Membrane depolarization is the initial action of crotoxin on isolated murine skeletal muscle.

Although much is known about the pathogenesis of crotoxin-induced muscle damage, the initial site and action of the toxin is still not clear. In this study we used an electrochromic fluorescent dye, Di-4-ANEPPS, to measure the changes in membrane potential of isolated murine omohyoid muscle to determine if depolarization could be one of the initial effects of crotoxin. Omohyoid isolates were pre-loaded with 1 microM Di-4-ANEPPS, exposed to various crotoxin treatments, and the change in fluorescence was recorded using either a dual-wavelength spectrofluorometer or digital imaging. Spectrofluorometry indicated that crotoxin depolarized isolated omohyoid muscles within 4 min as indicated by an increase in fluorescence to 122% of control values. Crotoxin also induced depolarization of extensor digitorum longus and soleus muscles as indicated by an increase in fluorescence of 140 and 110% of the control, respectively. Fluorescent images obtained from omohyoid muscle preparations exposed to crotoxin and Di-4-ANEPPS revealed localized areas of increased fluorescence, muscle contractions, derangement of myofibrils, and differing sensitivity to crotoxin of different muscle cells. Light microscopy results confirmed this variable disruption of muscle cell integrity and differing sensitivity to crotoxin. An increase in creatine kinase release rates confirmed damage to the plasma membrane. We conclude that plasma membrane depolarization is most likely the earliest indicator of cell damage from crotoxin and is quickly followed by hypercontraction of myofilaments, disruption of the plasma membrane, release of creatine kinase and necrosis.     

Antibacterial activity and inhibition against Staphylococcus aureus NorA efflux pump by ferulic acid and its esterified derivatives

Objective: To evaluate the inhibitory activity of ferulic acid and four of its esterified derivatives (methyl, ethyl, propyl, and butyl) against resistance mech...     

An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy

BACKGROUND/AIMS: To determine the potential of an intravitreal sustained release naproxen and 5-fluorouracil (NA/5-FU) codrug for the treatment of experimental proliferative vitreoretinopathy (PVR) in a model for trauma associated tractional retinal detachment (TRD). METHODS: Sustained release pellets were prepared by covalently linking naproxen to 5-fluorouracil. Drug release was tested in vitro and toxic effects were evaluated by electroretinography and light microscopy. Traumatic PVR was induced in pigmented rabbits by performing a scleral laceration, followed by repair and intravitreal injection of 0.4 ml of autologous blood. Thirty six eyes were treated with a sustained release implant containing 1.5 mg NA/5-FU as a codrug and 36 control eyes were submitted to surgery alone. Eyes were evaluated for TRD by serial indirect ophthalmoscope examination at different time points followed by postmortem fundus evaluation of the enucleated eye RESULTS: The NA/5-FU pellets were found to provide linear release of 5-FU and naproxen over the 30 day duration of the in vitro release test. Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly lower in eyes treated with the codrug pellet. There were no drug related toxic effects evident on histopathological or electroretinograph examination of eyes containing the NA/5-FU pellet. CONCLUSIONS: The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted.     

Distinct histopathological phenotypes of severe alcoholic hepatitis suggest different mechanisms driving liver injury and failure

Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neu^hi), but low levels of CD8⁺ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neu^hi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.     

头皮糠疹与巯氧吡啶锌

头皮糠疹是常见病是多发病,临床表现为头皮红斑和脱屑,提示皮损部位表皮结构和功能异常,头皮角质层代谢紊乱,最近对头皮糠疹病因和病理的研究证实马拉色菌,皮脂分泌和个体敏感性是形成上述皮损的3个关键因素,硫氧吡啶锌（PTZ或ZPT）可以有效地杀灭马拉色菌,PTZ的颗粒大小和形状对其在头皮的生物利用度有明显的影响。此外,PTZ的抗菌效果有赖于其分子结构的完整性,在外用制剂中加入附加的游离锌,可以有效防止PTZ解离,从而提高其疗效。