Combination Treatment with Ethyl Pyruvate and Aspirin Enhances Neuroprotection in the Postischemic Brain

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to act as an anti-inflammatory molecule in various pathological conditions, which include sepsis or hemorrhagic shock. Recently, we showed that ethyl pyruvate has a neuroprotective effect in the postischemic brain and also in KA-induced pathogenesis in the brain. In this study, we examined whether aspirin augments neuroprotective effect of ethyl pyruvate in transient focal ischemia model by complementing the neuroprotective effects of ethyl pyruvate. Although, most of neuroprotective effect of aspirin has been attributed to the anti-platelet action, aspirin also has direct neuroprotective effects, including NF-κB inhibition. Ethyl pyruvate dose-dependently suppressed infarct formation in the postischemic brain, wherein intravenous administration of 5 mg/kg ethyl pyruvate 30 min after the occlusion reduced infarct volume to 34.5 ± 15.5% (n = 6, P < 0.01) of that of the untreated control. In combination with aspirin (5 mg/kg, i.v.), the neuroprotective effect was enhanced, resulting in 16.0 ± 5.9% (n = 6, P < 0.01) infarct volume. The time window for synergistic neuroprotection by ethyl pyruvate and aspirin extended to 9 h post-MCAO. The synergistic reduction in infarct volume was accompanied by suppression of the clinical manifestations associated with cerebral ischemia including motor impairment and neurological deficits. Inflammatory processes including microglial activation and proinflammatory cytokine expression were notably suppressed by the combination treatment in the postischemic brain and in primary microglia cultures, wherein ethyl pyruvate and aspirin modulate NF-κB signaling differentially. Aspirin interferes with IκB phosphorylation and degradation in the cytoplasm, possibly by specifically inhibiting IκB kinase-beta, whereas, the effect of ethyl pyruvate seems to occur in the nucleus, where it may interfere with the binding of NF-κB to responsive promoter elements in the target genes. Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn²⁺ treatment or oxygen–glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-κB signaling pathway.     

Change in cross‐sectional area of esophageal muscle does not correlate with the outcome of achalasia after pneumatic balloon dilatation

Background and Aim: Patients with achalasia have a thicker muscularis propria compared to normal patients. Because pneumatic balloon dilatation (PD) is an effective treatment for achalasia, the changes in the esophageal muscles after PD may predict treatment outcomes, if muscular change is of primary importance. In the present study, we aimed to observe the changes in esophageal muscle thickness following PD and assessed whether symptom relapse can be predicted on the basis of the esophageal muscle cross‐sectional area (CSA), as measured by high‐frequency intraluminal ultrasound (HFIUS). Methods: Fifteen patients treated by PD were studied and followed up for a median of 3.6 years. An HFIUS was done before PD and 6 months after PD. The esophageal muscle CSA measured at the lower esophageal sphincter (LES), and 3 and 6 cm above the LES, was used to see whether any association was present between symptom recurrence and the esophageal muscle CSA. Results: A single PD resulted in a 2‐year remission rate of 66%. A significance variance in change (?65%–248%) was noticed in the muscle CSA after PD. The predilation muscle CSA, post‐dilation muscle CSA, and change in the muscle CSA after PD was not associated with symptom recurrence. Conclusion: Our findings suggest that measuring the muscle CSA does not help to predict treatment outcome. Muscular changes in achalasia might be just reactive changes.     

A case of closed reduction through metaphyseal window for a pilon fracture

A 52-year-old man presented with painful swelling of his left ankle after a fall from a ladder. The radiograph revealed fractures of the medial and lateral malleoli and a pilon fracture. The lateral portion of the plafond was broken, and the fractured bone fragment was impacted into the metaphysis. The fractured bone fragment was gently tapped through a metaphyseal window to be reduced into the anatomical position, and the joint surface was restored. The channel through which the impactor was introduced was grafted with an autogenous iliac bone graft. The fractured medial and lateral malleoli were stabilized with tension band wiring and plating. The unstable syndesmosis of the ankle mortise was fixed with a transfixation screw. At 6 months after surgery, the motion arc of the ankle ranged from dorsiflexion 20 to plantar flexion 30, and there were minimal difficulties in the activities of daily living. This paper reports a technique for treating a pilon fracture involving the lateral side of the plafond with intact anterior and posterior cortices by a closed reduction through the metaphyseal window. The precarious soft tissue around the ankle joint after a pilon fracture could be spared from additional surgical injury, and the saved soft tissue envelope around the injury could facilitate fracture healing.     

Expression of mitotic checkpoint proteins BUB1B and MAD2L1 in salivary duct carcinomas

J Oral Pathol Med (2010) 39 : 349–355 Objective: Defects in the mitotic checkpoint lead to aneuploidy and might facilitate tumorigenesis. However, the ploidy status in salivary duct carcinoma (SDC) has been reported to play limited role in prediction of prognosis. Thus, we need more reliable markers to reflect the rapid tumor progression in SDCs. We aimed here to investigate the expression of mitotic checkpoint proteins benzimidazole 1 homolog beta (BUB1B) and mitosis arrest‐deficient 2 like 1 (MAD2L1) in SDCs and to determine their possible role as surrogate prognostic markers. Methods: We analyzed the clinical courses, pathologic findings and immunohistochemical profiles of mitotic checkpoint proteins (BUB1B and MAD2L1) in 27 pathologically confirmed SDCs. The expression status of BUB1B and MAD2L1 was compared with clinicopathologic factors and other molecular markers, such as TGF‐beta, c‐erb‐B2, androgen receptor, vascular endothelial growth factor, and epidermal growth factor receptor, for prognostic significance. Results: High BUB1B expression was detected in 25.9% of subjects, and high MAD2L1 expression was in 55.6% of subjects. However, survival analysis revealed that mitotic checkpoint expression did not have prognostic significance in SDCs, nor did the other studied markers. Rather, the clinical variable of N classification at diagnosis (in N+ status, hazard ratio 5.19, 95% CI 1.26–21.32 for disease‐free survival and hazard ratio 7.18, 95% CI 1.09–46.99 for overall survival) was strongly associated with survival and prognosis based on the Cox proportional hazard model. Conclusions: Mitotic checkpoint proteins appeared to play a limited role in predicting prognosis in SDCs. Further study is required to elucidate the exact role of mitotic checkpoint proteins in SDCs.