Effects of theβ-adrenoceptor antagonists acebutolol and metoprolol on sleep pattern in normal subjects

Summary The effects of acute introduction and withdrawal of 2 new -adrenergic blockers, acebutolol and metoprolol, on sleep in normal subjects were investigated. Both the subjective effects of the drug and EEG sleep variables were determined during a baseline period with placebo and in relation to the drug. The results showed that neither drug had a significant effect on sleep pattern in normal subjects. However, a transient effect on certain sleep parameters was seen on the first night of drug administration, with complete return to baseline, on the following night without any evidence of rebound. Possible mechanisms to explain the central actions of -adrenergic blockers are briefly discussed.     

Molecular Characterization of Closely Related H6N2 Avian Influenza Viruses Isolated from Turkey,Egypt, and Uganda

Genetic analysis of circulating avian influenza viruses (AIVs) in wild birds at different geographical regions during the same period could improve our knowledge about virus transmission dynamics in natural hosts, virus evolution as well as zoonotic potential. Here, we report the genetic and molecular characterization of H6N2 influenza viruses isolated from migratory birds in Turkey, Egypt, and Uganda during 2017–2018. The Egyptian and Turkish isolates were genetically closer to each other than they were to the virus isolated from Uganda. Our results also suggest that multiple reassortment events were involved in the genesis of the isolated viruses. All viruses contained molecular markers previously associated with increased replication and/or pathogenicity in mammals. The results of this study indicate that H6N2 viruses carried by migratory birds on the West Asian/East African and Mediterranean/Black Sea flyways have the potential to transmit to mammals including humans. Additionally, adaptation markers in these viruses indicate the potential risk for poultry, which also increases the possibility of human exposure to these viruses.     

Pseudotumour cerebri presentation of systemic lupus erythematosus: more than an association

SIR, We describe a 22-yr-old female admitted with a 1-monthhistory of blurred vision. Five weeks prior to presentation,the patient started to experience headaches, diplopia and squintfollowed a week later by blurred vision. The headaches and diplopiagradually subsided, whereas her blurred vision worsened progressively.Prior to admission the patient was being treated with oral multivitamins,including B₁, B₆, B₁₂ and folic acid, for anaemia. On reviewof systems, the patient reported an itchy skin rash on the trunkand lower extremities. On physical examination, the patienthad severe haemorrhagic papilloedema,     

Nerve growth factor and enhancement of proliferation,invasion, and tumorigenicity of pancreatic cancer cells

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is overexpressed, and this overexpression is associated with increased perineural invasion. NGF has the potential to stimulate the growth of some pancreatic cancer cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase receptor A and mitogen-activated protein kinase activation; it is dependent on the expression levels of tyrosine kinase receptor A and p75 receptors. To determine whether cancer cell-derived NGF can participate in the regulation of pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were stably transfected with a full-length human beta-NGF expression vector. In vitro and in vivo growth characteristics were analyzed by proliferation assays and invasion assays and in a nude mouse tumor model. Stable transfection of NGF in PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in doubling times of up to 50%, and in an approximately twofold increase in anchorage-independent cell growth and cell invasion. Furthermore, stably transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These results suggest that NGF has the capacity to act in a paracrine and/or an autocrine manner in pancreatic cancer and that it enhances cancer cell growth and invasion in vivo, thereby contributing to the aggressiveness and poor prognosis of this disease.     

Practical application of patterned visual evoked responses in multiple sclerosis

Pattern reversal visual evoked potentials (VEP) were studied in a control group of 72 subjects and in 60 patients with multiple sclerosis. The recording system consisted of a visual stimulator for pattern production on a commercial TV connected to an EMG machine for displaying and averaging of the response. The normal values of latency, the upper limit of normality and right-left eye differences in our control group were compared with those given by different authors. Likewise a comparison of the positive VEP results in MS was carried out. The reasons for the variability of results were briefly discussed and the importance of control studies for each laboratory starting VEP recording was stressed. This test can easily be carried out in every clinical neurophysiological laboratory and it provides an excellent and rapid technique for the investigation of patients with suspected multiple sclerosis.     

Exercise reverses preamyloid oligomer and prolongs survival in alphaB-crystallin-based desmin-related cardiomyopathy

The R120G mutation in the small heat shock-like protein alphaB-crystallin (CryAB(R120G)) causes desmin-related myopathy (DRM), which is characterized by the formation of desmin- and CryAB-containing aggregates within muscle fibers. Mice with cardiac-specific overexpression of CryAB(R120G) develop cardiomyopathy at 3 months and die at 6-7 months from heart failure (HF). Previous studies showed that overexpression of CryAB(R120G) results in accumulation of preamyloid oligomer (PAO). PAO is considered to be the cytotoxic entity in many of the protein misfolding-based neurodegenerative diseases. On the basis of data from mouse models of neurodegenerative diseases showing that exercise or environmental enrichment reduces the amyloid oligomer level and improves cognitive ability, we hypothesized that CryAB(R120G)-induced DRM would also respond favorably to prolonged voluntary exercise, reducing HF symptoms and rescuing the mice from premature death. Six months of voluntary exercise in CryAB(R120G) animals resulted in 100% survival at a time when all unexercised mice had died. After 22 weeks of exercise, PAO levels were decreased by 47% compared with the unexercised CryAB(R120G) control mice (P = 0.00001). Although CryAB(R120G) expression led to decreased levels of the metallomembrane endopeptidase neprilysin, normal levels were maintained in the exercised CryAB(R120G) mice, and in vitro loss-of-function and gain-of-function experiments using adenovirus-infected cardiomyocytes confirmed the importance of neprilysin in ameliorating PAO accumulation. The data demonstrate that voluntary exercise slows the progression to HF in the CryAB(R120G) DRM model and that PAO accumulation is mediated, at least in part, by decreased neprilysin activity.     

Pore-Forming Proteins Share Structural and Functional Homology with Amyloid Oligomers

Degenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases are believed to be causally related to the accumulation of amyloid oligomers that exhibit a common structure and may be toxic by a common mechanism involving permeabilization of membranes. We discovered that amyloid oligomers and the pore-forming bacterial toxin, α-hemolysin (αHL), as well as human perforin from cytotoxic T lymphocytes, share a structural and functional homology at the level of their common reactivity with a conformation-dependent antibody that is specific for amyloid oligomers, A11. The αHL oligomeric pores and partially folded αHL protomer, but not the monomer αHL precursor reacts with A11 antibody. A11 antibody inhibits the hemolytic activity of αHL, indicating that the structural homology is functionally significant. Perforin oligomers were also recognized by A11. Amyloidogenic properties of αHL and perforin were confirmed spectroscopically and morphologically. These results indicate that pore forming proteins (PFP) and amyloid oligomers share structural homology and suggest that PFPs and amyloid oligomers share the same mechanism of membrane permeabilization.     

CNI-1493 inhibits Abeta production, plaque formation, and cognitive deterioration in an animal model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by neuronal atrophy caused by soluble amyloid beta protein (Abeta) peptide "oligomers" and a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. We show that CNI-1493, a tetravalent guanylhydrazone with established antiinflammatory properties, interferes with Abeta assembly and protects neuronal cells from the toxic effect of soluble Abeta oligomers. Administration of CNI-1493 to TgCRND8 mice overexpressing human amyloid precursor protein (APP) for a treatment period of 8 wk significantly reduced Abeta deposition. CNI-1493 treatment resulted in 70% reduction of amyloid plaque area in the cortex and 87% reduction in the hippocampus of these animals. Administration of CNI-1493 significantly improved memory performance in a cognition task compared with vehicle-treated mice. In vitro analysis of CNI-1493 on APP processing in an APP-overexpressing cell line revealed a significant dose-dependent decrease of total Abeta accumulation. This study indicates that the antiinflammatory agent CNI-1493 can ameliorate the pathophysiology and cognitive defects in a murine model of AD.