Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation.

BACKGROUND: Invasive mechanical ventilation in critically ill adults involves adjusting the fraction of inspired oxygen to maintain arterial oxygen saturation. The oxygen-saturation target that will optimize clinical outcomes in this patient population remains unknown. METHODS: In a pragmatic, cluster-randomized, cluster-crossover trial conducted in the emergency department and medical intensive care unit at an academic center, we assigned adults who were receiving mechanical ventilation to a lower target for oxygen saturation as measured by pulse oximetry (Spo2) (90%; goal range, 88 to 92%), an intermediate target (94%; goal range, 92 to 96%), or a higher target (98%; goal range, 96 to 100%). The primary outcome was the number of days alive and free of mechanical ventilation (ventilator-free days) through day 28. The secondary outcome was death by day 28, with data censored at hospital discharge. RESULTS: A total of 2541 patients were included in the primary analysis. The median number of ventilator-free days was 20 (interquartile range, 0 to 25) in the lower-target group, 21 (interquartile range, 0 to 25) in the intermediate-target group, and 21 (interquartile range, 0 to 26) in the higher-target group (P = 0.81). In-hospital death by day 28 occurred in 281 of the 808 patients (34.8%) in the lower-target group, 292 of the 859 patients (34.0%) in the intermediate-target group, and 290 of the 874 patients (33.2%) in the higher-target group. The incidences of cardiac arrest, arrhythmia, myocardial infarction, stroke, and pneumothorax were similar in the three groups. CONCLUSIONS: Among critically ill adults receiving invasive mechanical ventilation, the number of ventilator-free days did not differ among groups in which a lower, intermediate, or higher Spo2 target was used. (Supported by the National Heart, Lung, and Blood Institute and others; PILOT ClinicalTrials.gov number, NCT03537937.).

Hepatic apoptosis can modulate liver fibrosis through TIMP1 pathway.

Apoptotic injury participates in hepatic fibrosis, but the molecular mechanisms are not well understood. The present study aimed to investigate the role of inducible TIMP1 in the pathogenesis of hepatic apoptosis-fibrosis. Apoptosis was induced with GCDC, LPS, and alcohol in precision-cut liver slices or bile duct ligation (BDL) in rats, as reflected by caspase-3 activity, TUNEL assay, and apoptosis-related gene profiles. The hepatic fibrosis was detected with Picrosirius staining, hydroxyproline determination, and expression profiling of fibrosis-related genes. Levels of TIMP1 were upregulated by the hepatic apoptosis, but downregulated by caspase inhibitor. The inducible TIMP1 was apoptosis-dependent. Once TIMP1 was inhibited with treatment of TIMP1-siRNA, the fibrotic response was reduced as demonstrated by hydroxyproline assay. In addition, the expression of fibrosis-related genes aSMA, CTGF, and TGFb2r were down-regulated subsequent to the treatment of TIMP1-siRNA. TIMP1 could mediate the expression of fibrosis-related genes. TIMP1 was transcriptionally regulated by nuclear factor c-Jun as demonstrated by EMSA and ChIP assay. The treatment of c-Jun siRNA could significantly decrease the expression of TIMP1 induced by alcohol, GCDC, or LPS treatment. Hepatic apoptosis induces the expression of TIMP1. Inducible TIMP1 can modulate the expression of fibrosis-related genes in liver. TIMP1 pathway is a potential target for therapeutic intervention of fibrotic liver diseases.

C/EBPα and C/EBPß binding proteins modulate hepatocyte apoptosis through iNOS signaling pathway.

Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) involve many pathophysiologic conditions. The expression of iNOS is regulated at multiple stages. Presently, the regulatory details of iNOS signaling are still unclear. This study aimed to investigate the regulatory role of C/EBPα and C/EBPß in iNOS signaling pathway. By employing the techniques such as EMSA, ChIP assay, site-directed mutagenesis, and siRNA silencing, the relationship between iNOS and C/EBPα/C/EBPß in rat hepatocytes was clarified. iNOS promoter was the direct transcriptional targets of the C/EBPα, C/EBPß, and NF-κB binding proteins. There was the interactive influence between NF-κB and C/EBPα/C/EBPß. The expression of iNOS was modulated by C/EBPα/C/EBPß transcription factors. Moreover, the iNOS expression mediated glycochenodeoxycholate (GCDC)-induced apoptosis in hepatocytes. C/EBPα/C/EBPß binding proteins could affect the GCDC-induced apoptosis through iNOS cascade. These findings indicate that C/EBPα and C/EBPß regulate the iNOS expression, which may further modify cell responses such as apoptosis and cell survival.

Survivin signaling is regulated through nuclear factor-kappa B pathway during glycochenodeoxycholate-induced hepatocyte apoptosis.

UNLABELLED: Hepatocytes in primary culture undergo apoptosis upon exposure to glycochenodeoxycholate (GCDC). The signaling mechanisms of GCDC-induced apoptosis remain unclear. To investigate the role of antiapoptotic genes, we compared apoptotic response in primary hepatocytes following GCDC treatment. The hepatocytes from adult Sprague-Dawley rats were cultured in collagen-coated dishes and treated with GCDC in varying concentrations, or the same concentration at different time intervals. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, DNA fragmentation assay, and caspase assays. Expression of apoptosis-related genes and proteins was evaluated by RT-PCR, quantitative real-time PCR (qRT-PCR), and Western blotting, respectively. The DNA-binding property of a nuclear protein was assessed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. An interesting result was that GCDC caused hepatocyte apoptosis to display a biphasic phenomenon at a dosage of 50µM, whereas it was not found at higher dosages such as 200µM. GCDC stimulated the expression of antiapoptotic Survivin, which also presented a biphasic response. The activation of nuclear factor-kappaB (NF-κB) corresponded with the up-regulation of Survivin. The inhibitor of NF-κB, BAY 11-7082, suppressed the expression of Survivin and simultaneously eliminated the biphasic response. The expression of Survivin was transcriptionally mediated by the activation of NF-κB, as shown by EMSA and ChIP assay. CONCLUSIONS: These results demonstrated that a low dosage of GCDC induced the hepatocyte apoptosis to exhibit the biphasic response, which was regulated by the expression of Survivin through NF-κB signaling pathway.

Protocol and statistical analysis plan for the Pragmatic Investigation of optimaL Oxygen Targets (PILOT) clinical trial.

INTRODUCTION: Mechanical ventilation of intensive care unit (ICU) patients universally involves titration of the fraction of inspired oxygen to maintain arterial oxygen saturation (SpO2). However, the optimal SpO2 target remains unknown. METHODS AND ANALYSIS: The Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial is a prospective, unblinded, pragmatic, cluster-crossover trial being conducted in the emergency department (ED) and medical ICU at Vanderbilt University Medical Center in Nashville, Tennessee, USA. PILOT compares use of a lower SpO2 target (target 90% and goal range: 88%-92%), an intermediate SpO2 target (target 94% and goal range: 92%-96%) and a higher SpO2 target (target 98% and goal range: 96%-100%). The study units are assigned to a single SpO2 target (cluster-level allocation) for each 2-month study block, and the assigned SpO2 target switches every 2 months in a randomly generated sequence (cluster-level crossover). The primary outcome is ventilator-free days (VFDs) to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of invasive mechanical ventilation through 28 days after enrolment. ETHICS AND DISSEMINATION: The trial was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. TRIAL REGISTRATION NUMBER: The trial protocol was registered with ClinicalTrials.gov on 25 May 2018 prior to initiation of patient enrolment (ClinicalTrials.gov identifier: NCT03537937).

Agreement study of radiographic classification of rotator cuff tear arthropathy.

HYPOTHESIS: This study evaluated the intra-rater and inter-rater correlation of 3 commonly used x-ray image classifications and defined the clinical factors most correlated with a surgical recommendation for a hemiarthroplasty or a reverse total shoulder arthroplasty (RSA) for treatment of rotator cuff tear arthropathy (CTA). We hypothesized that specific radiographic criteria and clinical criteria would be most important and consistently used among experienced shoulder surgeons when determining the best surgical option for a particular patient. METHODS: Four experienced orthopedic surgeons evaluated standard anteroposterior radiographs and the clinical examination of 37 shoulders with CTA. On each reading, they classified the grade of pathology using the Seebauer, Favard, and Hamada classifications. Using radiographic criteria alone, or with the clinical findings, each evaluator determined the recommended prosthetic treatment for each shoulder. RESULTS: Intra-rater correlations for surgical recommendations using radiographic criteria ranged from 0.39 to 1.0 and improved in 3 of 4 evaluators when the clinical examination was included in the clinical decision. The inter-rater reliability using these same criteria were fair, at 0.32 for radiographic and .35 for radiographic and clinical data. The most significant radiographic factors associated with a surgical decision were the degree of humeral head superior migration and the escape of the humeral head from the coracoacromial arch. Clinical factors most associated with the decision for RSA were advanced age, loss of shoulder elevation, superior humeral head escape, and pseudoparalysis of the shoulder. Radiographic findings had a less significant effect on surgical recommendations when clinical factors were included. CONCLUSION: Clinical and radiographic criteria are needed for a decision for hemiarthroplasty or RSA in the treatment of CTA. A treatment algorithm based upon radiographic and clinical criteria is proposed.

A Content Analysis of Patient Advocacy Organization Policies Addressing Institutional Conflicts of Interest.

Introduction: Patient advocacy organizations (PAOs) provide patient education, raise public awareness, and influence health policy for a wide range of diseases. These organizations frequently receive financial support form from drug, device, and biotechnology companies. Though PAOs often develop policies to address institutional conflicts of interest arising from industry relations, little is known about the substance of these policies. Methods: We sampled all PAOs that are members of the National Health Council. Using a standardized search strategy, all policies were obtained from each organization if publicly available. We reviewed policies for content related to restrictions on corporate partnerships, disclosure of corporate funding, and governance and monitoring of corporate partnerships. Results: We found that 24 of 47 (51%) organizations had policies that addressed institutional conflict of interest. A total of 9 of those 24 (38%) policies placed any restriction on the types of corporations that the PAO would or would not partner with. While 16 of the 24 (67%) outlined some process for disclosure of the organization's corporate donors, only 5 of 24 (21%) specified a manner for disclosing the financial value of those donations. Further, 15 of the 24 (63%) policies identified the person or persons responsible for approving corporate partnerships. However, 17 (71%) failed to address or specify the person(s) responsible for ongoing review of those partnerships. Conclusion: Nearly half of the organizations studied did not have publicly available conflict of interest policies. Among those that did, few policies had a substantial level of detail or limitations to guard against conflicts of interest.

Masquerade: nonspinal musculoskeletal disorders that mimic spinal conditions.

Nonspinal musculoskeletal disorders frequently cause neck and back pain and thus can mimic conditions of the spine. Common mimics are rotator cuff tears, bursitis in the hip, peripheral nerve compression, and arthritis in the shoulder and hip. A thorough history and physical examination, imaging studies, and ancillary testing can usually help determine the source of pain.

Quantitative analysis of glenoid bone loss in osteoarthritis using three-dimensional computed tomography scans.

The 3-dimensional (3D) shape of the glenoid vault has been defined previously and shown to be a complex, yet consistent, shape in individuals without glenoid pathology. We proposed assessing whether this conserved shape could be used as a template to measure glenoid bone loss in subjects with glenohumeral osteoarthritis. Computed tomography (CT) scans of both shoulders were obtained from 12 subjects with unilateral glenohumeral osteoarthritis. The paired scapulae were reconstructed 3-dimensionally, using a previously developed graphic software package. Two methods of estimating glenoid bone loss were performed. First, using the software, a stereolithography model of the standardized vault shape was implanted into each glenoid and measurements made of the volume of the implant not contained within each vault. Second, direct measurements of the paired glenoid vault volumes were performed. The volume of the nonarthritic glenoid was used as a subject-specific template for normal glenoid vault volume for each pair. The glenoid bone volumes measured by each method were compared and Pearson's correlation coefficient determined. The average measurement of glenoid bone loss using the vault implant was within 0.8% (SD +/- 1.5%) of the measurement made using the contralateral, normal glenoid. For all patients, Pearson's correlation coefficient was .99, indicating a very high correlation between the two methods of measuring bone loss (P < .0001). The intricate, yet consistent 3D shape of the glenoid vault can be used as an accurate and reliable template to measure glenoid bone loss in glenohumeral osteoarthritis.

Inter-rater reliability of an arthritic glenoid morphology classification system.

To our knowledge, no independent analysis of the inter-rater agreement of the widely used Walch classification for osteoarthritic glenoid morphology has been performed. The computed tomography scans of 24 shoulders with primary osteoarthritis were used by 4 experienced shoulder surgeons to classify the glenoids independently according to Walch et al. The weighted kappa statistic was calculated to determine the inter-rater and intrarater agreement among observers. The overall inter-rater agreement for the Walch classification was fair (kappa = 0.37) when classified into the 5 types (A1, A2, B1, B2, and C). Agreement for the various subclassifications was as follows: A1, kappa = 0.22; A2, kappa = 0.33; B1, kappa = 0.17; B2, kappa = 0.32; and C, kappa = 0.86. When the classification system was simplified to just the 3 major types (A, B, and C), overall agreement was moderate (kappa = 0.44). Agreement for each type was moderate for A (kappa = 0.59) and B (kappa = 0.59) and almost perfect for C (kappa = 0.89). Overall intrarater agreement was fair (kappa = 0.37). We conclude that only fair agreement was found among experienced shoulder surgeons when classifying arthritic shoulders using the classification system of Walch et al. A glenoid classification scheme that relies more upon glenoid morphology and less upon humeral head position may demonstrate greater observer agreement and, therefore, may offer greater value.

Normal glenoid vault anatomy and validation of a novel glenoid implant shape.

Current glenoid implants are designed to be secured to the articular surface. When the articular surface is compromised, a glenoid component could be implanted if it obtained fixation from the endosteal surface of the glenoid vault. The first step for designing such a glenoid implant is to define the normal three-dimensional anatomy of the glenoid vault. The purpose of this study was to define the variations in glenoid vault shape in a large group of cadaver scapula. Computed tomographic (CT) scans of 61 normal scapulae (mean, 25-34 years) from the Haman-Todd Osteological Collection, with a wide range of sizes, were examined to define the normal glenoid vault anatomy. A custom software program was used to manipulate and measure the scans to determine the morphologic variations among the different glenoid vaults. From these data, we defined a unique glenoid vault shape and empirically developed 5 sizes to represent the study population of the 61 scapulae. A second group of 11 cadaver scapulae were used to validate the shape defined using the other 61. Prototype implants were placed into the real 11 scapulae using standard surgical techniques and then CT-scanned to analyze the shape of the glenoid vault. In the 61 scapulae, 85% of the points defining the endosteal surfaces vary among scapulae by less than 2 mm. For each of the 11 cadaver scapulae, the implant size used in the virtual computer implantation was the same size used for the plastic components placed into the cadaver scapulae. Fifty percent of the measured distances between the outer dimensions of the plastic models was within 2.4 mm of the glenoid endosteal surface. Eighty percent of the surface area of the plastic models was within 3.1 mm of the glenoid endosteal surface. Five percent of the dimensions were less than 1 mm and were considered to be areas of point contact. Before designing implants that can be used in pathologic glenoids, the shape of the normal glenoid vault must first be defined. This study defined a normal glenoid vault shape that can accommodate different sized scapula with 5 sizes. This glenoid shape may be used as a template to design a glenoid implant that obtains fixation within the glenoid vault.

Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial.

BACKGROUND: Evidence to justify the use of porcine small intestine submucosa to augment repairs of large and massive rotator cuff tears is based on favorable results found in studies of Achilles tendon and infraspinatus tendon repairs in canines. The purpose of this study was to determine the effectiveness of a small intestine submucosal patch to augment the repair of chronic two-tendon rotator cuff tears in humans. METHODS: Thirty shoulders with a chronic two-tendon rotator cuff tear that was completely repairable with open surgery were randomized to be treated with either augmentation with porcine small intestine mucosa or no augmentation. All patients completed a PENN shoulder-score questionnaire preoperatively and at the time of the latest follow-up (at an average of fourteen months). Magnetic resonance imaging showed that nine shoulders had a large tear and twenty-one had a massive tear. All patients underwent a magnetic resonance imaging scan with intra-articular gadolinium one year after the repair to assess the status of the rotator cuff. RESULTS: The rotator cuff healed in four of the fifteen shoulders in the augmentation group compared with nine of the fifteen in the control group (p = 0.11). The median postoperative PENN total score was 83 points in the augmentation group compared with 91 points in the control group (p = 0.07). Healing of the defects in both groups demonstrated a strong correlation with the patients' clinical scores. The median postoperative PENN total score was 96 points in the group with a healed repair and 81 points in the group with a failed repair (p = 0.007). The percentage change between the preoperative and postoperative patient satisfaction scores was 400% in the group with a healed repair, and 50% in the group with a failed repair (p = 0.04). CONCLUSIONS: Augmentation of the surgical repair of large and massive chronic rotator cuff tears with porcine small intestine submucosa did not improve the rate of tendon-healing or the clinical outcome scores. On the basis of these data, we do not recommend using porcine small intestine submucosa to augment repairs of massive chronic rotator cuff tears done with the surgical and postoperative procedures described in this study.

The effect of humeral component anteversion on shoulder stability with glenoid component retroversion.

BACKGROUND: Posterior glenoid bone loss is often seen in association with glenohumeral osteoarthritis. This posterior asymmetric wear can lead to retroversion of the glenoid component and posterior instability after total shoulder arthroplasty. Options for the treatment of this asymmetric wear include eccentric reaming of the so-called high side, bone-grafting, and/or anteverting the humeral component. Although anteverting the humeral component has been advocated by many, it has not been substantiated on the basis of biomechanical data. The purpose of the present study was to determine whether anteverting the humeral component increases the stability of a total shoulder replacement with a retroverted glenoid component. METHODS: A total shoulder arthroplasty was performed in eight human cadaveric shoulders. The glenoid component was placed in 15 degrees of retroversion. Two humeral versions were tested for each specimen: anatomic version and 15 degrees of anteversion relative to anatomic version. The specimens were mounted supine in a custom fixture on a servohydraulic testing system. The humerus was translated posteriorly by one-half of the width of the glenoid. Three positions of humeral rotation were tested for each position of humeral version. Both the energy and the peak load were analyzed as measures of joint stability. RESULTS: There was no significant difference in either energy or peak load between the tests performed with the humeral component in 15 degrees of anteversion and those performed with the component in anatomic version in any of the three rotational positions (p > 0.05). CONCLUSIONS: Although anteverting the humeral component during total shoulder arthroplasty to compensate for glenoid retroversion has been advocated, these data suggest that compensatory anteversion of the humeral component does not increase the stability of a shoulder replacement with a retroverted glenoid component.

Use of hepatitis B core antibody-positive donors in orthotopic liver transplantation.

HYPOTHESIS: Hepatic allografts from donors positive for antibody to hepatitis B core antigen (anti-HBc) frequently transmit hepatitis B virus (HBV) infection to recipients. Therefore, most transplantation centers will not use these organs for orthotopic liver transplantation (OLT). Although it is expensive and not always efficacious, hepatitis B immune globulin (HBIG) has been used routinely for indefinite periods to prevent HBV infection in liver allograft recipients. We assessed the effectiveness of long-term use of a nucleoside analog, lamivudine, in preventing HBV transmission by anti-HBc-positive allografts. DESIGN: Retrospective study. SETTING: A tertiary care center. PATIENTS: Twelve patients received hepatic allografts from anti-HBc-positive donors at Loyola University Medical Center, Chicago, between February 23, 1998, and March 13, 2001. INTERVENTION: All patients received 10 000 U/d of intravenous HBIG for 7 days. In addition, they received 300 mg/d of lamivudine in divided doses. Their liver biopsy specimens were tested for HBV DNA, hepatitis B surface antigen (HBsAg), and hepatitis B core antibody (HBcAb). Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody (HBsAb). MAIN OUTCOME MEASURE: The incidence of HBV infection in recipients who received HBcAb-positive donor livers and lamivudine prophylaxis. RESULTS: All recipients were anti-HBc negative before OLT. Five of the recipients had HBsAb titers greater than 150 U at the time of OLT. Three of the donor livers were HBV DNA positive and 2 were hepatitis B core antigen positive at the time of OLT. Donor serum was HBcAb positive in all 12 donors. None of the recipients have become infected with HBV with a follow-up of 2 to 38 months. CONCLUSION: Perioperative use of HBIG combined with long-term use of lamivudine can prevent HBV infection in recipients who receive hepatic allografts from HBcAb-positive donors.

Protection against concanavalin A-induced hepatocyte apoptosis by molsidomine is time-dependent.

BACKGROUND: Viral hepatitis and autoimmune liver diseases cause hepatocyte apoptosis. Concanavalin A (Con A)-induced hepatitis resembles human viral hepatitis and autoimmune hepatitis. The role of nitric oxide (NO) in liver injury was controversial in different liver injury models. We hypothesize both endogenous and exogenous NO protect liver against Con A-induced liver injury. Molsidomine is metabolized into SIN-1 by the liver, and SIN-1 subsequently generates NO. So, molsidomine was used as a NO donor in this study. STUDY DESIGN: To study a protective role of endogenous NO in Con A-induced liver injury, mice were pretreated with a specific inducible nitric oxide synthase (iNOS) inhibitor, L-N(6)-(1-iminoethyl)-lysine (L-NIL), before Con A challenge. To study a time-dependent protection against Con A-induced liver injury, animals were either given molsidomine, a NO donor, before or after Con A administration. Serum alanine aminotranferase (ALT) was analyzed. Liver samples were subjected to DNA fragmentation assay, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling stain, Western blot analysis, and caspase activity assays. RESULTS: Animals pretreated with L-NIL had significantly increased serum ALT levels compared with those challenged with Con A alone; but pretreatment with molsidomine dramatically decreased ALT levels in L-NIL-pretreated animals or in animals that received Con A alone. Administration of molsidomine 30 minutes before or 1, 2, and 3 hours after Con A injection significantly reduced serum ALT levels and attenuated hepatocyte apoptosis from caspase inactivation. The ALT reduction was associated with inhibition of both caspase-3 and caspase-8 activation and reduction of hepatocyte apoptosis. CONCLUSIONS: Endogenous NO plays an important protective role against Con A-induced liver injury by reducing hepatocyte apoptosis. Administration of a NO donor early after Con A injection protects the liver from injury. This is the first study demonstrating a time-dependent inhibition of liver injury induced by Con A administration.

The nitric oxide donor molsidomine improves survival and reduces hepatocyte apoptosis in cholestasis and endotoxemia.

BACKGROUND: Cholestasis and endotoxemia have been demonstrated to cause hepatocyte apoptosis through caspase-mediated pathways. In vitro nitric oxide (NO) donors reduce hepatocyte apoptosis and caspase activation in several models. The nitric oxide donor molsidomine improves survival in an in vivo model of endotoxemia. We tested the effect of molsidomine on survival and hepatocyte apoptosis in a model of obstructive jaundice and endotoxemia. STUDY DESIGN: Sprague-Dawley rats underwent common bile duct ligation on day 1. On day 3, animals were given either 100 mg/kg of molsidomine or an equivalent volume of saline, and 30 minutes later they were given endotoxin 3 mg/kg or 10 mg/kg intravenously. Animals were sacrificed 4 or 16 hours after endotoxin injection. Serum samples were analyzed for alanine aminotransferase and frozen liver samples were analyzed for caspase 3 activity. Paraffin-embedded liver sections were assayed for apoptosis using the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Survival was measured in a separate experiment in which animals underwent the same protocol, but were given three different doses of endotoxin and were observed for 72 hours before sacrifice. RESULTS: At endotoxin 3 mg/kg, the 72-hour survival in saline-treated animals was 92%, which decreased to 45% at 10 mg/kg and to 29% at 15 mg/kg. All of the molsidomine-treated animals survived all endotoxin doses. Alanine aminotransferase was reduced in molsidomine-treated animals compared with those treated with saline. Apoptosis was attenuated in molsidomine-treated animals. Caspase 3 activity was decreased in molsidomine-treated animals compared with those given saline. CONCLUSIONS: Molsidomine attenuates caspase activation and hepatocyte apoptosis and improves survival after cholestatic endotoxic injury.

Endotoxin potentiates hepatocyte apoptosis in cholestasis.

BACKGROUND: Cholestasis is a component of liver disease of almost any etiology, including septic liver injury. The cellular mechanisms of liver injury in cholestasis and sepsis remain unresolved. We evaluated apoptosis, a well-orchestrated and potentially reversible mechanism of cell death, in bile duct-ligated and endotoxin-injected rats. STUDY DESIGN: Male Sprague-Dawley rats were randomly assigned to six groups (n = 6-9): bile duct-ligated+endotoxin (B+E), sham+endotoxin (S+E), bile duct-ligated (B), sham (S), endotoxin (E), and normal (N). On day 1, the bile ducts of B+E and B rats were ligated and severed. S+E and S animals underwent biliary manipulation only. On day 3, B+E, S+E, and E groups received 3 mg/kg endotoxin i.v.. On day 4, livers from all rats were excised, fixed, and stained (hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL]). Portions were frozen for DNA fragmentation analysis. Caspase 3 activity was determined using isolated hepatocytes. RESULTS: Livers from all groups (B+E, S+E, E, and B) except normal and sham displayed apoptosis by hematoxylin and eosin staining, TUNEL staining, and DNA fragmentation. Histologic evaluation revealed 10% to 20% necrosis in endotoxin-treated animals (B+E, S+E, and E). Caspase 3 activity was significantly higher in endotoxin-treated animals versus animals without endotoxin (treated 0.450 +/- 0.08 versus nontreated 0.135 +/- 0.05, p < 0.0001) (mean +/- SD). CONCLUSIONS: Cholestatic livers had apoptosis without progression to necrosis. When exposed to the second insult of endotoxin, cholestatic livers received an acute on chronic apoptotic trigger, and proceeded to necrosis. Endotoxin was a potent hepatotoxic insult because all treated rat livers displayed both apoptosis and necrosis.

Liver transplantation for fulminant hepatic failure.

The etiology and prognosis of individuals with various forms of fulminant hepatic failure are reviewed. Special techniques of clinical management and decision making as to when and to whom to transplant in cases of fulminant hepatic failure are reviewed.

Open Roux-en-Y gastric bypass for the morbidly obese in the era of laparoscopy.

BACKGROUND: Roux-En-Y gastric bypass (RYGB) has been the preferred operative treatment for morbid obesity. Recently, laparoscopic RYGB has been described. We reviewed our data and believe that open RYGB is still the better option. METHODS: One hundred three consecutive cases were retrospectively reviewed for preoperative conditions, perioperative outcomes, and postoperative complications with weight/health changes. RESULTS: The mean follow-up was 5 months. The mean percent excess body weight loss was 33%. Comorbidities improved 50% of the time. The mean operative time was 117 minutes with blood loss averaging 208 cc. The mean intensive care unit stay was 1.3 days, with a total hospital stay of 4.4 days. There was an 8% major complication rate and a 1% mortality rate. CONCLUSIONS: The health improvement and complication rates are comparable to published series on laparoscopic RYGB. With the technical complexity of the laparoscopic technique, open RYGB should remain the current standard of care, in most centers.

Laser capsulorrhaphy for multidirectional instability of the shoulder. An outcomes study and proposed classification system.

BACKGROUND: Clinical data on the efficacy of laser capsulorrhaphy for the treatment of multidirectional instability of the shoulder are limited. HYPOTHESIS: The diagnosis of multidirectional instability includes a spectrum of pathologic symptoms that warrants subclassification; laser capsulorrhaphy alone is not uniformly effective for all subtypes. STUDY DESIGN: Retrospective review of prospectively collected data. METHODS: Twenty-five shoulders in 21 patients were treated with laser capsulorrhaphy for multidirectional instability. Functional outcomes at a mean duration of 32 months' follow-up (range, 24 to 48 months) were recorded. RESULTS: Instability recurred in 60% of patients with congenital multidirectional instability, 17% of patients with acquired multidirectional instability, and 33% of patients with posttraumatic multidirectional instability (overall recurrence rate, 40%). Generalized ligamentous laxity was a risk factor for recurrence. Patient satisfaction rates were 40%, 83%, and 22% for the congenital, acquired, and posttraumatic subgroups. Reasons for dissatisfaction included recurrent instability, persistent pain, and inability to return to athletic activity at desired capacity. The overall mean postoperative Simple Shoulder Test score was 84%. The mean postoperative numeric rating score for pain was 3.3 (10-point scale). CONCLUSIONS: Laser capsulorrhaphy may be effective for patients with acquired multidirectional instability secondary to repetitive microtrauma but is less predictable in the other subgroups.