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Background: Approximately half of the patients with acute ischemic stroke who receive intravenous thrombolysis (IVT) do not achieve an excellent outcome. Remote ischemic conditioning (RIC) as a promising neuroprotective treatment may improve clinical outcomes in this population. This study aimed to assess the efficacy and safety of RIC in patients with IVT., Methods: This multicenter, participant-blinded, blinded end point, randomized controlled clinical trial included 558 patients with acute ischemic stroke who underwent IVT in 18 hospitals from August 2021 to May 2023. After IVT, patients were randomized 1:1 to the RIC (unilateral upper limb; cuff pressure, 200 mm Hg, twice daily for 7 days) or sham RIC groups (the same procedure; cuff pressure, 60 mm Hg). The primary efficacy outcome was an excellent functional outcome (modified Rankin Scale score, 0-1) at 90 days after IVT., Results: In total, 558 eligible patients were randomized, and 11 (2.0%) were excluded because they did not receive an RIC or sham RIC. Thus, 547 patients (RIC, n=274; sham RIC, n=273) were included in the modified intention-to-treat analysis, of whom 15 patients were lost to follow-up and 532 (95.3%) completed the trial. At 90 days, 62.7% of patients in the RIC group and 56.8% in the sham RIC group had an excellent functional outcome (unadjusted risk ratio, 1.10 [95% CI, 0.96-1.27]; P =0.169). The proportion of patients with any adverse events was 11.2% in the RIC group and 8.1% in the sham RIC group, with no significant difference ( P =0.221)., Conclusions: RIC was safe in patients with acute ischemic stroke who received IVT. However, it did not significantly improve excellent functional outcome., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04980625.

Background: Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO)., Methods: This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments., Results: Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P <0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P =0.82). The interaction was marginally significant between groups ( P =0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P <0.001). Other safety outcomes were similar between the 2 treatments., Conclusions: Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411., Competing Interests: None.

Purpose of Review: Advances in intravenous thrombolysis and endovascular thrombectomy have significantly reduced disability and improved outcomes associated with acute ischemic stroke., Recent Findings: An expansion of indications for reperfusion therapies in select groups of patients to permit treatment in an extended time window, with large ischemic core, and with simplified imaging protocols have enabled a broader group of patients access to disability-sparing therapy. Cerebroprotection has had renewed development in the era of acute reperfusion., Summary: In this review, we highlight recent developments in stroke reperfusion research and related questions that are under study or remain unanswered., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: Remote ischemic conditioning (RIC) is a low-cost, accessible, and noninvasive neuroprotective treatment strategy, but its efficacy and safety in acute ischemic stroke are controversial. With the publication of several randomized controlled trials (RCTs) and the recent results of the RESIST trial, it may be possible to identify the patient population that may (or may not) benefit from RIC. This systematic review and meta-analysis aims to evaluate the effectiveness and safety of RIC in patients with ischemic stroke receiving different treatments by pooling data of all randomized controlled studies to date., Methods: We searched the PubMed, Embase, Cochrane, Elsevier, and Web of Science databases to obtain articles in all languages from inception until May 25, 2023. The primary outcome was the modified Rankin Scale (mRS) score at the specified endpoint time in the trial. The secondary outcomes were change in NIH Stroke Scale (NIHSS) and recurrence of stroke events. The safety outcomes were cardiovascular events, cerebral hemorrhage, and mortality. The quality of articles was evaluated through the Cochrane risk assessment tool. This study was registered in PROSPERO (CRD42023430073)., Results: There were 7,657 patients from 22 RCTs included. Compared with the control group, patients who received RIC did not have improved mRS functional outcomes, regardless of whether they received medical management, reperfusion therapy with intravenous thrombolysis (IVT), or mechanical thrombectomy (MT). In the medical management group, patients who received RIC had decreased incidence of stroke recurrence (risk ratio 0.63, 95% CI 0.43-0.92, p = 0.02) and lower follow-up NIHSS score by 1.72 points compared with the control group ( p < 0.00001). There was no increased risk of adverse events including death or cerebral hemorrhage in the IVT or medical management group., Discussion: In patients with ischemic stroke who are not eligible for reperfusion therapy, RIC did not affect mRS functional outcomes but significantly improved the NIHSS score at the follow-up endpoint and reduced stroke recurrence, without increasing the risk of cerebral hemorrhage or death. In patients who received IVT or MT, the benefit of RIC was not observed.

Abstract: Background: Traumatic brain injury (TBI) is a head trauma usually associated with death and endothelial glycocalyx damage. Syndecan-1 (SDC-1)-a biomarker of glycocalyx degradation-has rarely been reported in meta-analyses to determine the clinical prognostic value in TBI patients. Methods: We looked into PubMed, EMBASE, Cochrane Library, and Web of Science databases from January 1, 1990, to May 1, 2023, to identify eligible studies. A meta-analysis was conducted using RevMan 5.4 and Stata 16.0 with the search terms "SDC-1" and "traumatic brain injury." Results: The present study included five studies with a total of 640 enrolled patients included. Syndecan-1 concentrations were higher in the isotrauma TBI group than in the non-TBI group (standardized mean difference [SMD] = 0.52; 95% CI: 0.03-1.00; P = 0.04). Subgroup analysis revealed statistical significance when comparing the SDC-1 level of multitrauma TBI (TBI + other injuries) group with the isotrauma TBI group (SMD = 0.74; 95% CI: 0.42-1.05; P < 0.001), and the SDC-1 level of the TBI coagulopathy (+) group (TBI with early coagulopathy) with the TBI coagulopathy (-) group (SMD = 1.75; 95% CI: 0.41-3.10; P = 0.01). Isotrauma TBI patients with higher SDC-1 level were at a higher risk of 30-day in-hospital mortality (odds ratio = 3.32; 95% CI: 1.67-6.60; P = 0.0006). Conclusion: This meta-analysis suggests that SDC-1 could be a biomarker of endotheliopathy and coagulopathy in TBI, as it was increased in isotrauma TBI patients and was higher in multitrauma TBI patients. There is a need for additional research into the use of SDC-1 as a prognostic biomarker in TBI, especially in isotrauma TBI patients., Competing Interests: Disclosure: The authors have no conflicts of interest to disclose., (Copyright © 2023 by the Shock Society.)

Background: RICAMIS trial (The Remote Ischemic Conditioning for Acute Moderate Ischemic Stroke) has demonstrated efficacy of remote ischemic conditioning (RIC) in acute ischemic stroke. We conducted a post hoc analysis of RICAMIS to investigate whether large artery atherosclerosis (LAA) subtype contributed to the outcomes., Methods: This is a post hoc analysis of the RICAMIS trial. Patients randomized to RIC group and Control group in full analysis set of RICAMIS were classified into LAA and non-LAA subtypes. The primary outcome was excellent functional outcome at 90 days, defined as modified Rankin Scale score of 0 to 1. Compared with patients receiving usual care, we investigated the association of RIC effect with outcomes in stroke subtypes and the interaction between RIC effect and stroke subtypes. The primary analysis was adjusted analysis., Results: Among 1773 patients, 516 were assigned to LAA subtype (229 in the RIC group and 287 in the control group) and 1257 to non-LAA subtype (633 in the RIC group and 624 in the control group). Median age was 65 years, and 34.2% were women. A higher proportion of primary outcome was found to be associated with RIC treatment in LAA subtype (adjusted risk difference, 11.4% [95% CI, 3.6%-19.2%]; P =0.004), but not in non-LAA subtype (adjusted risk difference, 4.1% [95% CI, -1.1% to 9.3%]; P =0.12). There was no significant interaction between RIC effect and stroke subtypes ( P =0.12)., Conclusions: Patients with LAA subtype may benefit from RIC after stroke with respect to excellent functional outcome at 90 days., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03740971., Competing Interests: Disclosures None.

Background: The survival outcomes of patients with esophageal squamous cell carcinoma (ESCC) after open or thoracoscopic upfront esophagectomy remained unclear., Objective: The aim of this retrospective study was to compare overall survival between open and thoracoscopic esophagectomy for ESCC patients without neoadjuvant chemodatiotherapy (CRT)., Methods: The Taiwan Cancer Registry was investigated for ESCC cases from 2008 to 2016. We enrolled 2053 ESCC patients receiving open (n = 645) or thoracoscopic (n = 1408) upfront esophagectomy. One-to-two propensity score matching between the two groups was performed. Stage-specific survival was compared before and after propensity score matching. Univariate analysis and multivariate analysis were used to identify risk factors., Results: After one-to-two propensity score matching, a total of 1299 ESCC patients with comparable clinic-pathologic features were identified. There were 433 patients in the open group and 866 patients in the thoracoscopic group. The 3-year overall survival of matched patients in the thoracoscopic group was better than that of matched patients in the open group (58.58% vs 47.62%, P = 0.0002). Stage-specific comparisons showed thoracoscopic esophagectomy is associated with better survival than open esophagectomy in patients with pathologic I/II ESCC. In multivariate analysis, surgical approach was still an independent prognostic factor before and after one-to-two propensity score matching., Conclusion: This propensity-matched study revealed that thoracoscopic esophagectomy could provide better survival than open esophagectomy in ESCC patients without neoadjuvant CRT., Competing Interests: The authors report no conflicts of interest and no funding sources. Disclosures: B-Y.W., C-H.L., S-C.W., and H-S.C. have no conflict of interest or financial ties to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Although uveitis can be an intraocular presentation of systemic lymphoma, it may be associated with direct lymphomatous infiltration and immune-mediated alterations. There have been no published studies describing the incidence of uveitis after systemic lymphoma. We conducted a nationwide cohort study to investigate the incidence of uveitis after systemic lymphoma diagnosis in Taiwan. Data were collected from the Taiwan National Health Insurance system and included patients newly diagnosed with systemic lymphoma between 2000 and 2017. We observed the risk of uveitis among study population since the index date until December 2017. The 1:8 of systemic lymphoma patient and paired comparison was identified by time distribution matching and individual paired with sex and age. Subsequent propensity score matching (PSM) was used to select the 1:1 of systemic lymphoma patient and paired comparison by greedy algorism with caliper of 0.05. The multiple Cox proportional hazard regression model was used to compare the developmental risk of uveitis (time-to-uveitis) between the systemic lymphoma and non-systemic lymphoma, while controlling for selected covariates. After time distribution matching, we selected 6846 patients with systemic lymphoma, and 54,768 comparisons. Among patients with systemic lymphoma groups, there were more men than women (52.94% vs 47.06%) and the mean age was 53.32 ± 21.22 years old. Systemic lymphoma incidence rates (per 10,000 person-months) of uveitis were 1.94 (95% confidence interval [CI], 1.60-2.35) in the systemic lymphoma cohort and 1.52 (95% CI, 1.42-1.63) in the non-systemic lymphoma cohort. Compared with the non-systemic lymphoma cohort, adjusted hazard ratio (aHR) of developing uveitis were 1.24 (95% CI, 1.00-1.52) in people with systemic lymphoma. But not significant in after PSM, aHR of developing uveitis were 1.17 (95% CI, 0.90-1.53). This 18-year nationwide population-based cohort study in Taiwan, showed that the risk of uveitis in patients' systemic lymphoma was not significantly higher than non-systemic lymphoma after PSM. In elderly and rheumatic patients with intraocular inflammation, it is important to first exclude uveitis masquerade syndrome, which could be a harbinger of intraocular involvement from systemic lymphoma. Further large-scale prospective clinical studies to investigate whether systemic lymphoma influences the incidence of uveitis are warranted., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: To evaluate the duration of topical brimonidine therapy before the onset of brimonidine-related allergic conjunctivitis and the clinical characteristics associated with the development of brimonidine allergy.We retrospectively enrolled patients who presented brimonidine allergy from December 1, 2008 to November 30, 2020. The duration of brimonidine treatment, concomitant medications, benzalkonium chloride (BAK) exposure, change in IOP, and season of onset were evaluated.292 patients were included, among which 147 were female and 145 were male. The mean age was 58.3 ± 13.6 years old. The mean (median) duration of brimonidine therapy was 266.6 (196) days, with a peak at 60-120 days. The duration was similar whether the patients received brimonidine monotreatment or in combination with other glaucoma drugs, with or without BAK. The IOP increased by 5.6% after brimonidine allergy (P < .001), which was even higher in the brimonidine monotherapy group (9.2%, P < .001). There was no significant IOP elevation in patients treated with multiple glaucoma medications.Around half of brimonidine allergy occurred within 6 months, with a peak in 2 to 4 months. The duration did not differ in patients receiving brimonidine monotherapy or multiple glaucoma medications. The presence of BAK did not affect the duration either. When brimonidine allergy occurred, there was a loss of IOP control, especially in patients receiving brimonidine monotherapy. It is recommended to switch to other types of glaucoma medications for better IOP control., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: We investigate whether patients with chronic kidney disease (CKD) are at increased risk of retinal vascular disease (RVD). Data was collected from the Taiwan National Health Insurance system and included patients newly diagnosed with CKD between 2000 and 2012. The endpoint of interest was a diagnosis of RVD. Follow-up data of 85,596 patients with CKD and 85,596 matched comparisons (non-CKD) from 2000 to 2012 were analyzed. Patients with CKD were found to have a significantly higher cumulative incidence of RVD (Kaplan-Meier analysis, log-rank test P < .0001). Through multivariate Cox regression analysis, the CKD group was found to have higher risk of developing RVD (adjusted hazard ratio (HR) [95% confidence interval (CI)]: 2.30 [2.16-2.44]) when compared to the control cohort. When comparison of CKD group and non-CKD group was stratified by gender, age and comorbidities (hypertension, diabetes, and hyperlipidemia), the higher risk of RVD in patients with CKD remained significant in all subgroups. Patients with CKD were found to have higher risk of developing RVD in this cohort study. In addition, CKD imposed the same risk for RVD development in all age groups and in patients with or without hypertension or diabetes. Thus, patients with CKD should be vigilant for symptoms of RVD. Understanding the link between CKD and RVD could lead to the development of new treatment and screening strategies for both diseases., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Increased interarm systolic blood pressure difference (IASBPD) is associated with cardiovascular prognosis in the general population. This study aimed to evaluate whether IASBPD or ankle brachial index (ABI) is strongly associated with cardiovascular outcomes in patients with type 2 diabetes.Total 446 type 2 diabetes followed up for a mean 5.8 years divided by ABI (<0.9 vs ≥0.9) or IASBPD (<10 vs ≥10 mm Hg). The primary outcome was a composite of all-cause mortality, hospitalization for coronary artery disease, nonfatal stroke, carotid, or peripheral revascularization, amputations, and diabetic foot syndrome. The secondary endpoint was all-cause mortality.Sixty-four composite events and 17 deaths were identified. The primary and secondary outcomes were higher than those in the group with ABI < 0.9 vs ABI ≥ 0.9 (32.8% vs 11.6%, P < .005 for primary outcome; 14.0% vs 2.3%, P < .005 for all-cause mortality) but IASBPD cannot exhibit a prognostic value. ABI < 0.9 was also the dominant risk factor of both endpoints demonstrated by multivariate Cox proportional analysis (composite events: adjusted hazard ratio [HR], 2.39; 95% confidence interval [CI], 1.26-4.53; P = .007; all-cause mortality: adjusted HR, 3.27: 95% CI, 1.91-5.60; P < .001).The ABI was more associated with cardiovascular outcomes in patients with diabetes than IASBPD.

Background: Polycystic ovary syndrome (PCOS) is inconsistently associated with increased risk of adverse pregnancy outcomes. The purpose of this meta-analysis was to summarize the evidence regarding the strength of the association between pregnancy in women with PCOS and pregnancy complications., Methods: We systematically searched PubMed, EmBase, and the Cochrane Library to identify observational studies up to January 2016. The primary focus was pregnancy outcomes, including gestational diabetes mellitus (GDM), preeclampsia, pregnancy-induced hypertension (PIH), preterm delivery, cesarean delivery, oligohydramnios, and polyhydramnios. Effect estimates were pooled using the random-effects model. The analysis was further stratified by factors that could affect these associations., Results: We included 40 observational studies that reported data on a total of 17,816 pregnancies with PCOS and 123,756 pregnancies without PCOS. Overall, PCOS in pregnancy was associated with greater risk of GDM, preeclampsia, PIH, preterm delivery, cesarean delivery, miscarriage, hypoglycemia, and perinatal death. However, PCOS in pregnancy had little or no effect on oligohydramnios, polyhydramnios, large-for-gestational age (LGA), small-for-gestational-age (SGA), fetal growth restriction (FGR), preterm premature membrane rupture, fasting blood glucose (FBG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride, total cholesterol, congenital malformation, macrosomia, and respiratory distress syndrome. Subgroup analysis suggested that these associations might be influenced by study design and pre-BMI., Conclusion: PCOS in pregnancy is associated with a significantly increased risk of adverse pregnancy, fetal, and neonatal outcomes., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Purpose: This study investigates whether patients with viral hepatitis and cirrhosis are at risk of uveitis in the years following hepatitis., Methods: We used data from Taiwan National Health Insurance system. The cases were patients newly diagnosed with viral hepatitis from 2000 to 2011. The end point of interest was a diagnosis of uveitis. A chi-square test was used for the difference of demographic characteristics between viral hepatitis and comparison. The risk of uveitis in hepatitis was stratified using Cox proportional hazard regression., Results: We selected 17,389 patients with viral hepatitis and 34,778 matched comparison. The risk of uveitis in hepatitis cohort was 1.30-fold (95% confidence interval = 1.01-1.69). Patients with hepatitis B virus and hepatitis C virus coinfection had the highest risk (hazard ratio = 2.88; 95% confidence interval = 1.07-7.78), and followed by only hepatitis C virus infection (hazard ratio = 1.75; 95% confidence interval = 1.10-2.79). Patients with cirrhosis had a higher risk in the multivariable model but did not attach statistic difference., Conclusion: Patients with hepatitis B virus and hepatitis C virus coinfection had the highest risk of uveitis. In patients with hepatitis C virus and/or hepatitis B virus infection, the symptoms of uveitis should be alerted. Although these epidemiologic studies yielded informative results, the underlying mechanisms and the host's genetic factors remain to be investigated., Competing Interests: The authors were involved in design and conduct of study; data collection; analysis, management, and interpretation of data; and preparation, review, and approval of manuscript. None of the authors have any financial/conflicting interests to disclose.

Background: The role of adjuvant chemoradiation in esophageal cancer has been underestimated in the literature. This study was undertaken to determine whether adjuvant chemoradiation improves survival compared with surgery alone., Methods: Data of 1095 esophageal squamous cell carcinoma (ESCC) patients, including 679 in surgery alone group (group 1) and 416 in surgery followed adjuvant chemoradaition group (group 2), were obtained from the Taiwan Cancer Registry database. Propensity score matching (PSM) analysis was used to identify 147 well-balanced patients in each group for overall survival comparison., Results: After PSM, the 3-year survival rates and median survival were 44.9% and 27.2 (95% confidence interval [CI]: 17.6-40.3) months in group 2, which is significantly higher than that in group 1 (28.1% and 18.2 [95% CI: 14.3-24.5] months, P = 0.0043). In the multivariate survival analysis, pT3/4 stage (Hazard Ratio [HR]: 2.03, 95% CI: 1.38-2.97, P < 0.001), pN+ stage (HR: 1.83, 95% CI: 1.31-2.57, P = 0.0004), tumor length more than 32 mm (HR: 1.93, 95% CI: 1.33-2.79, P < 0.001), R1/2 resection (HR: 1.75, 95% CI: 1.15-2.66, P = 0.009), and adjuvant chemoradiation (HR: 0.57, 95% CI: 0.42-0.78, P < 0.0001) were independent prognostic factors. Subgroup analysis suggested patients with pT3/4 stage, pN+ stage tumors, larger tumor size, poorly differentiated tumors, and R1/2 resections were more likely to demonstrate survival benefit from adjuvant chemoradiation., Conclusions: Compared with surgery alone, adjuvant chemoradiation provides a survival benefit to ESCC patients, especially those with pT3/4 stage, N+ tumors, larger tumor size, poorly differentiated tumors, and R1/2 resections.

Instrumented spinal fusion has become one of the most common surgeries for patients with various spinal disorders. Only few studies have reported subsequent vertebral compression fractures (VCFs) after instrumented spinal fusion. The purpose of this study was to evaluate the risk of new VCFs in patients undergoing instrumented spinal fusion.We obtained claims data from the National Health Insurance Research Database of Taiwan and retrospectively reviewed 6949 patients with instrumented spinal fusion as the spinal fusion cohort. Control subjects were individually matched at a ratio of 10:1 with those of the spinal fusion cohort according to age, sex, and the index day. Comorbidities were classified as those existing before the index day, and these included diabetes mellitus, hypertension, osteoporosis, and cerebrovascular accident. The end of the follow-up period for the analyses was marked on the day new VCFs developed, enrolment in the National Health Insurance was terminated, on the day of death, or until the end of 2012. We used the Cox proportion hazards model to analyze the hazard ratio (HR) for developing new VCFs.Patients with instrumented spinal fusion were significantly more likely to develop new VCFs (1.87% vs .25%, HR: 8.56; P < 0.001). Female, elderly, and osteoporotic patients had a high incidence of new VCFs after spinal fusion. The HR for developing new VCFs after instrumented spinal fusion was higher in patients younger than 65 years than in those 65 years or older (HR: 10.61 vs 8.09). Male patients with instrumented spinal fusion also had a higher HR of developing new VCFs than female patients (men, HR: 26.42; women, HR: 7.53).In our retrospective cohort study, patients who had undergone instrumented spinal fusion surgery exhibited an increased risk of developing new VCFs. Particularly, the HR increased in young (age <65 years) and male patients., Competing Interests: The authors report no conflicts of interest.

The optimal treatment modality for locoregional esophageal squamous-cell carcinoma (ESCC) is still undetermined. This study investigated the treatment modalities affecting survival of patients with ESCC in Taiwan.Data on 6202 patients who underwent treatment for locoregional esophageal squamous-cell carcinoma during 2008 to 2012 in Taiwan were collected from the Taiwan Cancer Registry. Patients were stratified by clinical stage. The major treatment approaches included definitive chemoradiotherapy, preoperative chemoradiation followed by esophagectomy, esophagectomy followed by adjuvant therapy, and esophagectomy alone. The impact of different treatment modalities on overall survival was analyzed.The majority of patients had stage III disease (n = 4091; 65.96%), followed by stage II (n = 1582, 25.51%) and stage I cancer (n = 529, 8.53%). The 3-year overall survival rates were 60.65% for patients with stage I disease, 36.21% for those with stage II cancer, and 21.39% for patients with stage III carcinoma. Surgery alone was associated with significantly better overall survival than the other treatment modalities for patients with stage I disease (P = 0.029) and was associated with significantly worse overall survival for patients with stage III cancer (P < 0.001). There was no survival risk difference among the different treatment methods for patients with clinical stage II disease.Multimodality treatment is recommended for patients with stage II-III esophageal squamous-cell carcinoma. Patients with clinical stage I disease can be treated with esophagectomy without preoperative therapy., Competing Interests: The authors have no funding and conflicts of interest to disclose.

The aim of this study was to determine the correlation between pre- and postsurgical loss of blood and blood components among patients undergoing treatment of facial deformities by bilateral parasymphyseal osteotomy (BPsO).The pre- and postoperative values of blood components were determined in 30 facial deformity patients who underwent orthognathic surgery by hypotensive anesthesia. Correlations among the blood loss, sex, age, operation time, and reduced values of blood components were assessed by a correlation matrix. The mean blood loss and operation time were 437.5 (± 52.5) mL and 355.8 (± 209.42) minutes, respectively. Two patients included in this study had required blood transfusion. The mean reduced red blood cell (× 10/μL), hemoglobin (g/dL), and hematocrit (%) were -1.02, -2.98, and -9.18, respectively. There was no significant correlation between blood loss and other related factors (eg, age, operation time, and reduced blood components). All patients, however, showed significantly lower values of blood components after surgery. In conclusion, no significant factor was associated with blood loss and reduced blood components among patients undergoing BPsO. Furthermore, hypotensive anesthesia is a well-accepted method to reduce blood loss during orthognathic surgery.

While preoperative chemoradiation followed by surgery (pre-OP CRT) has been widely applied in the treatment of patients with esophageal cancer, some studies have shown a survival benefit of postoperative chemoradiation (post-OP CRT). The optimal combination of multimodality therapy and the sequence of surgery and chemoradiation for esophageal cancer remain to be investigated. A total of 1385 patients with clinical stage II and III esophageal squamous cell carcinoma (ESCC) were included. On the basis of the sequence of surgery and chemoradiation, the patients were grouped as follows: preoperative chemoradiation followed by surgery (pre-OP CRT+S), surgery alone (S), and surgery followed by postoperative chemoradiation (S+post-OP CRT). Propensity score matching analysis was used to identify 78 well-balanced patients in each group for outcome comparison.In all, 753, 339, and 293 patients were in the pre-OP CRT+S, S, and S+post-OP CRT groups, respectively. Before matching, no differences were observed in the overall survival among the patients in these 3 groups (P = 0.422). After matching, both the pre-OP CRT+S and S+post-OP CRT groups were significantly associated with a better survival compared with the S group (pre-OP CRT+S vs. S: P < 0.001; S+post-OP CRT vs. S: P = 0.005). In contrast, the survival was similar between the pre-OP CRT+S and S+post-OP CRT groups (P = 0.544). In the subgroup analysis, patients with clinical T3/4 stage tumors or those with a tumor size greater than 5 cm were more likely to demonstrate an overall survival benefit from pre-OP CRT compared with post-OP CRT. Both pre-OP CRT and post-OP CRT demonstrated a survival benefit compared with surgery alone, which indicates the importance of trimodality therapy in patients with clinical stage II/III ESCC. However, no survival difference was observed among patients in the pre-OP CRT+S and S+post-OP CRT groups, which suggests that the sequence of surgery and chemoradiation may be irrelevant to the outcome.

Complicated infectious spondylitis is an infrequent infection with severe spinal destruction, and is indicated for combined anterior and posterior surgeries. Staged debridement and subsequent reconstruction is advocated in the literature. The purpose of this study is to evaluate the feasibility and clinical outcome of patients who underwent single-stage combined anterior debridement and fibular allograft implantation followed by supplemental posterior fixation for complicated infectious spondylitis. We retrospectively reviewed the medical records of 20 patients who underwent single-stage combined anterior and posterior surgeries for complicated infectious spondylitis from January 2005 to December 2010. Complicated infectious spondylitis was defined as at least 1 vertebral osteomyelitis with pathological fracture or severe bony destruction and adjacent discitis, based on imaging studies. The severity of the neurological status was evaluated using the Frankel scale. The clinical outcomes were assessed by careful physical examination and regular serological tests to determine the visual analog scale (VAS) score and Macnab criteria. Correction of the sagittal Cobb angle on radiography was also compared before and after surgery. The Wilcoxon signed-rank test was used to analyze patient surgical prognosis and radiological findings. All patients with complicated infectious spondylitis were successfully treated by single-stage combined anterior and posterior surgeries. No patients experienced neurologic deterioration. The average VAS score was 7.8 before surgery and significantly decreased to 2.1 at discharge. Three patients had excellent outcomes and 17 had good outcomes, based on Macnab criteria. The average length of the allograft for reconstruction was 64.0 mm. Kyphotic deformity improved in all patients, with an average correction angle of 13.4°. There was no implant breakage or allograft dislodgement during at least 36 months of follow-up. Single-stage anterior debridement and fibular allograft implantation followed by posterior pedicle screw instrumentation provide immediate stability, satisfactory alignment, and successful infection control. Fibular allograft implantation seems to be a good alternative for anterior reconstruction; it can proceed to bony incorporation and avoids donor site morbidity.

Background: Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy., Methods and Results: We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end., Conclusions: This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

Study Design: A retrospective study., Objective: To evaluate the efficacy and safety of percutaneous vertebroplasty (PV) for treating patients with symptomatic osteoporotic vertebral compression fractures (VCFs) adjacent to lumbar instrumented circumferential fusion., Summary of Background Data: Few studies have investigated adjacent VCFs and their management after spinal fusion surgery for degenerative lumbar disease., Patients and Methods: From January 2005 to July 2011, a total of 23 patients with lumbar instrumented circumferential fusion suffered from adjacent symptomatic osteoporotic VCFs. All of these patients received PV using polymethylmethacrylate bone cement augmentation in our institute. Radiography and magnetic resonance imaging were used for imaging studies. The visual analog scale and modified Brodsky criteria were used to compare clinical outcomes before and after surgery. The minimum follow-up period was 18 months (range, 18-45 mo)., Results: One level PV was performed in 18 patients and 2 levels were performed in 5 patients. The patients' visual analog scale scores improved by an average of 54.3 points after the procedure. Twenty patients returned to their preinjury activities of daily living. Lumbar lordosis was increased from 28.9 degrees before PV to 36.2 degrees after PV. The average restoration of the fractured vertebral body height was 14.0%. No surgery-related complications occurred except asymptomatic cement leakage in 4 patients., Conclusions: PV is a minimally invasive and effective procedure to treat patients with symptomatic osteoporotic VCFs adjacent to lumbar instrumented circumferential fusion.

It is generally believed that the development of neuropathic pain primarily results from injuries to sensory afferent fibers. Recent studies found that injuries to the motor efferent fibers (e.g. ventral root transection) also contribute to the development of neuropathic pain. Furthermore, an increase in brain-derived neurotrophic factor (BDNF) synthesis has been found in the ventral root transection model, suggesting a possible role of BDNF in this model. To determine the role of BDNF, we observed the effects of intrathecal antibody against BDNF treatment on ventral root transection-induced mechanical hyperalgesia. Paw withdrawal thresholds to mechanical stimuli were measured before and after surgery. The results showed that ventral root transection in rats produced a significant, lasting decrease of mechanical withdrawal thresholds, presenting the development of mechanical hyperalgesia. Intrathecal antibody against BDNF treatment markedly inhibited ventral root transection-induced mechanical hyperalgesia in a dose-related manner. The findings suggest that BDNF-mediated signaling pathway within spinal cord may be involved in the development of neuropathic pain involving injuries to motor efferent fibers.

Background: Percutaneous vertebroplasty (PV) with polymethylmethacrylate is widely used to treat osteoporotic vertebral compression fracture and satisfactory clinical outcomes have been reported in the literature. However, recurrent or persistent back pain after PV is not uncommon. Sometimes, the pain may result from pathogenesis within the previously treated vertebra. In this study, we evaluated the efficacy and safety of repeat PV for treating patients with recurrent back pain caused by the previously cemented vertebrae., Methods: We retrospectively reviewed the medical records of 18 patients who underwent repeat PV to treat symptomatic cemented vertebrae. Patients were categorized into 3 groups based on clinical presentation and imaging studies: those with refracture (RF), residual vacuum (RV), and osteonecrosis (ON) along the bone-cement interface. A bipedicle approach was used for repeat PV in all patients. The visual analogue scale (VAS) and modified Brodsky criteria were used to evaluate clinical outcomes before and after surgery. The Kruskal-Wallis test, Wilcoxon signed-rank test, and Spearman correlation analyses were used to analyze patient surgical prognosis and radiologic findings., Results: Nine patients were diagnosed with RF, 5 with RV, and 4 with ON. The average VAS score was 77.1 (range, 62-90) before repeat PV (80.1, 72.4, and 76.3 for the RF, RV, and ON groups, respectively) and 34.4 (range, 25-45) after repeat PV treatment (33.1, 36.8, and 34.3 for the RF, RV, and ON groups, respectively). The VAS score significantly decreased in all 3 groups. The vertebral body height was significantly restored by a mean of 13.9% across all groups (17.8%, 12.7%, and 6.8% in the RF, RV, and ON groups, respectively). Fifteen patients recovered from vertebral compression fracture and regained their preinjury activities of daily living. No surgery-related complications occurred except asymptomatic cement leakage in 5 patients., Conclusions: The results of this research demonstrate that repeat PV may be an effective method for relieving recurrent or persistent pain in patients with symptomatic cemented vertebrae, allowing them to regain functional activity.

Purpose: This study aimed to assess the association between patient- and operation-related factors and postoperative pain in patients undergoing intraoral vertical ramus osteotomy (IVRO) or IVRO + genioplasty (GeP) for the treatment of mandibular prognathism., Materials and Methods: A visual analog scale (VAS) was used to evaluate postoperative pain for 2 days in 63 patients who underwent orthognathic surgery (42 IVRO and 21 IVRO + GeP). Correlations between VAS and patient age, sex, blood loss, operation time, and intraoperative reduction in blood parameters were assessed and compared between IVRO and IVRO + GeP procedures., Results: Mean operation time and blood loss were 252.02 minutes and 99.64 mL in the IVRO group and 317.62 minutes and 187.86 mL in the IVRO + GeP group, respectively. Operation time, blood loss, and postoperative reduction in blood parameters were significantly greater in the IVRO + GeP group than in the IVRO group. Mean VAS scores on the first and second postoperative days were 3.02 and 1.33 in the IVRO group and 2.95 and 1.14 in the IVRO + GeP group. However, postoperative pain did not differ significantly between the IVRO and IVRO + GeP groups on the first or second postoperative day., Conclusions: Postoperative pain associated with orthognathic surgery was acceptable, controllable, and not different between IVRO and IVRO + GeP procedures.

Objective: This study aimed to investigate the remote effect of acupuncture (AcP) on the pain intensity and the irritability of the myofascial trigger point in the upper trapezius muscle., Design: Forty-five patients were equally divided into three groups: patients in the placebo control group received sham AcP, those in the simple needling group were treated using simple needling, and those in the modified AcP received AcP with the rapid "screwed in and out" into multiple sites to elicit local twitch responses. The acupoints of Wai-guan and Qu-chi were treated. The outcome assessments included changes in subjective pain intensity, pressure pain threshold, range of motion, and mean amplitude of endplate noise in the myofascial trigger point region., Results: Immediately after acupuncture, all measured parameters improved significantly in the simple needling and modified AcP groups, but not in the placebo control group. There were significantly larger changes in all parameters in the modified AcP group than that in the simple needling group., Conclusions: The myofascial trigger point irritability could be suppressed after a remote acupuncture treatment. It appears that needling to the remote AcP points with multiple needle insertions of modified AcP technique is a better technique than simple needling insertion of simple needling technique in terms of the decrease in pain intensity and prevalence of endplate noise and the increase in pressure pain threshold in the needling sites (represented either AcP points and or myofascial trigger points). We have further confirmed that the reduction in endplate noise showed good correlation with a decreased in pain.

Objective: This study aimed to analyze the association of thiazolidinedione (TZD)-related edema with genetic and clinical variables and develop a simple points system to predict the risk of developing TZD-related edema., Methods: Fifty-eight (21.6%) of 268 individuals who received TZD for type 2 diabetes developed peripheral edema. Twenty-eight tag single nucleotide polymorphisms (SNPs) from candidate genes involved in sodium and water reabsorption were genotyped. Cox regression and logistic regression models were used to analyze the associations of different genotypes and weighted genotypic scores with TZD-related edema risk., Results: Individuals with edema were older, predominantly female, and had greater weight gain. The AQP2 rs296766 T allele was associated with TZD-related edema [allelic P=0.0059; odds ratio (OR), 2.89; 95% confidence interval (CI), 1.61-5.17]. The SLC12A rs12904216 G allele had borderline significance (allelic P=0.049), which disappeared after correction for multiple testing. Patients with two SNP-based (AQP2 rs296766 and SLC12A1 rs12904216), who weighted genotypic scores within the top quartile, had a higher risk of developing TZD-related edema (OR, 16.45; 95% CI, 3.05-88.76). Combining the weighted genetic scores of two SNPs or all SNPs with age and sex information significantly improved the predictive power for TZD-related edema. We also developed a simple risk factor-based points system to predict an individual's risk of developing TZD-related edema., Conclusion: A clinically applicable prediction model including age, sex, and genetic information from AQP2 rs296766 and/or SLC12A rs12904216 SNPs can be developed to estimate the risk of TZD-related edema in type 2 diabetes patients.

Background: Spinal N-methyl-D-aspartate receptors have been demonstrated to play an important role in the facilitation and maintenance of nociception. To avoid adverse effects of blocking N-methyl-D-aspartate receptors in the central nervous system, blocking N-methyl-D-aspartate receptor in peripheral nervous system is an ideal alternative. Transfection of small interfering RNAs (siRNAs) into cells has been revealed to provide potent silencing of specific genes. In this study, the authors examined the effect of subcutaneous injection of siRNA targeting the NR1 subunit of the N-methyl-D-aspartate receptor on silencing NR1 gene expression and subsequently abolishing inflammatory nociception in rats., Methods: Male Sprague-Dawley rats received intradermal injection of NR1 siRNA and underwent injection of formalin or complete Freund's adjuvant. The flinch response and mechanical hypersensitivity by von Frey filaments were assessed. Then the messenger RNA and protein of NR1 in skin and dorsal root ganglion were analyzed., Results: The results revealed that subcutaneous injection of 1 nmol NR1 siRNA effectively diminished the nociception induced by formalin and complete Freund's adjuvant stimuli and attenuated the level of NR1 messenger RNA and protein in skin and ipsilateral dorsal root ganglion. The antinociception effect and the inhibition of NR1 expression persisted for about 7 days after administration of NR1 siRNA., Conclusions: The data of this study suggest that NR1 siRNA has potential therapeutic value in the treatment of inflammatory pain induced or maintained by peripheral nociceptor activity and support the potential application of this method to the study of nociceptive processes and target the validation of pain-associated genes.

Objectives: To develop a warfarin-dosing algorithm that could be combined with pharmacogenomic and demographic factors, and to evaluate its effectiveness in a randomized prospective controlled clinical trial., Methods: A pharmacogenetics-based dosing model was derived using retrospective data from 266 Chinese patients and multiple linear regression analysis. To prospectively validate this model, 156 patients with an operation of heart valve replacement were enrolled and randomly assigned to the group of pharmacogenetics-guided or traditional dosing for warfarin therapy. All patients were followed up for 50 days after initiation of warfarin therapy. The log-rank test was compared with the time-to-event (Kaplan-Meier) curves. Cox proportional hazards-regression model was used to assess the hazard ratio of the time to reach stable dose., Results: The linear regression model derived from the pharmacogenomic model correlated with 54.1% of warfarin dosing variance. The final multiple linear regression model included age, body surface area, VKORC1, and CYP2C9 genotype. The study showed that the hazard ratio for the time to reach stable dose was 1.932 for the traditional dosing group versus the model-based group and a close and highly significant relationship was observed to exist between the predicted and the actual warfarin dose (R=0.454)., Conclusion: A pharmacogenetics-based dosing algorithm has been developed for improvement in the time to reach the stable dosing of warfarin. This model may be useful in helping the clinicians to prescribe warfarin with greater safety and efficiency.

The roles of central protein kinases A and C (PKA and PKC) in various pain states have intensively been investigated during the past decade. The aim of the present study was to investigate the peripheral involvement of PKA and PKC in persistent nociceptive response, evoked pain behaviors, and inflammation induced by subcutaneous (s.c.) injection of bee venom (BV, 0.2mg/50 microl) in rats. The effects of intraplantar injection of H-89 (a PKA inhibitor, 5-100 microg/50 microl) and chelerythrine chloride (a PKC inhibitor, 5-100 microg/50 microl) on BV-elicited persistent nociception (nociceptive flinching reflex), mechanical hyperalgesia, and inflammation were systematically investigated. Pre-treatment with H-89 dose-dependently inhibited only BV-induced mechanical hyperalgesia, but not the persistent nociception and inflammation. In contrast, pre-treatment with chelerythrine chloride dose-dependently inhibited BV-induced sustained nociception and inflammation, but not the mechanical hyperalgesia. Topical pre-treatment of the sciatic nerve with 1% capsaicin significantly blocked the inhibitory effects of the PKC inhibitor on BV-induced inflammation, but not the persistent flinching response. These results indicate that peripheral PKA and PKC involvements in BV-induced pain behaviors differ, and capsaicin-sensitive afferents appear to participate in the pro-inflammatory role of PKC in the BV pain model. Findings from the present study also suggest that targeting specific peripheral protein kinases might prove effective in the treatment of persistent pain and inflammation.

Study Design: The topical capsaicin treatment of the sciatic nerve, which was proved to destroy capsaicin-sensitive primary afferent (CSPA) fibers, was performed to determine the effect on decreases in paw withdrawal mechanical threshold (PWMT) and changes in spatial expression pattern of spinal c-Fos protein induced by the direct compression of L5 nerve root with autologous disc., Objective: To investigate the role of CSPA fibers in the development of mechanical hyperalgesia in the new sciatica model., Summary of Background Data: To date, CSPA fibers have been shown to be involved in development of thermal hyperalgesia in various pain models. But the controversy still exists as to whether CSPA fibers are involved in the development of mechanical hyperalgesia in different pain models. To our best knowledge, the role of CSPA in sciatica was not investigated. Therefore, the present study was designed to determine the role of CSPA fibers in the newly developed sciatica model., Methods: All surgeries were performed in Sprague-Dawley rats. PWMT was measured at the different time points postsurgery and presurgery. The changes in spatial expression pattern of c-Fos protein in the spinal cord were also determined at 3 weeks when PWMT decreased to the peak., Results: The pretreatment with capsaicin produced a complete prevention of mechanical hyperalgesia induced by disc compression. The direct compression of L5 nerve root produced an obvious expression of Fos-like immunoreactivity neurons in the dorsal horn of the spinal cord, which was significantly decreased by pretreatment with capsaicin., Conclusion: We conclude that CSPA fibers, which mainly terminated in superficial layers of dorsal horn, may play a key role in mechanical hyperalgesia in the new sciatica model.

Objective: To describe the results of ultrasonographic examination in a series of patients with chronic wrist pain and to define the proportion of occult carpal ganglion in these patients., Design: A retrospective study including 57 patients with wrist pain consecutively referred for sonographic examination. The inclusion criteria for this study were a history of wrist pain longer than 3 mos with no wrist trauma, and no palpable mass at the wrist. Ultrasound examination with a 10-MHz linear transducer was used to detect wrist pathology. A well-demarcated anechoic mass with posterior enhancement and without vascularity within the mass on sonography was defined as a ganglion cyst., Results: Thirty-three of the 57 patients (58%) were diagnosed by sonographic examination as having a ganglion in the wrist joint. The size of the ganglion demonstrated on sonographic imaging ranged from 2 x 5 mm to 10 x 9 mm on a longitudinal scan of the wrist (with a mean of 4 x 7 mm.). Surgical excision was carried out in 12 patients who had ganglions diagnosed by sonographic examination; in all cases, the mucin content of the specimen was demonstrated. Eight patients underwent local aspiration followed by steroid injection under the guidance of ultrasound. The aspirated content was a jelly-like substance. In these 20 treated patients, symptoms of wrist pain improved after intervention., Conclusions: The prevalence of occult carpal ganglion is common in chronic wrist pain patients. High-resolution sonographic examination facilitates early detection of occult carpal ganglion.

Background: Microsurgical procedures performed in patients with hematological disorders can pose significant challenges. The literature is lacking in reports that specifically address the safety, reliability, and management techniques related to performing microvascular surgery in this group of patients., Methods: A retrospective chart review of all patients with hematological disorders who received free flaps from 1995 to 2004 was performed. All patients had a hematologic work-up that confirmed the stability of the underlying disease. There were three male and three female patients with an average age of 27.6 years (range,12 to 63 years). Patients had leukemia (n = 2), hereditary spherocytosis, non-Hodgkin's lymphoma, and hemophilia (n = 2). Their defects were in the areas of the nasocolumella/upper lip, palate, palate and midface, and lower extremities., Results: All patients received free flaps and all but one had an uneventful postoperative course. That patient, with hemophilia, 1 day after factor replacement was halted, had bleeding that required surgical re-exploration along with aggressive hematologic management. All flaps survived without vascular compromise. No wound infections were observed. All donor sites healed without complications., Conclusions: Essential ingredients in the treatment plan of patients with hematologic disorders undergoing free flaps include familiarity with the preoperative medical condition and potential postoperative complications, close monitoring of the patients and their medical condition before and after surgery, meticulous surgical technique, and close cooperation with the hematologists and infectious disease specialists. By following this regimen, patients with hematologic disorders and an otherwise stable medical history can undergo free tissue transfer safely and effectively with reliable outcomes.

Unlabelled: We report an unexpected difficult ventilation with a double-lumen endotracheal tube in a patient receiving left upper lobe lung mass resection. The manufacturing defect in both limbs of the Opti-Port Right Angle Double Swivel Connector of the double-lumen tube resulted in this problem. This defect is difficult to localize by the usual recommended methods. We discuss a modified algorithm for difficult ventilation with a double-lumen endotracheal tube., Implications: Difficult ventilation occurred during general anesthesia as the result of a manufacturing defect in both limbs of the connector of the double-lumen endotracheal tube. The problem was resolved with a careful approach, and there were no serious consequences.

The effects of different volumes of fluid resuscitation on traumatic hemorrhagic shock in unacclimated rats to high altitude were investigated. Seventy-eight Wistar rats were transported to LaSa, Tibet, 3760 meters above sea level, and traumatic hemorrhagic shock was induced by right-femur fracture plus bleeding to 45 mmHg of mean arterial pressure (MAP) for 1 h under the anesthesia of sodium pentobarbital (40 mg/kg, i.p.). Experiments were conducted in two series. In series I, 36 rats were equally divided into six groups: sham-operated, untreated (traumatic shock without fluid infusion), and with lactated Ringer's resuscitation (LR) of 1.0, 1.5, 2.0 or 3.0 times the shed blood (1, 1.5, 2, 3 vol LR group). MAP, left intraventricular systolic pressure, the maximal change rate of intraventricular pressure rise or decline (+/-dp/dtmax), the maximal physiological velocity of contractile element shortening, and the area of left intraventricular pressure-dp/dt vector loop (Lo) were observed at 30, 60, 90, and 120 min and the blood gases were determined at 30 and 120 min after resuscitation. Meanwhile the survival time was observed after the observation period. In series II, 42 rats were used to observe the effects of different volumes of fluid resuscitation on water content of lung and brain and hematocrit. One and 1.5 vol LR resuscitation significantly lifted MAP, left intraventricular systolic pressure, +dp/dtmax, and Lo, partially improved the blood gases and significantly prolonged the survival time. Although 2 and 3 vol of LR resuscitation caused apparent hemodilution and lung edema, they only partially improved hemodynamic parameters. Meanwhile 2 and 3 vol of LR resuscitation decreased the survival time. These results suggest that 1 and 1.5 vol of LR resuscitation can effectively resuscitate traumatic hemorrhagic shock at high altitude. More than two volumes of LR resuscitation would deteriorate the resuscitation outcome.

The pathophysiological mechanisms underlying sciatica and back pain are not well understood. In the present study, a sciatica model was developed to investigate the contributions of inflammation and compression of the dorsal root (DR). The procedure used autologous disc to apply direct pressure to the L5 DR (disc compression, DC group). For control, five additional groups were included: (1). mechanical compression of L5 DR without disc (compression, CP group); (2). epidurally placed disc without mechanical compression (disc group); (3). epidurally placed nucleus pulposus (NP) without mechanical compression (NP group); (4). epidurally placed annulus fibrosus (AF) without mechanical compression (AF group) and (5). sham group. The paw withdrawal latency to heat stimulation, paw withdrawal threshold to mechanical stimulation, body weight, and motor function were determined pre- and post-surgery. It was observed that all experimental groups with the exception of the sham group showed a progressive and prolonged mechanical hyperalgesia with the DC group having the strongest effect. Furthermore, the disc group showed a greater mechanical hyperalgesia with earlier onset in comparison with the CP group and disc, AF, and NP groups developed thermal hyperalgesia in addition to mechanical hyperalgesia following surgery. Finally, rats in all groups showed normal motor function and body weight increase. These data suggest that this model is suitable to investigate the mechanisms of sciatica and inflammation as well as mechanical compression is involved in the pathogenesis of this condition. Moreover, AF and NP may contribute similarly to the development of sciatica and back pain.

Background: The roles of descending facilitatory pathway from the rostral medial medulla (RMM) in development of persistent spontaneous nociception and hyperalgesia were evaluated in the bee venom (BV) test and the formalin test., Methods: Bilateral lesions of the RMM with ibotenic acid, a soma-selective neurotoxin, were performed to study their effects on the spontaneous pain-related behaviors and hyperalgesia, which were determined by counting the number of flinching reflex per 5 min (1 h) and by measuring paw withdrawal thermal latency (PWTL) and mechanical threshold (PWMT) to radiant heat and von-Frey filaments to both hind paws in conscious rats, respectively., Results: 1) Bilateral lesions of the RMM produced a similarly significant inhibition of persistent spontaneous flinching reflexes in the BV test and the formalin test; however, the inhibitory effect occurred in the late 50 min (11-60 min), but not the first 10 min (0-10 min) following intraplantar injection of either BV or formalin. 2) Bilateral lesions of the RMM prevented the development of the BV-induced referred mirror heat hyperalgesia occurred in the noninjected paw, but had no effect on the primary heat and mechanical hyperalgesia occurred in the injected paw., Conclusions: The present results provide a new line of behavioral evidence that tonic activation of descending facilitatory pathway contributes to the establishment of 1) the BV and formalin-induced persistent spontaneous nociception; and 2) the BV-induced referred mirror heat hyperalgesia and the central sensitization, but not the primary heat and mechanical hyperalgesia.

Purpose: We evaluated the clinical results of nonsimultaneous penetrating keratoplasty, cataract extraction, and intraocular lens (IOL) implantation (two-stage surgery) for combined corneal disease and cataract., Methods: Twenty-six eyes of 24 patients with an average age of 46 years who underwent two-stage surgery were studied retrospectively. Variables included visual acuity, refractive status, specular microscopy before and after IOL implantation (6 months), and the occurrence of graft failure. Astigmatism was corrected by suture removal and relaxing incision. The mean follow-up after IOL placement was 16 months., Results: Unaided visual acuity was 20/100 or better in 22 (83%) eyes after the second procedure. Twenty-one (81%) eyes had an aided visual acuity of at least 20/40. The mean refractive and absolute errors were -1.49 +/- 1.39 diopters (D) and 1.55 +/- 1.30 D, respectively. The mean keratometric and refractive cylinders were 3.50 D and 2.26 D, respectively. Nineteen (73%) eyes had a spherical equivalent refraction within 2 D of emmetropia. Anisometropia (> or =3 D) occurred in four (15%) eyes. The endothelial cell density, the coefficient of variation, and the percentage of hexagonal cells documented by specular microscopy were not significantly different before and after IOL implantation. Complications included three rejections, two cases of herpetic recurrence, and one late decompensation. Two graft failures (8%) occurred after secondary surgery., Conclusion: The two-stage surgery is a safe and effective modality.

To investigate the roles of primary afferent fibers in development of the bee venom (BV)-induced persistent spontaneous nociception (PSN) and hyperalgesia (HA), the sciatic nerve or both the sciatic and saphenous nerves of rats were topically treated with capsaicin respectively under pentobarbital anesthesia to destroy the capsaicin-sensitive primary afferent (CSPA) fibers. Effect of the sciatic nerve capsaicin on the formalin-induced PSN was also evaluated. Destruction of the CSPA fibers of the sciatic nerve or both the sciatic and saphenous nerves only produced 34 or 69% inhibition of the mean total number of 1 h BV-induced paw flinches. However, the total number of 1 h formalin-induced paw flinches was inhibited by 90% (85% for phase 1 and 91% for phase 2). In naïve rats, destruction of the CSPA fibers of the sciatic nerve caused 237 and 60% increase in paw withdrawal thermal latency (PWTL) to radiant heat in the injection site (paw pad) and at the heel of the treated hind paw compared to the baseline values. However, it was without significant influence upon the PWTL in the non-treated side or the paw withdrawal mechanical threshold (PWMT) to von Frey filament stimuli in both hind paws. In the BV-treated rats, the CSPA fiber destruction of the sciatic nerve completely blocked development of the heat and mechanical HA in the BV injection site. However, the reduction in either PWTL (drop to baseline level) or PWMT (drop by 56% from the baseline level) at the heel of the BV-treated side was not affected by this treatment. However, destruction of the CSPA fibers of both the sciatic and saphenous nerves was able to block development of both heat and mechanical HA in the whole BV-treated hind paw and heat hyperalgesia in the non-injected hind paw. Taken together, we conclude that: (1) the CSPA (C- and A delta-) fibers play a pivotal role in mediation of either the heat or the mechanical hyperalgesia induced by s.c. BV; (2) the CSPA fibers may play a crucial role in mediation of the formalin-induced PSN, but play a partial role in the BV-induced nociceptive process; (3) in addition to the sciatic nerve, the saphenous nerve is also involved in mediation of the BV-induced PSN as well as heat and mechanical hyperalgesia, while it is not likely to be involved in the formalin-induced nociception.

We investigated whether transtracheal insufflation of oxygen with different insufflation flow rates protects against aspiration of gastric contents during cardiopulmonary resuscitation (CPR). Its ventilation and oxygenation effects were also evaluated. Cardiac arrest was induced in anesthetized and paralyzed 18 mongrel dogs. Chest compression using an automatic thumper was performed while the dogs randomly received no mechanical ventilation (Group I, n = 6) or were transtracheally insufflated with 4 L/min oxygen (Group II, n = 6) or 10 L/min oxygen (Group III, n = 6). Blood samples were drawn every 5 min for 20 min for blood gas analysis. the mouths of the dogs were then filled with 70 mL mixed barium, and 10 min after chest compression, chest radiographs were taken to evaluate the incidence of pulmonary aspiration. Results showed that pulmonary aspiration occurred in all dogs of Group I and three of the six dogs in Group II, whereas dogs in Group III were free from pulmonary aspiration. Both transtracheal oxygen insufflation groups maintained oxygen saturation significantly better than Group I, but mild hypercapnia was observed in all groups after 20 min of CPR. We conclude that transtracheal oxygen insufflation, but not chest compression alone, was able to maintain oxygenation for 20 min during CPR in dogs with cardiac arrest. Mild hypercapnia was noted in all groups. Chest compression alone caused pulmonary aspiration, whereas insufflation of 10 L O(2)/min provided better protection against pulmonary aspiration than that of 4 L O(2)/min.

This study was designed to investigate the effect of a calcium sensitizer on the Ca2+ sensitivity of myocardial fibers in endotoxic shock rats. Right ventricular papillary muscles from sham shock or endotoxic shock rats were skinned by incubation in saponin solution. Forces of the skinned muscles were recorded when they were activated sequentially by different pCa (-log[Ca2+]) activating solutions with or without positive inotropic agents. Tension-pCa relationship curve of skinned fibers delineated the affinity of troponin C(TnC) for Ca2+ and the medium value pCa50 (pCa required for producing 50% of maximal Ca2+-activated tension) was taken as the quantitative index of Ca2+ sensitivity of TNC. It was found that the maximal Ca2+ activated tension (Tmax) was lower, tension-pCa relationship curve was shifted rightward, and the pCa50 was reduced significantly in endotoxic shock group compared with that of sham shock group. Milrinone could not counteract the above abnormalities. However, when skinned right ventricular papillary fibers from endotoxic shock rats were dealt with activating solutions containing 1 x 10(-5) M MCI-154, the Tmax was significantly increased, the tension-pCa relationship curve was shifted leftward. The pCa50 in MCI-154 group was increased to an extent similar to that of sham shock group and markedly higher than the values of endotoxic shock group and milrinone group. Furthermore, such effects of MCI-154 were concentration dependent. It can been concluded that the sensitivity of cardiac contractile proteins to Ca2+ in endotoxic shock rats is decreased. MCI-154, a calcium sensitizer, can significantly reverse the decreased sensitivity and increase Tmax of myocardial muscles from endotoxic shock rats.

This study was designed to observe the effects of MCI-154, a calcium sensitizer, on cardiac dysfunction after endotoxic shock in rabbits. Ten hours after the rabbits were given injection of 1.0 mg/kg endotoxin (Escherichia coli, O111:B4) via marginal ear veins, 0.1 mg/kg MCI-154 was injected intravenously and then 50 mL/kg normal saline (NS) + 0.1 mg/kg MCI-154 was infused continuously at a rate of 0.7 mL/min. During this process, the parameters of cardiac function were measured. It was found that 10 h after the endotoxin injection, heart rate (HR) was increased significantly while the mean arterial blood pressure (MAP), left ventricular systolic pressure (LVSP), isovolumetric pressure (IP), myocardial contractility (MC), and the area of p-dp/dt(max) vector loop (Lo) all were markedly decreased. Treatment with 50 mL/kg NS alone had slight effects on these parameters. On the contrary, LVSP, IP, MC, and Lo all were increased significantly while HR was not obviously changed and left ventricular end-diastolic pressure (LVEDP) was reduced remarkably following MCI-154 administration in endotoxic shock rabbits. The parameters of myocardial contractility were improved nearly to the values in sham shock group and were markedly higher than that in NS alone-treated group. It can be concluded that MCI-154 can exert significant therapeutic effects on cardiac dysfunction after endotoxic shock, for it improves cardiac function, dilates peripheral blood vessels, and slightly affects HR.

In order to further elucidate effect of hemorrhagic shock on endotoxin-inducing cytokine production, the present study was designed to investigate the production of tumor necrosis factor alpha (TNF alpha) induced by low-dose (1 microgram/kg) of lipopolysaccharide (LPS) and its cellular sources after hemorrhagic shock (HS) in rats. With combination of expression of lipopolysaccharide-binding protein (LBP) mRNA in the liver, lungs, and kidneys, we further analyzed a possible mechanism for increasing sensitivity to LPS by shock. We found in vivo that plasma TNF alpha levels in the HS + LPS group were 20-fold higher than those in the HS group (p < .01) and 2.7-fold higher than those in the LPS group (p < .05). It was shown in vitro that the capacity of the peripheral white blood cells to produce TNF alpha in response to LPS stimulation was significantly decreased by 126% (p < .01) and 57% (p < .05) compared with the pre-shock levels and sham group, respectively, at the end of resuscitation following shock, and still markedly inhibited 3 h after resuscitation, while the capacity of hepatic Kupffer's cells to produce TNF alpha was significantly increased by 110% compared with the sham group (p < .01) after shock and resuscitation. Results from RT-PCR showed that expression of LBP mRNA in the liver, lungs, and kidneys was increased after shock and resuscitation. It is suggested that hemorrhagic shock could significantly strengthen endotoxin to induce TNF alpha production, which might be due to up-regulation of LBP expression in tissues after shock, and the tissue macrophage population may be the main source for cytokine production in shock.

Many studies have demonstrated that thyrotropin-releasing hormone (TRH) produces various beneficial effects in the treatment of shock. TRH has been proposed to reverse the cardiovascular depression of endogenous opioid peptides. Nevertheless, it remains unknown whether opioid receptors are truly involved in this process. We designed experiments to study the importance of delta and kappa opioid receptors in the beneficial effects of TRH in hemorrhagic shock in rabbits and on opiate receptors following hemorrhagic shock in rats. The results indicated that TRH (50 micrograms, i.c.v.) significantly improved the mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), and the maximal rate of ventricular systolic pressure changes (+/- dp/dtmax) during hemorrhagic shock in rabbits. This TRH effect was abolished by pretreatment with ICI174,864 (50 micrograms, i.c.v.), a highly selective delta opioid receptor antagonist, but not by pretreatment with nor-binaltorphimine (Nor-BNI, 50 micrograms, i.c.v.), a highly selective kappa opioid receptor antagonist. The maximal binding capacity (Bmax) of brain delta and kappa opioid receptors significantly increased following hemorrhagic shock, but the receptor affinity (Kd) did not change. TRH (5 mg/kg, i.v.) decreased the number (Bmax) of brain delta opioid receptors significantly, but it did not influence the receptor affinity. TRH did not influence the Bmax or affinity of brain kappa opioid receptors. These findings suggest that opioid receptors play an important role in mediating the antishock property of TRH. TRH-induced down-regulation of the number of brain opioid receptors may be one of the important mechanisms by which TRH exercises its protective effects in the treatment of shock.

Although studies have indicated that thyrotropin-releasing hormone (TRH) produces various beneficial effects following low flow conditions, it remains unknown whether this agent has any salutary effect on myocardial alpha- and beta-adrenergic and dopaminergic (DA) receptors following hemorrhagic shock. To study this, rats (220-280 g) were bled to a mean arterial pressure of 40 mmHg and maintained for 1.5 h following shock. TRH or an equivalent volume of normal saline was administered. Receptor binding assay was carried out in myocardial plasma membrane preparations at 15 and 45 min after TRH administration. The results indicate that the maximal binding capacity (Bmax) of myocardial alpha- and beta-adrenergic receptors and their affinity decreased significantly following hemorrhage. The Bmax of DA receptors was also reduced, while the affinity was not significantly affected by hemorrhagic insult. Administration of TRH (5 mg/kg body wt) at 1.5 h after the onset of hemorrhage, however, markedly increased the Bmax of myocardial beta-adrenergic and DA receptors. The decreased affinity of beta-adrenoceptors observed in hemorrhaged animals was also improved with TRH treatment. TRH did not, however, significantly affect the altered Bmax and affinity of alpha-adrenoceptors following hemorrhagic shock. These results suggest that TRH-induced upregulation of beta-adrenoceptor and DA receptor binding capacity and the enhanced affinity of beta-adrenoceptors may be one of the mechanisms by which TRH produces the beneficial effects following hemorrhagic shock.