The alpha2-adrenergic agonist guanfacine reduces excitability of human motor cortex through disfacilitation and increase of inhibition.

OBJECTIVE: To test the acute effects of the alpha2-adrenoceptor agonist guanfacine (GFC) on motor excitability in intact humans. METHODS: Eight healthy right-handed adults received a single oral dose of 2 mg of GFC. Motor cortex excitability was tested by focal transcranial magnetic stimulation of the hand area of the left motor cortex. Motor evoked potentials (MEP) were recorded from the right abductor pollicis brevis muscle. In addition, spinal and neuromuscular excitability were tested. All measures were obtained immediately before GFC intake (baseline), and 2, 6, and 24 h later. RESULTS: GFC decreased the slope of the MEP intensity curve, increased paired-pulse short-interval intracortical inhibition, and decreased paired-pulse intracortical facilitation and I-wave facilitation. These effects were maximal at 2-6 h and returned to baseline at 24 h. Motor threshold, cortical silent period, and the measures of spinal (peripheral silent period, F waves) and neuromuscular excitability (maximum M wave) remained unaffected. CONCLUSIONS: This is the first study on the effects of an anti-noradrenergic drug on human motor cortex excitability. GFC reduced cortical excitability by disfacilitation and increased inhibition. These findings support the idea that anti-noradrenergic drugs are detrimental for cortical plasticity and learning which are down-regulated by disfacilitation or increased inhibition.     

Employment, medical absenteeism, and disability perception in Parkinson's disease: A pilot double-blind, randomized, placebo-controlled study of entacapone adjunctive therapy.

The objective of this study was to test the impact of entacapone (ENT) addition to levodopa with a decarboxylase inhibitor (LD) in full-time-employed patients with Parkinson's disease (PD), focusing on retirement rates, medical absenteeism, self-perception of disability, as well as motor assessments of parkinsonism, motor fluctuations, and dyskinesias. Thirty full-time-employed PD patients (disease onset before age 60 years) and on optimized monotherapy with LD exhibiting minor motor fluctuations or dyskinesias were entered into a 2-year randomized double-blind placebo-controlled study of ENT adjunctive therapy. The outcome measures were the number of full-time-employed patients at study end, cumulative days of medical absenteeism, patient-completed disability assessments, diary records, and the Unified Parkinson's Disease Rating Scale-based measures of motor fluctuations and dyskinesias. LD + ENT treatment was associated with a lower retirement rate (2 [17%] of 12 vs. 6 [50%] of 12; P = 0.12), lower absenteeism rate (21.5 vs. 43.5 days; P < 0.0001), improved self-perception of disability progression over 2 years (change score 1.0 vs. 4.5; P < 0.0001), and lower scores for both motor fluctuations and dyskinesia assessments compared to LD monotherapy. In this pilot study, LD with ENT adjunctive therapy positively influenced employment rate over 2 years; this effect was associated with reduced motor complications and patient perceptions of stabilized disability.     

小鼠背根神经节中三个不同的钙激活氯离子通道基因家族的表达(英文)

目的在背根神经节(dorsal root ganglion,DRG)中等大小感觉神经元中可以观察到钙激活氯离子流(I_(Cl(Ca)))。在坐骨神经损伤模型中,在大多数大中神经元上诱导出类似的氯离子流。本文旨在探讨引起这个离子流的分子基础。方法使用常规的定量RT-PCR方法检测在DRG中三个基因家族的表达,这三个基因家族都具有诱导I_(Cl(Ca))的特点。结果在成年小鼠的DRG中,分别显示了在正常状态和坐骨神经损伤3天后CLCA,Bestrophin和Tweety基因家族成员的转录产物。结论mBestl和Tweety2可能在损伤诱导的DRG神经元I_(Cl(Ca))中发挥作用。     

Complex modulation of human motor cortex excitability by the specific serotonin re-uptake inhibitor sertraline

Monoamines are powerful modulators of cortical function. Serotonin has complex excitatory and inhibitory effects on animal cortex. Here, the effects of a single oral dose (100mg) of the selective serotonin re-uptake inhibitor sertraline on human motor cortex excitability were investigated in healthy subjects. Transcranial magnetic stimulation was used to test motor threshold, motor evoked potential intensity curve, cortical silent period, paired-pulse inhibition and facilitation and I-wave facilitation. Sertraline resulted in a steeper intensity curve and in depressed paired-pulse facilitation (PPF). All other measures and spinal and neuromuscular excitability remained unaffected. The steeper intensity curve points to an increased excitability of the cortico-spinal neurone, while the depressed PPF suggests an enhanced control of the cortico-spinal neurone by inhibitory interneurones. These features may improve the signal-to-noise ratio of output cells in human motor cortex.     

Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.     

Inpatient β-lactam test-dose protocol and antimicrobial stewardship in patients with a history of penicillin allergy

Background

Penicillin allergy is the most commonly reported drug allergy in hospitalized patients, resulting in increased second-line antibiotic use, nosocomial infections, and health care use. Given that most patients are not truly allergic, a safe strategy that empowers the admitting physician is needed.

Microwave Spectroscopy of Myocardial Ischemia and Infarction. 2. Biophysical Reconstruction

The proposed dielectrical relaxation model of the myocardium in the microwave spectrum has been verified both on test solutions and on normal canine myocardium. Furthermore, the model was utilized to reconstruct the changes in tissue properties (including myocardial bulk resistance and water content) following myocardial acute ischemia and chronic infarction. It was shown that the reconstructed myocardial resistance and water content correlate dynamically with the process of the development of acute myocardial ischemic injury. In chronic cases the reconstructed resistance and water content of infarcted myocardium are significantly different from that of normal myocardium: the resistance is lower and water content is higher than in normal myocardium. © 2000 Biomedical Engineering Society. PAC00: 8764-t, 8719Xx     

Species-Specific Differences in Organization of Orthopoxvirus Kelch-Like Proteins

Organization of orthopoxvirus proteins of the kelch superfamily and their genes were analyzed and compared. Complete genomic sequences of variola (VAR), monkeypox (MPV), vaccinia (VAC), and species-specific regions of cowpox (CPV) viruses were used in the work. Despite the multiplicity of kelch-like proteins in orthopoxviruses, their function is still vague. It has been discovered that the genes of orthopoxvirus kelch-like proteins are localized only to the terminal variable regions of the genome and display species-specific differences in the lengths of the proteins they potentially encode. All the genes belonging to kelch superfamily in the genome of VAR, which has the only host–the man, are mutationally destroyed. However, CPV, displaying the widest host range among orthopoxviruses, encode the most numerous set of kelch-like proteins. Weak homologies between kelch-like proteins of one virus were demonstrated as well as high homologies between isologues of different orthopoxvirus species. The comparison performed suggest that CPV virus is most ancient and may be considered as the ancestor of other orthopoxviruses pathogenic for humans.     

Variola and camelpox virus-specific sequences are part of a single large open reading frame identified in two German cowpox virus strains

A large open reading frame (ORF) has been identified in two German cowpox virus strains. The ORFs (5676 and 5679 nt, respectively) differ in 10 nucleotides, resulting in an amino acid homology of 99.8%. In searching GenBank nucleotide sequences (>90% identity) were present in several small ORFs in variola major, variola minor and camelpox virus genomes. Alignments revealed that these small ORFs are fragments of a large ORF. However, sequences of the ORF described here are entirely absent in the two cowpox virus reference strains. Databank analysis revealed amino acid identities (ranging from 25 to 39%) with so-called B22R-like poxviral proteins with unknown function encoded by several chordopoxviruses. Further sequencing of one cowpox virus strain under study identified an ORF (5790 nt) which displays high levels of nucleotide identity to ORFs present in several orthopoxvirus species. Taken together, the two cowpox viruses analyzed here contain one large ORF which is conserved within the genus Orthopoxvirus and a unique, more distantly related ORF of similar size, which is conserved in the subfamily Chordopoxvirinae.