Metal binding drugs induce synthesis of four proteins in normal cells

The synthesis of four proteins in chick embryo cells in culture is induced by exposure to several metal binding drugs and several cations. We reported previously that two chelating agents, kethoxal bis(thiosemicarbazone) and disulfiram induce these proteins. We now extend these findings to include 8-hydroxyquinoline, ortho-phenanthroline, and thiosemicarbazide. The non-chelating analogues of these latter three compounds; 4-hydroxyquinoline, metaphenanthroline, and semicarbazide, do not induce. Other chelating agents, such as thenoyl trifluoroacetone, mercaptopyridine N-oxide, mercaptobenzothiazole, and methimazole induce. However, not all chelators induce since EDTA, penicillamine, α,α-dipyridyl, and several others are ineffective. Several cations, such as copper, zinc, cadmium, and mercuric ions induce, but cobalt, nickel, manganese, iron, lead, and platinum do not. The anions arsenite and arsenate induce, but bromide, dichromate, fluoride, metabisulfite, molybdate, nitrite, permanganate, phosphate, sulfite, and sulfate ions do not. The chelating agents that induce the proteins are ionophores for⁶⁴Cu. The chelating agents that do not induce, such as EDTA, penicillamine, and the nonchelating analogs of the inducers, are not ionophores for copper. Since arsenite induces but is not a copper ionophore, we hypothesize that the common mechanism for both these compounds and the inducing cations is an interaction with a sulfhydryl group site.     

新疆罗布泊小河墓地居民的口腔健康与饮食

小河墓地是新疆罗布泊地区一处重要的早期青铜时代墓地。本文主要对该墓地出土颅骨所附牙齿的磨耗程度及牙结石沉积状况进行了观察、量化统计和分析,同时也对该人群其他的口腔疾病如根尖脓肿、颞下颌关节病变、生前牙齿脱落等做了简单的统计,以期从古病理学的角度获取当时居民的口腔健康、食物类型和饮食习惯等信息。本研究发现:1)小河人群的牙齿磨耗程度远远高于对比组的古代居民,其上腭圆枕及颞下颌关节炎出现率较高,存在牙齿崩裂现象,且其前后部牙齿磨耗差异不大。这一方面说明其食物加工技术比较落后,食物粗糙坚硬;另一方面小河居民的经济生活方式和食物构成都比较复杂,不同的食物对前部和后部牙齿磨耗的程度造成了不同的影响;此外,小河人群风沙肆虐的生活环境也对其严重牙齿磨耗的形成产生了一定影响。2)小河人群异常严重的牙结石沉积归功于其高蛋白质和碳水化合物的饮食,以及生活用水的水质。3)统计分析发现两性存在上、下颌犬齿的磨耗差异,而这一情况可能暗示了在家庭手工业方面存在男女分工的现象。     

Validation of a Rapid Rabies Diagnostic Tool for Field Surveillance in Developing Countries

BackgroundOne root cause of the neglect of rabies is the lack of adequate diagnostic tests in the context of low income countries. A rapid, performance friendly and low cost method to detect rabies virus (RABV) in brain samples will contribute positively to surveillance and consequently to accurate data reporting, which is presently missing in the majority of rabies endemic countries.Conclusion/SignificanceThe RIDT shows excellent performance qualities both in regard to user friendliness and reliability of the result. In addition, the test cassettes can be used as a vehicle to ship viral RNA to reference laboratories for further laboratory confirmation of the diagnosis and for epidemiological investigations using nucleotide sequencing. The potential for satisfactory use in remote locations is therefore very high to improve the global knowledge of rabies epidemiology. However, we suggest some changes to the protocol, as well as careful further validation, before promotion and wider use.     

Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial

BackgroundTKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated.ConclusionsAdministration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls.

Trial registration

Pan African Clinical Trials Registry PACTR201501000997429     

Nitric oxide regulation of gene transcription via soluble guanylate cyclase and type I cGMP-dependent protein kinase

Nitric oxide (NO) regulates the expression of multiple genes but in most cases its precise mechanism of action is unclear. We used baby hamster kidney (BHK) cells, which have very low soluble guanylate cyclase and cGMP-dependent protein kinase (G-kinase) activity, and CS-54 arterial smooth muscle cells, which express these two enzymes, to study NO regulation of the human fos promoter. The NO-releasing agent Deta-NONOate (ethanamine-2,2'-(hydroxynitrosohydrazone)bis-) had no effect on a chloramphenicol acetyltransferase (CAT) reporter gene under control of the fos promoter in BHK cells transfected with an empty vector or in cells transfected with a G-kinase Ibeta expression vector. In BHK cells transfected with expression vectors for guanylate cyclase, Deta-NONOate markedly increased the intracellular cGMP concentration and caused a small (2-fold) increase in CAT activity; the increased CAT activity appeared to be from cGMP activation of cAMP-dependent protein kinase. In BHK cells co-transfected with guanylate cyclase and G-kinase expression vectors, CAT activity was increased 5-fold in the absence of Deta-NONOate and 7-fold in the presence of Deta-NONOate. Stimulation of CAT activity in the absence of Deta-NONOate appeared to be largely from endogenous NO since we found that: (i) BHK cells produced high amounts of NO; (ii) CAT activity was partially inhibited by a NO synthase inhibitor; and (iii) the inhibition by the NO synthase inhibitor was reversed by exogenous NO. In CS-54 cells, we found that NO increased fos promoter activity and that the increase was prevented by a guanylate cyclase inhibitor. In summary, we found that NO activates the fos promoter by a guanylate cyclase- and G-kinase-dependent mechanism.     

DNA vaccination breaks tolerance for a neo-self antigen in liver: a transgenic murine model of autoimmune hepatitis

Understanding the pathogenesis of autoimmune hepatitis requires an animal model in which chronic progressive immune injury develops spontaneously or with minimal manipulations. The new transgenic mouse model proposed in this study is based on the hypothesis that infectious agents have the potential to initiate autoreactivity through molecular mimicry. A transgenic mouse expressing lymphocytic choriomeningitis virus nucleoprotein (NP) in a H-2(b) background developed liver injury when vaccinated with plasmids expressing NP as an intracellular or a secretory protein. Coinjection of plasmids coding for NP and IL-12 facilitated the induction of a Th1 phenotype as detected by a specific B lymphocyte response characterized by a predominance of IgG2 subclass anti-NP Abs. CTLs activated in peripheral lymphoid organs by DNA vaccination migrated to the periportal and lobular areas of the liver. Their presence was associated with a significant degree of cytolysis, as evidenced by elevated transaminases several weeks after immunization. As activated specific T lymphocytes proliferated in the periphery and caused cytolysis of target cells, this study suggests that autoimmune hepatitis can be triggered by molecular mimicry, and that local injury may not be essential to initiate autoreactivity in the liver.     

Spatial heterogeneity of the restitution portrait in rabbit epicardium

Spatial heterogeneity of repolarization can provide a substrate for reentry to occur in myocardium. This heterogeneity may result from spatial differences in action potential duration (APD) restitution. The restitution portrait (RP) measures many aspects of rate-dependent restitution: the dynamic restitution curve (RC), S1-S2 RC, and short-term memory response. We used the RP to characterize epicardial patterns of spatial heterogeneity of restitution that were repeatable across animals. New Zealand White rabbit ventricles were paced from the epicardial apex, midventricle, or base, and optical action potentials were recorded from the same three regions. A perturbed downsweep pacing protocol was applied that measured the RP over a range of cycle lengths from 1,000 to 140 ms. The time constant of short-term memory measured close to the stimulus was dependent on location. In the midventricle the mean time constant was 19.1 +/- 1.1 s, but it was 39% longer at the apex (P < 0.01) and 23% longer at the base (P = 0.03). The S1-S2 RC slope was dependent on pacing site (P = 0.015), with steeper slope when pacing from the apex than from the base. There were no significant repeatable spatial patterns in steady-state APD at all cycle lengths or in dynamic RC slope. These results indicate that transient patterns of epicardial heterogeneity of APD may occur after a change in pacing rate. Thus it may affect cardiac electrical stability at the onset of a tachycardia or during a series of ectopic beats. Differences in restitution with respect to pacing site suggest that vulnerability may be affected by the location of reentry or ectopic foci.