Cyclical changes of cortical excitability and metaplasticity in migraine: Evidence from a repetitive transcranial magnetic stimulation study

The primary brain dysfunctions leading to the onset of a migraine attack remain largely unknown. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain, and the changes in brain function underlying migraine transformation. Brief trains of high-frequency repetitive transcranial magnetic stimulation (rTMS), when applied to the primary motor cortex at suprathreshold intensity (?120% of resting motor threshold [RMT]), elicit in healthy subjects a progressive, glutamate-dependent facilitation of the motor evoked potentials (MEP). Conversely, in conditions of increased cortical excitability, the rTMS trains induce inhibitory MEP responses likely mediated by cortical homeostatic mechanisms. We enrolled 66 migraine-without-aura patients, 48 migraine-with-aura patients, 14 patients affected by chronic migraine (CM), and 20 healthy controls. We assessed motor cortical response to 5-Hz rTMS trains of 10 stimuli given at 120% RMT. Patients with episodic migraine were studied in different phases of the migraine cycle: interictal, preictal, ictal, and postictal states. Results showed a facilitatory MEP response during the trains in patients evaluated in the preictal phase, whereas inhibitory responses were observed during and after a migraine attack, as well as in CM patients. In the interictal phase, different responses were observed, depending on attack frequency: facilitation in patients with low and inhibition in those with high attack recurrence. Our findings suggest that changes in cortical excitability and fluctuations in the threshold for inhibitory metaplasticity underlie the migraine attack recurrence, and could be involved in the process of migraine transformation.     

Differential recognition of a tyrosine-dependent signal in the basolateral and endocytic pathways of thyroid epithelial cells

Trafficking of receptors is of crucial importance for the physiology of most exocrine and endocrine organs. It is not known yet if the same mechanisms are used for sorting in the exocytic and endocytic pathways in the different epithelial tissues. In this work, we have used a deletion mutant of the human neurotrophin receptor p75(hNTR) that is normally localized on the apical membrane when expressed in Madin-Darby canine kidney cells. This internal 57-amino acid deletion of the cytoplasmic tail leads to a relocation of the protein from the apical to the basolateral membrane and to rapid and efficient endocytosis. These events are mediated by a signal localized within 9 amino acids of the mutated cytoplasmic tail that is strictly dependent on a tyrosine residue (Tyr-308). We have analyzed the basolateral sorting efficiency and endocytic capacity of this signal in Fischer rat thyroid (FRT) cells, in which basolateral and endocytic determinants have not yet been identified. We found that this targeting signal can mediate efficient transport to the basolateral membrane also in FRT cells with similar tyrosine dependence as in MDCK cells. In contrast to MDCK cells, this Tyr-based signal was not able to mediate coated pits localization and endocytosis in FRT cells. These data represent the first characterization of basolateral/endocytic signals in thyroid epithelial cells. Furthermore, our results indicate that requirements for tyrosine-dependent basolateral sorting signals are conserved among cell lines from different tissues but that the recognition of the colinear endocytic signal is tissue specific.     

Does the Early Administration of Beta‐blockers Improve the In‐hospital Mortality Rate of Patients Admitted with Acute Coronary Syndrome?

Objectives:  Beta-blockade is currently recommended in the early management of patients with acute coronary syndromes (ACS). This was a systematic review of the medical literature to determine if early beta-blockade improves the outcome of patients with ACS.
Methods:  The authors searched the PubMed and EMBASE databases for randomized controlled trials from 1965 through May 2009 using a search strategy derived from the following PICO formulation of our clinical question: Patients included adults (18+ years) with an acute or suspected myocardial infarction (MI) within 24 hours of onset of chest pain. Intervention included intravenous or oral beta-blockers administered within 8 hours of presentation. The comparator included standard medical therapy with or without placebo versus early beta-blocker administration. The outcome was the risk of in-hospital death in the intervention groups versus the comparator groups. The methodologic quality of the studies was assessed. Qualitative methods were used to summarize the study results. In-hospital mortality rates were compared using a forest plot of relative risk (RR; 95% confidence interval [CI]) between beta-blockers and controls. Statistical analysis was done with Review Manager V5.0.
Results:  Eighteen articles (total N  = 72,249) met the inclusion/exclusion criteria. For in-hospital mortality, RR = 0.95 (95% CI, 0.90–1.01). In the largest of these studies ( n  = 45,852), a significantly higher rate (p < 0.0001) of cardiogenic shock was observed in the beta-blocker (5.0%) versus control group (3.9%).
Conclusions:  This systematic review failed to demonstrate a convincing in-hospital mortality benefit for using beta-blockers early in the course of patients with an acute or suspected MI.
ACADEMIC EMERGENCY MEDICINE 2010; 17:1–10 © 2010 by the Society for Academic Emergency Medicine     

A multicenter pharmacokinetic study of the B-domain deleted recombinant factor VIII concentrate using different assays and standards

Summary. When the one‐stage clotting assay is used in comparison with the chromogenic and immunological assays, plasma levels of factor (F)VIII are underestimated by 40–50% after infusion of B‐domain deleted recombinant FVIII (BDD‐rFVIII) in patients with hemophilia. A possible way to counteract the underestimation of FVIII levels by the one‐stage assay is the adoption of a recombinant FVIII reference standard instead of a plasma standard. To evaluate the usefulness of such a standard [ReFacto^® Laboratory Standard (RLS)], the pharmacokinetic parameters of a single dose of BDD‐rFVIII (25 U kg^?1) were evaluated in a multicenter study carried out in 18 patients with severe hemophilia A. The very low in vivo recovery, obtained with the combination of the one‐stage assay and plasma reference standard, was increased up to the values obtained by the chromogenic assay when the results were expressed in terms of RLS. When the plasma standard was used, the one‐stage/chromogenic ratio was 0.82 ± 0.12 for FVIII levels above 25 U dL^?1 and 1.42 ± 0.99 for FVIII levels below 25 U dL^?1. Using the RLS, the one‐stage/chromogenic ratio increased to 1.01 ± 0.19 at FVIII levels above 25 U dL^?1, as a consequence of a complete overlap of the two decays; however, at FVIII levels below 25 U dL^?1, the one‐stage/chromogenic ratio was still 1.6 ± 0.85. After the twelfth hour, FVIII concentrations obtained by chromogenic assay were always lower than those resulting from the one‐stage clotting assay, independently of the standard used. Results obtained by chromogenic assay were not affected by the type of standard used. Compared with those obtained by the one‐stage assay, higher values of clearance, lower volume of distribution area and shorter plasma half‐life or mean residence time were obtained by chromogenic assay because of a shape change of the decay curve due to a shift to higher values in the first part (time interval 0–12 h) and to lower values in the second part of the decay curve (time interval 12–48 h). As a consequence, the slope of the decay curve obtained by means of chromogenic assay was steeper. In conclusion, the more homogeneous results of in vivo recovery and pharmacokinetic analysis, due to the decrease of discrepancy between the two methods when RLS was used, make the cheaper and more widely used one‐stage assay preferable to the more expensive chromogenic assay, on condition that the ReFacto specific standard has used.     

Clinical and morphological features of undifferentiated monomorphous GH/TSH-secreting pituitary adenoma.

A 41-year-old male presented with progressive visual defects, acromegaly and hyperthyroidism. After clinical evaluation a giant GH/TSH-secreting pituitary adenoma was diagnosed. Administration of the somatostatin analog octreotide at doses of 150 microg s.c. per day inhibited the secretion of both GH and TSH. A three-week treatment with octreotide prior to surgery led to slight visual improvement and CT scan showed some new necrotic areas within the tumor mass. Transcranial surgery was performed. By immunohistochemical analyses of the adenoma tissue GH, prolactin and beta-chorionic gonadotropin were detected; TSH was negative. Electron microscopy revealed an undifferentiated, monomorphous adenoma with morphological features of an acidophil stem cell adenoma such as the presence of misplaced exocytoses, fibrous bodies and mitochondrial gigantism. However, the tumor cells contained small secretory granules (up to 250 nm) accumulated along the cell membrane characteristic of thyrotrope cells. Furthermore, some adenoma cells were fusiform with long cytoplasmic processes resembling thyrotropes. Two months after the operation CT scan revealed a large residual tumor. Serum GH and TSH levels had increased again and the TSH level was even higher than before the treatment. The patient died suddenly, most probably of lethal arrhythmia. Specimens of the adenoma tissue obtained at autopsy confirmed the previous findings with the exception of positive immunostaining for TSH which was found in less than 1% of the adenoma cells. This undifferentiated, monomorphous GH/TSH-secreting pituitary adenoma represents an entity that is unusual both in its ultrastructural features and clinical manifestations suggesting a cytogenesis from an early, undifferentiated stem cell.     

Retrospective comparison of pregnancy outcomes of fresh and frozen-warmed single blastocyst transfer: a 5-year single-center experience

Journal of Assisted Reproduction and Genetics - To assess whether live birth rates (LBR) and maternal/neonatal complications differed following single fresh and frozen-warmed blastocyst transfer....     

Elevated cerebrospinal fluid and plasma homocysteine levels in ALS

Background:  High cerebrospinal fluid (CSF) and plasma levels of homocysteine (HC) have been reported in certain neurodegenerative disorders, such as Alzheimer's, Parkinson's diseases and, recently, amyotrophic lateral sclerosis (ALS).
Objectives:  To assay the CSF and plasma levels of HC in ALS patients and controls, and to evaluate the relationship between HC levels and clinical variables of the disease.
Methods:  Cerebrospinal fluid from sixty-nine (M/F 1.87) and plasma from sixty-five ALS patients (M/F 1.83) were taken and stored at −80°C until use. Controls (CSF = 55; plasma = 67) were patients admitted to our hospital for neurological disorders with no known relationship to HC changes. CSF and plasma from ALS patients and controls were obtained as a necessary step of the diagnostic workup. HC levels in CSF and plasma were assayed using a high performance liquid chromatograph (HPLC) and a fluorimeter detector.
Results:  The median level of total HC in the CSF of ALS patients was 0.46 μM, significantly higher than that of the controls (0.24 μM, +91.6%, P  < 0.001). A similar trend was observed when HC was assayed in plasma (ALS, 12.4 μM vs. controls, 7.26 μM, +70.8%, P  < 0.001). The CSF and plasma HC levels showed no relationship with the disease progression, age at onset, and the site of onset.
Conclusions:  Homocysteine is a biochemical marker in ALS, and it might be related to the pathophysiology of the disease.