Sirt5 is known to functionally regulate mitochondrial proteins by altering posttranslational modifications, including lysine desuccinylation. While roles for Sirt5 as either a tumor promoter or suppressor, or in chemoresistance, have been implicated in other cancers, the function of Sirt5 in cutaneous melanoma has not been well examined. Therefore, to determine whether Sirt5 is necessary for BrafV600E‐mediated melanoma formation and/or disease progression, we crossed a genetically engineered murine melanoma model (TyrCreERT2/+; BrafLSL‐V600E/+; Ptenflox/flox) to Sirt5?/? knockout animals. In addition, we tested for synergism with a selective BRAF (V600E) inhibitor in Sirt5?/? mouse melanoma cells. Taken together, this report demonstrates that, in these models, Sirt5 is dispensable for BrafV600E‐mediated cutaneous melanoma formation and growth in vivo, and does not improve sensitivity to a selective BRAF inhibitor. 相似文献
Background Familial partial lipodystrophy (FPLD) is a monogenic form of diabetes characterised by a dominantly inherited disorder of adipose tissue associated with the loss of subcutaneous fat from the limbs and trunk, with excess fat deposited around the face and neck. The lipodystrophy causes severe insulin resistance, resulting in acanthosis nigricans, diabetes, dyslipidaemia, and increased risk of cardiovascular disease. Preliminary results from animals and man suggest that increasing subcutaneous fat by treatment with thiazolidinediones should improve insulin resistance and the associated features of this syndrome. Case report We report a 24-year-old patient with FPLD caused by a mutation in the LMNA gene (R482W) treated with 12 months of rosiglitazone. Subcutaneous fat increased following rosiglitazone treatment as demonstrated by a 29% generalised increase in skin-fold thickness. Leptin levels increased from 5.8 to 11.2 ng/ml. Compared with treatment on Metformin, there was an increase in insulin sensitivity (HOMA S% 17.2–31.6) but no change in glycaemic control. The lipid profile worsened during the follow-up period. Conclusion This initial case suggests that, for modification of cardiovascular risk factors, there are no clear advantages in treating patients with FPLD with rosiglitazone despite increases in subcutaneous adipose tissue. Larger series will be needed to identify moderate beneficial effects and treatment may be more effective in patients with generalised forms of lipodystrophy. 相似文献
STUDY OBJECTIVES: Use of fast track has been shown to improve the emergency department flow of less urgent patients. It has been speculated, however, that this could negatively affect the care of urgent patients. The objective of this study was to determine whether a dedicated fast track for less urgent patients [Canadian Triage and Acuity scale category 4/5 (CTAS 4/5)] affected (1) the time to assessment for urgent patients (CTAS 3), (2) the length of stay for less urgent patients (CTAS 4 and 5), and (3) the left-without-being-seen rate. METHODS: In June 2003, fast track was opened in our emergency department from 13:00 to 19:00 h. A before-after intervention comparison analysis was completed for 1 week in Aug 2002 and the same week in Aug 2003. Data collected included (1) time to assessment of CTAS 3 patients, (2) the length of stay for CTAS 4/5 patients, and (3) percentage of patients who left without being seen. RESULTS: A total of 368 patients were reviewed for 2002 and 380 patients were reviewed for 2003. Median time to assessment of CTAS 3 patients presenting from 13:00 to 19:00 h was reduced from 66 min (Interquartile range: 40, 94 min) in 2002 to 60 min (IQR: 38, 108 min) after fast track was open in 2003 (P = 0.95). Median length of stay of CTAS 4 and 5 patients was reduced from 170 min (IQR: 111, 256 min) to 110 min (IQR: 69, 185 min) (P < 0.001). The overall left-without-being-seen rate decreased from 5% (20/368) to 2% (9/380). CONCLUSION: A dedicated fast track for CTAS 4/5 patients can reduce the length of stay and the left-without-being-seen rate with no impact on CTAS 3 patients seen in the main emergency department. 相似文献
Background: Previous studies have shown that propofol and sevoflurane enhance the function of [gamma]-aminobutyric acid type A (GABAA) receptors. However, it is not known whether these two drugs modulate the same molecular pathways. In addition, little is known about receptor function in the presence of both propofol and sevoflurane. The aim of this study was to better understand the interactions of propofol and sevoflurane with the GABAA receptor.
Methods: Wild-type [alpha]1, [beta]2, [gamma]2s GABAA receptor subunit complementary DNAs were transfected into human embryonic kidney cells grown on glass coverslips using a calcium phosphate transfection method. After transfection (36-72 h), cells were whole cell patch clamped and exposed to combinations of the following: 0.3-1,000 [mu]m [gamma]-aminobutyric acid (GABA), 0-10 [mu]m propofol, and 0-1,650 [mu]m sevoflurane. Chemicals were delivered to the cells using two 10-channel infusion pumps and a rapid solution exchanger.
Results: Both propofol and sevoflurane alone enhanced the amplitude of GABAA receptor responses to submaximal concentrations of GABA in a dose-dependent manner. The enhancement was underpinned by an increase in the apparent affinity of the receptor for GABA. Coapplication of both anesthetics further enhanced the apparent affinity of the receptor for GABA. 相似文献
A 72-year-old man presented with a short duration of symptoms relating to a right fronto-parietal glioblastoma and a family history of children with brain tumours. Analysis of the patient's family tree revealed that out of seven children, he had a living son with anaplastic astrocytoma, a daughter who had died with a glioblastoma, and a son who had died with a histologically undiagnosed intrinsic brain tumour. One niece was also thought to have died from a brain tumour. All of the other affected family members had onset in their third or fourth decades. Tissue was only available from two of the affected individuals, precluding familial genetic analysis at this stage. There is no clinical evidence to support a diagnosis of a multiple cancer or neurocutaneous syndrome in this family. In view of what is known about the genetics of familial glioma, it is interesting to note the clinical evidence of both 'primary' glioblastoma and anaplastic astrocytoma in the same kindred. 相似文献
The authors discuss techniques for Monte Carlo (MC) cohort simulations that reduce the number of simulation replications required to achieve a given degree of precision for various output measures. Known as variance reduction techniques, they are often used in industrial engineering and operations research models, but they are seldom used in medical models. However, most MC cohort simulations are well suited to the implementation of these techniques. The authors discuss the cost of implementation versus the benefit of reduced replications. 相似文献
OBJECTIVE: To study the effect of high-frequency (100 Hz) repetitive conditioning electrical stimulation (CES, 10 min) on human somatosensory evoked potentials (SEPs) to evaluate if short-term cortical plasticity could be induced. METHODS: Painful electrical stimulations were applied to thumb (D1) and little finger (D5) fingertips, respectively. The 124-channel EEG was recorded from 10 healthy male volunteers. Peak stages around 34, 45, 212, 331 ms were analyzed with focal maximum amplitude (FA) and area magnitude (AM) of scalp field potential, topography, and equivalent current dipole source localisation, comparing before and after two-level CES (high- vs. low-level) applied to the He-Gu acupoint. RESULTS: After a high-level CES, the positive FA and AM of the current efflux showed a significant increase at the early phase 34 ms, and significantly decreased at 45 ms in D1 SEPs. The negative FA and AM of the current influx were significantly increased at late phase 350 ms of the D5 SEPs. Only 36 ms, the z-axis position of dipole was significantly changed from (x: -15.9 mm, y: 29.6 mm, z: 43.9 mm) to (x: -12.9 mm, y: 29.4mm, z: 51.5mm) for the D5 SEPs. CONCLUSIONS: The high-level CES significantly attenuated the subsequent cortical activation (45 ms peak for D1 stimulation). Both low- and high-level CES significantly enhanced the late activities (226, 350 ms) in D5 stimulation. This may be explained by pain sensation change at the level of subcortical cingulate cortex induced by the site-dependent post-effect of CES. SIGNIFICANCE: This study showed cortical plasticity induced by conditioning somatosensory stimulation. 相似文献