity score matched analysis including the NIHSS score, clot location, delay to groin puncture, neurointerventionalist, and anesthetic management, 57 matched pairs were identified. RESULTS: Patients treated with the ERIC device compared with classic stent retrievers showed equal rates of recanalization (86% versus 81%, P = .61), equal favorable 3-month clinical outcome (mRS 0-2: 46% versus 40%, P = .71), and procedural adverse events (28% versus 30%, P = 1.00). However, in patients treated with the ERIC device, thrombectomy procedures were less time-consuming (67 versus 98 minutes, P = .009) and a rescue device was needed less often (18% versus 39%, P = .02) compared with classic stent retrievers. CONCLUSIONS: Mechanical thrombectomy with the ERIC device is effective and safe. Rates of favorable procedural and clinical outcomes are at least as good as those with classic stent retrievers. Of note, the ERIC device might be time-saving and decrease the need for rescue devices. These promising results call for replication in larger prospective clinical trials.

Initial Performance of NI-RADS to Predict Residual or Recurrent Head and Neck Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: The Head and Neck Imaging Reporting and Data System (NI-RADS) surveillance template for head and neck cancer includes a numeric assessment of suspicion for recurrence (1-4) for the primary site and neck. Category 1 indicates no evidence of recurrence; category 2, low suspicion of recurrence; category 3, high suspicion of recurrence; and category 4, known recurrence. Our purpose was to evaluate the performance of the NI-RADS scoring system to predict local and regional disease recurrence or persistence. MATERIALS AND METHODS: This study was classified as a quality-improvement project by the institutional review board. A retrospective database search yielded 500 consecutive cases interpreted using the NI-RADS template. Cases without a numeric score, non-squamous cell carcinoma primary tumors, and primary squamous cell carcinoma outside the head and neck were excluded. The electronic medical record was reviewed to determine the subsequent management, pathology results, and outcome of clinical and radiologic follow-up. RESULTS: A total of 318 scans and 618 targets (314 primary targets and 304 nodal targets) met the inclusion criteria. Among the 618 targets, 85.4% were scored NI-RADS 1; 9.4% were scored NI-RADS 2; and 5.2% were scored NI-RADS 3. The rates of positive disease were 3.79%, 17.2%, and 59.4% for each NI-RADS category, respectively. Univariate association analysis demonstrated a strong association between the NI-RADS score and ultimate disease recurrence, with P < .001 for primary and regional sites. CONCLUSIONS: The baseline performance of NI-RADS was good, demonstrating significant discrimination among the categories 1-3 for predicting disease.

The Safety, Pharmacokinetics, and Nervous System Effects of Two Natural Sources of Caffeine in Healthy Adult Males.

This double-blind crossover clinical trial randomized 12 adult males to receive 200 mg of caffeine from a green coffee extract, a guayusa leaf extract, and a synthetic control to compare their safety, absorption, and effect on neurotransmitters. The results showed no statistically significant changes in blood pressure or heart rate from baseline to 120 min postdose of each natural source compared with changes from baseline in the control (0.094 < = P < = 0.910). The ratios of Cmax , AUC0-4 , and AUC0-∞ of each natural source to the control were bioequivalent by US Food and Drug Administration standards (90% CI within 80-125%). The guayusa leaf extract stimulated a significantly lower increase in epinephrine compared with the control (+0.5 vs. +2.78 µg/gCr, P = 0.04), while the green coffee extract provoked an increase in epinephrine similar to the control (+3.21 vs. +2.78 µg/gCr, P = 0.569). Implications for future clinical research are discussed.