Induction of p53-independent growth inhibition in lung carcinoma cell A549 by gypenosides.

The objectives of this study are to investigate antiproliferative effect and mechanisms of bioactive compounds from Gynostemma pentaphyllum (G. pentaphyllum) on lung carcinoma cell A549. Saponins, carotenoids and chlorophylls were extracted and fractionated by column chromatography, and were subjected to high-performance liquid chromatography-mass spectrometry analyses. The saponin fraction, which consisted mainly of gypenoside (Gyp) XXII and XXIII, rather than the carotenoid and chlorophyll ones, was effective in inhibiting A549 cell growth in a concentration- and a time-dependent manner as evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The estimated half maximal inhibitory concentration (IC50 ) of Gyp on A549 cells was 30.6 µg/ml. Gyp was further demonstrated to induce an apparent arrest of the A549 cell cycle at both the S phase and the G2/M phase, accompanied by a concentration- and a time-dependent increase in the proportions of both the early and late apoptotic cells. Furthermore, Gyp down-regulated cellular expression of cyclin A and B as well as BCL-2, while up-regulated the expression of BAX, DNA degradation factor 35 KD, poly [ADP-ribose] polymerase 1, p53, p21 and caspase-3. Nevertheless, both the treatment of a p53 inhibitor, pifithrin-α, and the small hairpin RNA-mediated p53 knockdown in the A549 cells did not alter the growth inhibition effect induced by Gyp. As a result, the cell cycle arrest and apoptosis of A549 cells induced by Gyp would most likely proceed through p53-independent pathway(s).

Use of robotic C-arm cone-beam computed tomography in surgical stabilization of rib fractures.

INTRODUCTION: The effectiveness of using intraoperative robotic C-arm cone-beam computerized tomography (CT) to locate rib fractures during surgery was compared to using pre-operative CT. METHODS: Patients diagnosed with multiple rib fracture and treated surgically in the hospital between January 2019 and September 2020 were included. The study included two groups of patients. One group had their rib fractures identified using pre-operative CT, while the other group had their fractures localized using intraoperative cone-beam CT during surgery. The operative time, blood loss, number of incisions, length of incision, duration of chest drains, visual analogue scale (VAS) score, and duration of post-operation stays were measured. RESULTS: A total of 12 patients received intraoperative cone-beam CT, while the remaining 18 patients only received pre-operative CT. Statistical analysis showed that the group treated with cone-beam CT had lower blood loss (p = 0.012), shorter incisions (p = 0.005), and better post-operation VAS scores (p = 0.027). There were also non-significant trends towards fewer incisions, shorter operation times, and shorter duration of chest drains in the group treated with cone-beam CT. CONCLUSIONS: Intraoperative localization of rib fracture sites with cone-beam CT is an effective method for rib fracture stabilization.

Prediction consistency and clinical presentations of breast cancer molecular subtypes for Han Chinese population.

BACKGROUND: Breast cancer is a heterogeneous disease in terms of transcriptional aberrations; moreover, microarray gene expression profiles had defined 5 molecular subtypes based on certain intrinsic genes. This study aimed to evaluate the prediction consistency of breast cancer molecular subtypes from 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) as well as clinical presentations of each molecualr subtype in Han Chinese population. METHODS: In all, 169 breast cancer samples (44 from Taiwan and 125 from China) of Han Chinese population were gathered, and the gene expression features corresponding to 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50) were retrieved for molecular subtype prediction. RESULTS: For Sørlie 500 and Hu 306 intrinsic gene set, mean-centring of genes and distance-weighted discrimination (DWD) remarkably reduced the number of unclassified cases. Regarding pairwise agreement, the highest predictive consistency was found between Hu 306 and PAM50. In all, 150 and 126 samples were assigned into identical subtypes by both Hu 306 and PAM50 genes, under mean-centring and DWD. Luminal B tended to show a higher nuclear grade and have more HER2 over-expression status than luminal A did. No basal-like breast tumours were ER positive, and most HER2-enriched breast tumours showed HER2 over-expression, whereas, only two-thirds of ER negativity/HER2 over-expression tumros were predicted as HER2-enriched molecular subtype. For 44 Taiwanese breast cancers with survival data, a better prognosis of luminal A than luminal B subtype in ER-postive breast cancers and a better prognosis of basal-like than HER2-enriched subtype in ER-negative breast cancers was observed. CONCLUSIONS: We suggest that the intrinsic signature Hu 306 or PAM50 be used for breast cancers in the Han Chinese population during molecular subtyping. For the prognostic value and decision making based on intrinsic subtypes, further prospective study with longer survival data is needed.

Psychometric comparison of the shortened Fugl-Meyer Assessment and the streamlined Wolf Motor Function Test in stroke rehabilitation.

OBJECTIVE: We aimed to compare the responsiveness, concurrent and predictive validity of the shortened Fugl-Meyer Assessment (S-FMA) and the streamlined Wolf Motor Function Test (S-WMFT) in persons with subacute stroke. DESIGN: Test-retest design. SETTING: Departments of physical medicine and rehabilitation at three hospitals. PARTICIPANTS: PARTICIPANTS with first-time stroke (N = 51; 38 men, 13 women; mean age ± SD, 55.1 ± 11.7 years) based on scores of Mini-Mental State Examination and Brunnstrom stage. INTERVENTIONS: PARTICIPANTS received one of three rehabilitation therapies for three weeks and were evaluated at baseline and end of treatment. MAIN OUTCOME MEASURES: Responsiveness was examined using the paired t-test and the standardized response mean (SRM). Criterion validity was investigated using the Pearson's correlation coefficient (r). RESULTS: Changes from baseline to end of treatment assessed by both tests were significant (P < 0.001). The value for responsiveness of the S-FMA was significantly higher than that of the S-WMFT (SRM difference, 0.48; 95% confidence interval, 0.23-0.63). There were stronger associations between the comparison scales and the S-FMA (r = 0.57-0.68) than with the S-WMFT (r = 0.39-0.58). CONCLUSIONS: The S-FMA had better concurrent and predictive validity than the S-WMFT and was more sensitive to changes caused by rehabilitation therapies. The S-FMA is recommended for expedited assessment of arm motor function outcome in stroke patients receiving rehabilitative therapy.

FJU-C28 inhibits the endotoxin-induced pro-inflammatory cytokines expression via suppressing JNK, p38 MAPK and NF-κB signaling pathways.

Despite marked improvements in supportive care, the mortality rate of acute respiratory distress syndrome due to the excessive inflammatory response caused by direct or indirect lung injury induced by viral or bacterial infection is still high. In this study, we explored the anti-inflammatory effect of FJU-C28, a new 2-pyridone-based synthetic compound, on lipopolysaccharide (LPS)-induced inflammation in vitro and in vivo models. FJU-C28 suppressed the LPS-induced mRNA and protein expression of iNOS, COX2 and proinflammatory cytokines. The cytokine protein array results showed that LPS stimulation enhanced the secretion of IL-10, IL-6, GCSF, Eotaxin, TNFα, IL-17, IL-1ß, Leptin, sTNF RII, and RANTES. Conversely, the LPS-induced secretion of RANTES, TIMP1, IL-6, and IL-10 was dramatically suppressed by FJU-C28. FJU-C28 suppressed the LPS-induced expression of RANTES, but its parental compound FJU-C4 was unable to diminish RANTES in cell culture media or cell lysates. FJU-C28 blocked the secretion of IL-6 and RANTES in LPS-activated macrophages by regulating the activation of JNK, p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). FJU-C28 prevented the LPS-induced decreases in lung function including vital capacity (VC), lung compliance (C chord), forced expiratory volume at 100 ms (FEV100), and forced vital capacity (FVC) in mice with LPS-induced systemic inflammatory responses. FJU-C28 also reduced neutrophil infiltration in the interstitium, lung damage and circulating levels of IL-6 and RANTES in mice with systemic inflammation. In conclusion, these findings suggest that FJU-C28 possesses anti-inflammatory activities to prevent endotoxin-induced lung function decrease and lung damages by down-regulating proinflammatory cytokines including IL-6 and RANTES via suppressing the JNK, p38 MAPK and NF-κB signaling pathways.

Prognostic factors of postrecurrence survival in completely resected stage I non-small cell lung cancer with distant metastasis.

OBJECTIVE: Distant metastasis after surgical resection is the most frequent cause of death in patients with non-small cell lung cancer (NSCLC). This study aimed to investigate the patterns of distant metastasis and the prognostic factors of postrecurrence survival in patients with resected stage I NSCLC with distant metastases. METHODS: The clinicopathological characteristics of 166 patients with distant metastases after complete resection of stage I NSCLC at Taipei Veterans General Hospital between 1980 and 2000 were retrospectively reviewed. The patients were divided into two groups according to patterns of distant metastasis (single or multiple organ metastases). Predictors of postrecurrence survival were analysed. RESULTS: The patterns of distant metastasis included single organ metastasis in 106 (63.9%) and multiple organ metastases in 60 (36.1%) patients. The 1- and 2-year postrecurrence survival rates for those with single organ metastasis were 30.2% and 15.1%, respectively. The most common site of single organ metastasis was bone (32.1%), followed by the brain (29.2%). Multivariate analysis revealed that disease-free interval >16 months (HR 0.534; 95% CI 0.288 to 0.990; p=0.046) and treatment for distant metastasis (including re-operation, chemotherapy and/or radiotherapy) (HR 0.245; 95% CI 0.089 to 0.673; p=0.006) were significant predictors of better postrecurrence survival in resected stage I NSCLC with single organ metastasis. CONCLUSIONS: A longer disease-free interval is a favourable prognostic predictor for postrecurrence survival in resected stage I NSCLC with single organ metastasis. Treatment for distant metastasis significantly prolongs postrecurrence survival.

Responsiveness and validity of three outcome measures of motor function after stroke rehabilitation.

BACKGROUND AND PURPOSE: This study investigated and compared the responsiveness and validity of the Fugl-Meyer Assessment (FMA), the Action Research Arm Test (ARAT), and the Wolf Motor Function Test (WMFT) for patients after stroke rehabilitation. METHODS: A total of 57 patients with stroke received 1 of 3 rehabilitation treatments for 3 weeks. At pretreatment and posttreatment, the 3 outcome measures, as well as the Functional Independence Measure (FIM) as the external criterion, were administered. The standardized response mean (SRM) and the Wilcoxon signed rank test were used to examine the responsiveness. Construct validity and predictive validity were examined by the Spearman correlation coefficient (rho). RESULTS: The responsiveness of the FMA, ARAT, and WMFT functional ability scores was large (SRM=0.95-1.42), whereas the WMFT performance time score was small (SRM=0.38). The responsiveness of the FMA was significantly larger than those of the ARAT and the WMFT-TIME, but not the WMFT functional ability scores. With respect to construct validity, correlations between the FMA and other measures were relatively high (rho=0.42-0.76). The FMA and the WMFT performance time scores at pretreatment had moderate predictive validity with the FIM scores at posttreatment (rho=0.42-0.47). In addition, the ARAT and the WMFT functional ability scores revealed a low predictive validity with the FIM (rho=0.17-0.26). CONCLUSIONS: The results support the FMA and the WMFT-FAS are suitable to detect changes over time for patients after stroke rehabilitation. While simultaneously considering the responsiveness and validity attributes, the FMA may be a relatively sound measure of motor function for stroke patients based on our results. Further research based on a larger sample is needed to replicate the findings.

Constraint-induced therapy versus dose-matched control intervention to improve motor ability, basic/extended daily functions, and quality of life in stroke.

BACKGROUND: Trials of constraint-induced movement therapy (CIT) to improve upper extremity function after stroke have usually not included an actively treated control group. OBJECTIVE: This study compared a modified CIT intervention with a dose-matched control intervention that included restraint of the less affected hand and assessed for differences in motor and functional performance and health-related quality of life. METHODS: This 2-group randomized controlled trial, using pretreatment and posttreatment measures, enrolled 32 patients within 6 to 40 months after onset of a first stroke (mean age, 55.7 years). They received either CIT (restraint of the less affected limb combined with intensive training of the affected limb for 2 hours daily 5 days per week for 3 weeks and restraint of the less affected hand for 5 hours outside of the rehabilitation training) or a conventional intervention with hand restraint for the same duration. Outcome measures were the Fugl-Meyer Assessment, Functional Independence Measure, Motor Activity Log, Nottingham Extended Activities of Daily Living Scale, and Stroke Impact Scale. RESULTS: Compared with the control group, the CIT group exhibited significantly better performance in motor function, level of functional independence, mobility of extended activities during daily life, and health-related quality of life after treatment. CONCLUSIONS: The robust effects of this form of CIT were demonstrated in various aspects of outcome, including motor function, basic and extended functional ability, and quality of life.

Minimal detectable change and clinically important difference of the Wolf Motor Function Test in stroke patients.

OBJECTIVES: This study aimed to establish the minimal detectable change (MDC) and clinically important differences (CID) of the Wolf Motor Function Test (WMFT) in patients with stroke, and to assess the proportions of patients' change scores exceeding the MDC and CID after stroke rehabilitation. METHODS: A total of 57 patients received 1 of the 3 treatments for 3 weeks and underwent clinical assessments before and after treatment. The MDC, at 90% confidence (MDC( 90)), was calculated from the standard error of measurement to indicate a real change for individual patients. Anchor-based and distribution-based approaches were used to triangulate the values of minimal CID. The percentages of patients exceeding the MDC and minimal CID were also examined. RESULTS: The MDC(90) of the WMFT was 4.36 for the performance time (WMFT time) and 0.37 for the functional ability scale (WMFT FAS). The minimal CID ranged from 1.5 to 2 seconds on the WMFT time and from 0.2 to 0.4 points on the WMFT FAS. The MDC and CID proportions ranged from 14% to 30% on the WMFT time and from 39% to 65% on the WMFT FAS, respectively. CONCLUSIONS: The change score of an individual patient has to reach 4.36 and 0.37 on the WMFT time and WMFT FAS to indicate a real change. The mean change scores of a stroke group on the WMFT time and WMFT FAS should achieve 1.5 to 2 seconds and 0.2 to 0.4 points to be regarded as clinically important changes. Furthermore, the WMFT FAS may be more responsive than the WMFT time based on the results of proportions exceeding the threshold criteria.

System approach to prevent common bile duct injury and enhance performance of laparoscopic cholecystectomy.

Experience collected from 5200 cases of laparoscopic cholecystectomy (LC) and 29 patients (6 ours, 23 referred) with major common bile duct (CBD) injury during LC in our institute between December 1990 and July 2004 was reported to demonstrate that the system approach we applied in performing LC prevents CBD injury and enhances surgical performance. Each case of CBD injury was meticulously analyzed to identify causative factors. We developed preventive strategies focusing on 4 dimensions: patient, environment, procedure, and operator. Surgical performance was then evaluated to demonstrate improvements. Incidence of CBD injury was calculated for early and latter halves of the series to compare 5 parameters of surgical performance: patient selection, operation time, indwelling drainage tube, surgeon, and conversion rate. Results of accident analysis demonstrated that CBD injury followed definite mechanisms; several warning signs appearing before and during injury were identified and classified. According to these results, we designed strategies to prevent injury, including: setting up patient-selection program, controlling surgical environment, developing error-proof procedures, and constructing training programs. Incidence of CBD injury in the whole series was 0.12% (6/5200), 0.27% in early half (6/2224), and zero (0/2967) in latter half. Attending doctors had significantly shorter operation times in latter period for both elective and emergent LC. Rate of using drainage tubes for elective surgery by attending doctors was significantly decreased in latter period. Operation time for elective surgery by residents was similar in both early and latter periods. However, residents in latter period had longer operation times (around 23 min long, P<0.001) for emergent LC. Steps of our system approach include: (1) detailed accident analysis focusing on patient, environment, procedure, and surgeon; (2) developing 4 strategies directly responding to accident analysis results, including proper patient selection, control of environment, error-proof procedures, and a well-designed training program; and (3) demonstrating improved patient safety and surgical performance. Consistent use of systems approach promises continuing quality improvement. We believe our working model will help perform safer LC and also benefit other medical disciplines.

Estrogen receptor status prediction by gene component regression: a comparative study.

The aim of the study is to evaluate gene component analysis for microarray studies. Three dimensional reduction strategies, Principle Component Regression (PCR), Partial Least Square (PLS) and Reduced Rank Regression (RRR) were applied to publicly available breast cancer microarray dataset and the derived gene components were used for tumor classification by Logistic Regression (LR) and Linear Discriminative Analysis (LDA). The impact of gene selection/filtration was evaluated as well. We demonstrated that gene component classifiers could reduce the high-dimensionality of gene expression data and the collinearity problem inherited in most modern microarray experiments. In our study gene component analysis could discriminate Estrogen Receptor (ER) positive breast cancers from negative cancers and the proposed classifiers were successfully reproduced and projected into independent microarray dataset with high predictive accuracy.

Rasch validation of a combined measure of basic and extended daily life functioning after stroke.

BACKGROUND: Tools used to measure poststroke functional status must include basic and instrumental activities of daily living and reflect the patient's and the clinician's perspective of the disease and its effect on daily living performance. OBJECTIVE: The authors combined the Functional Independence Measure (FIM) and the Nottingham Extended Activities of Daily Living (NEADL) to create a scale providing a comprehensive evaluation of ADLs functional status in patients with stroke. METHODS: The study participants were 188 patients completing the FIM and the NEADL. The psychometric properties of the combined measure were examined with Rasch analysis. RESULTS: A 3-point scale and a dichotomous scale were suggested for use in the FIM and the NEADL, respectively. The combined 40 items worked consistently to reflect a single construct, and "bladder management" and "bowel management" were highly related. After "bowel management" was removed from the combined scale, all but 3 items fit the model's expectations, and the 39-item scale showed reasonable item difficulty hierarchy, with high reliability. The 3 misfit items were removed, and no differences in unidimensionality, differential item functioning, and reliability were found between the 36-item and 39-item scales. CONCLUSIONS: The combined measure of the FIM and the NEADL provides a comprehensive picture of ADLs. It extends the utility of the FIM and the NEADL and is recommended for use to measure the independence of patients after discharge home.

FJU-C4, a new 2-pyridone compound, attenuates lipopolysaccharide-induced systemic inflammation via p38MAPK and NF-κB in mice.

Despite advances in antibiotic therapy and intensive care, the mortality caused by systemic inflammatory response syndrome and severe sepsis remains high. The use of anti-inflammatory agents to attenuate inflammatory response during acute systemic inflammatory reactions may improve survival rates. Here we show that a newly synthesized 2-pyridone compound (FJU-C4) can suppress the expression of late inflammatory mediators such as iNOS and COX-2 in murine macrophages. The pro-inflammatory cytokines, including TNFα, IL-1ß, and IL-6, were dose-dependently suppressed by FJU-C4 both in mRNA and protein levels. In addition, the expression of TNFα was inhibited from as early as 2 hours after exposure to LPS stimulation. The production of mature pro-inflammatory cytokines was also suppressed by pretreatment with FJU-C4 in either cell culture medium or mice serum when stimulated by LPS. FJU-C4 prolongs mouse survival and prevents mouse death from LPS-induced systemic inflammation when the dose of FJU-C4 is over 5 mg/kg. The activities of ERK, JNK, and p38MAPK were induced by LPS stimulation on murine macrophage cell line, but only p38MAPK signaling was dramatically suppressed by pretreatment with the FJU-C4 compound in a dose-dependent manner. NF-κB activation also was suppressed by FJU-C4 compound. These findings suggest that the FJU-C4 compound may act as a promising therapeutic agent against inflammatory diseases by inhibiting the p38MAPK and NF-κB signaling pathway.

Neonatal Candidemia Exacerbated the Progression of Retinopathy of Prematurity in an Extremely-Low-Birth-Weight Infant with Persistent Tunica Vasculosa Lentis.

Eyes with threshold retinopathy of prematurity (ROP) often show dilation of the existing tunica vasculosa lentis (TVL), which is a prognostic factor in ROP screening and treatment, but can be frequently misdiagnosed as true iris neovascularization (NV). Besides, candidemia in preterm infants can aggravate the severity of ROP, possibly to the threshold stage requiring laser treatment. A case of prolonged candidemia without ophthalmic infection in an extremely-low-birth-weight (ELBW) (birth weight: 800 g), pre-term (gestation: 26 weeks) infant with persistent TVL and severe ROP are reported. The threshold ROP was successfully treated with argon laser therapy. Candidemia without eye infection in this case was associated with early use of a systemic antifungal drug. To our knowledge, no similar cases have been reported in the literature.

Minimal detectable change and clinically important difference of the Stroke Impact Scale in stroke patients.

OBJECTIVES: The purpose of this study was to establish the minimal detectable change (MDC) and clinically important differences (CIDs) of the physical domains of the Stroke Impact Scale (SIS) and to assess the proportions of patients' change scores exceeding the MDC and CIDs after stroke rehabilitation. METHODS: Seventy-four patients received 1 of 3 treatments for 3 weeks and underwent clinical assessment before and after treatment. The MDC was calculated from the standard error of measurement to indicate a real change with 95% confidence for individual patients (MDC(95)). Anchor-based and distribution-based approaches were adopted to triangulate the ranges of minimal CIDs. The percentage of patients exceeding MDC(95) and minimal CIDs were also calculated. RESULTS: The MDC(95) of the strength, activities of daily living/instrumental activities of daily living, mobility, and hand function subscales were 24.0, 17.3, 15.1, and 25.9, respectively. The respective minimal CIDs for these 4 subscales were 9.2, 5.9, 4.5, and 17.8 points, respectively, and the MDC(95) and CID proportions were 14% to 43%, 16% to 49%, 10% to 50%, and 23% to 64%, respectively. CONCLUSIONS: The change score of an individual patient has to reach 24.0, 17.3, 15.1, and 25.9 on the 4 subscales to indicate a true change. The mean change scores of a stroke group on the 4 subscales should reach 9.2, 5.9, 4.5, and 17.8 points to be regarded as clinically important changes. Future research with larger sample sizes is warranted to validate these estimates.

Surgical outcomes in resected non-small cell lung cancer < or = 1 cm in diameter.

BACKGROUND: The goal of this study was to investigate the prognostic factors and patterns of recurrence in patients with resected non-small cell lung cancer (NSCLC) < or = 1 cm in diameter. METHODS: We conducted a retrospective review of the clinicopathological characteristics of 71 patients with NSCLC < or = 1 cm in diameter in Taipei Veterans General Hospital between 1982 and 2007. Overall survival and its predictors were analyzed. RESULTS: Median follow-up time of the 71 patients was 33.3 months. Complete resection was performed in 68 patients (95.8%) with stage I disease. The 5- and 10-year overall survival rates of patients who underwent complete resections were 81.7% and 44.9%, respectively. There was tumor recurrence in 6 (8.8%) of these 68 patients. Five (9.3%) of 54 patients who underwent standard resection experienced tumor recurrence, but only 1 (7.1%) of 14 patients who received sublobar resection had recurrent disease. The difference was not statistically significant (p = 0.569). Multivariate analysis revealed that sublobar resection (hazard ratio, 5.00; 95% confidence interval, 1.28-20.00; p = 0.020) was a significant predictor for worse overall survival. CONCLUSION: Survival in patients with NSCLC pound 1 cm in diameter is satisfactory. Sublobar resection, performed in patients unfit for standard resection, is a poor prognostic factor for overall survival.