Mutation and loss of expression of ARID1A in uterine low-grade endometrioid carcinoma

ARID1A is a recently identified tumor suppressor gene that is mutated in approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas. The mutation is associated with loss of protein expression as assessed by immunohistochemistry. In this study, we evaluated ARID1A immunoreactivity in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas. Mutational analysis of ARID1A was carried out in selected cases. Immunoreactivity was not detected (corresponding to inactivation or mutation of ARID1A) in 36 (3.6%) of 995 tumors. Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. The other tumor that had a relatively high-frequency loss of ARID1A expression was gastric carcinoma (11%). Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. All mutations in endometrioid carcinomas were nonsense or insertion/deletion mutations, and tumors with ARID1A mutations showed complete loss or clonal loss of ARID1A expression. In conclusion, this study is the first large-scale analysis of a wide variety of carcinomas showing that uterine low-grade endometrioid carcinoma is the predominant tumor type harboring ARID1A mutations and frequent loss of ARID1A expression. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A.     

Effects of Propranolol on the Left Ventricular Volume of Normal Subjects During CT Coronary Angiography

Objective

The purpose of this study is to determine the effects of propranolol on the left ventricular (LV) volume during CT coronary angiography.

Materials and Methods

The LV volume of 252 normal Chinese subjects (126 subjects with propranolol medication and 126 age- and gender-matched Chinese subjects without medication) was estimated using 64 slices multi-detector CT (MDCT). The heart rate difference was analyzed by the logistic linear regression model with variables that included gender, age, body height, body weight, systolic blood pressure (SBP), diastolic blood pressure (DBP) and the dosage of propranolol. The following global LV functional parameters were calculated: the real-end diastolic volume (EDV), the real-end systolic volume (ESV) and the real-ejection fraction (EF).

Results

The female subjects had a greater decrease of heart rate after taking propranolol. The difference of heart rate was negatively correlated with the dosage of propranolol. The real-EDV, the real-ESV and the real-EF ranged from 48.1 to 109 mL/m², 6.1 to 57.1 mL/m² and 41% to 88%, respectively. There was no significant difference in the SBP and DBP between the groups without and with propranolol medication (123 ± 17 and 80 ± 10 mmHg; 120 ± 14 and 80 ± 11 mmHg, respectively). The real-EDV showed no significant difference between these two groups, but the real-ESV and real-EF showed significant differences between these two groups (69.4 ± 9.3 and 70.6 ± 8.9 mL/m²; 23.5 ± 5.7 and 25.6 ± 3.7 mL/m², 66.5 ± 5.1% and 63.5 ± 4.6%, respectively).

Conclusion

The difference of heart rate is significantly influenced by gender and the dosage of propranolol. Propranolol will also increase the ESV, which contributes to a decreased EF, while the SBP, DBP and EDV are not statistically changed.     

Elephantopus scaber inhibits lipopolysaccharide-induced liver injury by suppression of signaling pathways in rats

Elephantopus scaber (ES, Teng-Khia-U) has been traditionally used for the treatment of nephritis, pain, and fever; however, the direct evidence is lacking. We investigated the effect of ES on lipopolysaccharide (LPS) induced inflammation of BV-2 microglial cells and acute liver injury in Sprague-Dawley (SD) rats. Our results showed that ES reduced LPS-induced nitric oxide (NO), interleukin (IL)-1, IL-6, reactive oxygen species (ROS), and prostaglandin (PGE(2)) production in BV-2 cells. ES significantly decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in LPS-treated rats. Furthermore, the water extract, but not the ethanol extract, of ES dose-dependently inhibited LPS-induced JNK, p38 mitogen-activated protein kinases (MAPK), and slightly inhibited cyclooxygenase (COX-2) in BV-2 cells but decreased p38 MAPK and COX-2 expressions in the liver of LPS-treated rats. Taken together, these results indicate that the protective mechanism of ES involves an antioxidant effect and inhibition of p38 MAP kinase and COX-2 expressions in LPS-stressed acute hepatic injury in SD rats.     

Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases

Bisphosphonate drugs (e.g., Fosamax and Zometa) are thought to act primarily by inhibiting farnesyl diphosphate synthase (FPPS), resulting in decreased prenylation of small GTPases. Here, we show that some bisphosphonates can also inhibit geranylgeranyl diphosphate synthase (GGPPS), as well as undecaprenyl diphosphate synthase (UPPS), a cis-prenyltransferase of interest as a target for antibacterial therapy. Our results on GGPPS (10 structures) show that there are three bisphosphonate-binding sites, consisting of FPP or isopentenyl diphosphate substrate-binding sites together with a GGPP product- or inhibitor-binding site. In UPPS, there are a total of four binding sites (in five structures). These results are of general interest because they provide the first structures of GGPPS- and UPPS-inhibitor complexes, potentially important drug targets, in addition to revealing a remarkably broad spectrum of binding modes not seen in FPPS inhibition.     

Radiographic comparison of sagittal plane stability between cast and boots

BACKGROUND: The importance of postoperative stability when considering surgery on the foot and ankle cannot be overestimated. To our knowledge, no literature exists to describe the radiographic sagittal plane motion with varying types of immobilization devices. The purpose of this study was to evaluate the sagittal plane range of motion allowed in different types of boots in comparison to fiberglass cast treatment on normal human subjects. MATERIALS AND METHODS: Ten healthy volunteers without preexisting foot and ankle pathology were chosen for the study. Five types of immobilization were selected for testing, including 4 off-the-shelf braces and a fiberglass cast. Maximum dorsiflexion and maximum plantarflexion lateral radiographs were taken without any immobilization and in the fiberglass cast and all walkers. RESULTS: The mean range of motion in a fiberglass cast was 8.4 degrees (SD, 4.3 degrees); FP Foam Walker, 16 degrees (SD, 6.7 degrees); XP Pneumatic Walker, 15.4 degrees (SD, 5.6 degrees); Donjoy Max Walker, 19.1 degrees (5.4 degrees); and the SP Walker, 39 degrees (SD, 10.7 degrees). The cast was noted to have a significantly greater limitation of sagittal plane motion compared to all other forms of immobilization (p < 0.05). CONCLUSION: Sagittal plane motion is restricted significantly more with a fiberglass cast compared to the FP Foam Walker, and XP Pneumatic Walker, Donjoy Max Walker, and the SP Walker. Therefore, in patients whom maximum restriction of sagittal plane motion is required, use of a fiberglass cast offers superior control.     

Fresh osteochondral total ankle allograft transplantation for the treatment of ankle arthritis

BACKGROUND: Fresh osteochondral total ankle allograft transplantation has been reported in the literature with survival rates between 50% and 92% at 1- to 12-years followup. The goal of this study was to present the results of total ankle allografts from another institution. MATERIALS AND METHODS: Twenty-nine patients underwent osteochondral total ankle transplant at our institution between July 2003 and July 2005. The mean patient age was 41 years old and the mean followup duration was 2 years. RESULTS: At followup, 14 of the 29 transplants had been revised to a repeat ankle transplant, prosthetic total ankle arthroplasty, or bone block arthrodesis. In addition, 6 of the remaining 15 transplants were deemed to be radiographic failures due to allograft fracture, allograft collapse, or progressive loss of joint space. The remaining 9 allografts (31%) were considered successes. In comparing the success versus the failure group, patients who were older, who had a lower body-mass index, and who had minimal preoperative angular deformity did significantly better. CONCLUSION: This is the largest series of osteochondral total ankle allograft transplants reported in the literature to date. There is an extremely high rate of failure associated with this procedure, and we currently consider it only rarely in patients who are too young for ankle replacement, have excellent range of motion, low body mass index, normal radiographic alignment, and who refuse arthrodesis.