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AimIf progressive liver injury and subsequent hepatic encephalopathy can be prohibited in fulminant liver failure (FLF), it would be ideal for intensive care of FLF and provide an expanded opportunity for liver transplantation (LT). We hypothesized that matrix metalloproteinase (MMP)‐9 plays an important role in FLF progression, and investigated MMP‐9 behaviors in a murine FLF model, especially at the coma stage.MethodsThe murine FLF model with azoxymethane recapitulates FLF in humans. The detailed coma status was evaluated, on the assumption that LT is indicated at early, but not late, stage 3. To investigate whether MMP‐9 deletion or reduction has beneficial effects, an MMP‐9 inhibitor (GM6001) and transfection of tissue inhibitor of metalloproteinases (TIMP)‐1 cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP‐1 plasmid transfection 24 h before disease onset; and FLF with TIMP‐1 plasmid transfection 48 h before disease onset. Neurological findings, including survival, were followed. Samples were obtained at early and late stage 3. Biochemical examinations and histopathological assessments were performed. The expression and function of MMP‐9 and TIMP‐1 were evaluated by western blotting and zymography. A brain permeability study was also performed.ResultsMMP‐9 was strongly increased in FLF. The MMP‐9 inhibitions worked well, and prolonged the survival, interval to stage 3 and duration of early stage 3. MMP‐9 inhibition improved the liver and subsequent brain injuries at early stage 3, with no remarkable improvements at late stage 3.ConclusionMMP‐9 has therapeutic potential for FLF progression.

SummaryPatients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health‐related quality of life (HRQoL). Here, we report post‐hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease‐related symptoms and HRQoL in MF patients from the large phase 3 COMFORT‐II study (N = 219). During the follow‐up period of 48 weeks, HRQoL and MF‐associated symptoms improved from baseline for ruxolitinib‐treated patients but remained the same or worsened for best available therapy (BAT)‐treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ‐C30), treatment‐induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0·05) up to week 48 (P < 0·05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy‐Lymphoma (FACT‐Lym) summary scores versus BAT at most time points (P < 0·05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT‐General, FACT‐Lym trial outcome index, and FACT‐Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF.

BACKGROUNDPartial nephrectomy (PN) and radical nephrectomy (RN) are standard treatments for a small renal mass. Retrospective studies suggest an overall survival (OS) advantage, however a randomized phase 3 trial suggests otherwise. The effects of both surgical modalities on OS were evaluated compared with controls.METHODSA matched cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER)‐Medicare dataset. Individuals treated with PN or RN for localized renal cell carcinoma (RCC) measuring ≤4 cm were compared with 2 control groups (non–muscle‐invasive bladder cancer (BCC) and noncancer controls (NCC). Using a greedy algorithm, RCC groups were matched with controls by demographics and comorbidities. OS for surgical groups and controls were compared. The cause of death was evaluated for cancer groups when differences in OS were noted.RESULTSPatients undergoing PN and RN were matched with controls. All cancer groups had >95% 10‐year cancer‐specific survival (CSS). Median OS was similar between RN (9.05 years) and BCC (8.67 years; P = .067) and NCC (8.77 years; P = .49). Median OS was improved for PN (10.45 years) compared with BCC (8.75 years; P<.001) and NCC controls (8.76 years; P<.001). A multivariate Cox hazards model demonstrated that PN improved OS compared with NCC (hazard ratio, 1.257; P<.001) and BCC (hazard ratio, 1.364; P<.001).CONCLUSIONSRN patients had similar OS compared with controls, suggesting that this treatment modality does not compromise survival. Patients undergoing PN had improved OS compared with controls, suggesting possible selection bias. The apparent survival advantage conferred by PN in SEER‐Medicare case series is likely the result of selection bias involving unmeasured confounders. Cancer 2013;119:2981—2989. © 2013 American Cancer Society.

AimThe minimally‐invasive Nuss procedure has become the preferred technique for pectus excavatum repair. This procedure is still associated with significant postoperative pain, and an optimal pain‐management strategy is yet to be determined. The purpose of this study was to compare the efficacy of patient‐controlled analgesia (PCA) to thoracic epidural analgesia (TEA).Patients and MethodsWe retrospectively reviewed 112 charts from a single paediatric centre. Patients were grouped according to pain‐management strategy: 90 patients received a PCA, and 22 patients received TEA. Outcomes included length of hospitalization and daily pain scores, operating room time and duration of Foley catheterization.ResultsDemographic data were similar between the two groups. The daily pain scores were not statistically different between the groups. Length of hospitalization was similar (PCA: 4.6 days, epidural: 4.3 days, P = 0.33). The PCA group required less operating room time (2:44 vs 2:58, P = 0.04) and shorter Foley catheter duration (2.1 days vs 2.5 days, P = 0.04).ConclusionIn our patient population, TEA for the Nuss procedure does not offer an advantage over PCA‐centred analgesia in terms of subjective daily pain scores or length of hospital stay. The potential risks of TEA need to be carefully considered in this patient population.

Background: Symptomatic femoroacetabular impingement (FAI) is associated with hip pain, functional limitations, and secondary osteoarthritis. There is limited information from large patient cohorts defining the specific population affected by FAI. Establishing a large cohort will facilitate the identification of “at-risk” patients and will provide a population for ongoing clinical research initiatives. The authors have therefore established a multicenter, prospective, longitudinal cohort of patients undergoing surgery for symptomatic FAI. Purpose: To report the clinical epidemiology, disease characteristics, and contemporary surgical treatment trends in North America for patients with symptomatic FAI. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Upon approval of the institutional review boards at 8 institutions, 12 surgeons enrolled consecutive patients undergoing surgical intervention for symptomatic FAI. Patient demographics, physical examination data, radiographic data, diagnoses, operative data, and standardized patient-reported outcome measures were collected. The first 1130 cases are summarized in this study. Results: A total of 1076 consecutive patients (1130 hips) were enrolled; 55% (n = 622) were female, and 45% (n = 508) were male, with an average age of 28.4 years and average body mass index (BMI) of 25.1. Demographics revealed that 88% of patients who were predominantly treated for FAI were white, 19% reported a family history of hip surgery, 47.6% of hips had a diagnosis of cam FAI, 44.5% had combined cam/pincer FAI, and 7.9% had pincer FAI. Preoperative clinical scores (pain, function, activity level, and overall health) indicated a major dysfunction related to the hip. Surgical interventions were arthroscopic surgery (50.4%), surgical dislocation (34.4%), reverse periacetabular osteotomy (9.4%), limited open osteochondroplasty with arthroscopic surgery (5.8%), and limited open by itself (1.5%). More than 90% of the hips were noted to have labral and articular cartilage abnormalities at surgery; femoral head-neck osteochondroplasty was performed in 91.6% of the surgical procedures, acetabular rim osteoplasty in 36.7%, labral repair in 47.8%, labral debridement in 16.3%, and acetabular chondroplasty in 40.1%. Conclusion: This multicenter, prospective, longitudinal cohort is one of the largest FAI cohorts to date. In this cohort, FAI occurred predominantly in young, white patients with a normal BMI, and there were more female than male patients. The disease pattern of cam FAI was most common. Contemporary treatment was predominantly arthroscopic followed by surgical hip dislocation.

A Na+ current is present in human jejunal circular smooth muscle cells. The aim of the present study was to determine the role of the cytoskeleton in the regulation of the Na+ current. Whole cell currents were recorded by using standard patch-clamp techniques with Cs+ in the pipette to block K+currents. Cytochalasin D and gelsolin were used to disrupt the actin cytoskeleton and phalloidin to stabilize it. Colchicine was used to disassemble the microtubule cytoskeleton (and intermediate filaments) and paclitaxel to stabilize it. Acrylamide was used to disrupt the intermediate filament cytoskeleton. Perfusion of the recording chamber at 10 ml/min increased peak Na+ current recorded from jejunal smooth muscle cells by 27 ± 3%. Cytochalasin D and gelsolin abolished the perfusion-induced increase in Na+current, whereas incubation with phalloidin, colchicine, paclitaxel, or acrylamide had no effect. In conclusion, the Na+ current expressed in human jejunal circular smooth muscle cells appears to be regulated by the cytoskeleton. An intact actin cytoskeleton is required for perfusion-induced activation of the Na+ current.

Smooth muscle exhibits mechanosensitivity independent of neural input, suggesting that mechanosensitive pathways reside within smooth muscle cells. The native L-type calcium current recorded from human intestinal smooth muscle is modulated by stretch. To define mechanosensitive mechanisms involved in the regulation of smooth muscle calcium entry, we cloned the α1C L-type calcium channel subunit (CaV1.2) from human intestinal smooth muscle and expressed the channel in a heterologous system. This channel subunit retained mechanosensitivity when expressed alone or coexpressed with a β2 calcium channel subunit in HEK-293 or Chinese hamster ovary cells. The heterologously expressed human cardiac α1C splice form also demonstrated mechanosensitivity. Inhibition of kinase signaling did not affect mechanosensitivity of the native channel. Truncation of the α1C COOH terminus, which contains an inhibitory domain and a proline-rich domain thought to mediate mechanosensitive signaling from integrins, did not disrupt mechanosensitivity of the expressed channel. These data demonstrate mechanical regulation of calcium entry through molecularly identified L-type calcium channels in mammalian cells and suggest that the mechanosensitivity resides within the pore forming α1C-subunit.