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Current evidence suggests it may be difficult for patients with chronic pain to quit smoking and, based on previous formative work, a 7-session individual and group-based cognitive behavioral (CB) intervention was developed. The primary aim of this randomized controlled pilot trial was to test the hypothesis that abstinence at month 6 would be greater among patients with chronic pain who received the CB intervention compared to a control condition. Upon admission to a 3-week interdisciplinary pain treatment (IPT) program, patients were randomized to receive the CB intervention (n=30) or the control condition (n=30). The 7-day point prevalence of self-reported smoking status was assessed at week 3 (upon completion of the 3-week IPT program) and at month 6 in an intent-to-treat analysis. At week 3, 30% (n=9) of patients in the CB condition were abstinent from smoking compared to 10% (n=3) in the control group (P=.104). At month 6, 20% (n=6) of patients who received the CB intervention were abstinent compared to none in the control group (P=.024). At week 3, a significant group by time interaction effect was found where the CB patients experienced greater improvements in self-efficacy from baseline compared to the control group (P=.002). A greater proportion of patients randomized to the CB group completed the IPT program (P=.052). The findings of this pilot trial suggest that integration of a CB-based smoking abstinence intervention into ongoing pain therapy may be an effective treatment for smokers with chronic pain., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: We will provide a context to health information technology systems (HIT) safety hazards discussions, describe how electronic health record-computer prescriber order entry (EHR-CPOE) simulation has already identified unrecognized hazards in HIT on a national scale, helping make EHR-CPOE systems safer, and we make the case for all stakeholders to leverage proven methods and teams in HIT performance verification., Methods: A national poll of safety, quality improvement, and health-care administrative leaders identified health information technology safety as the hazard of greatest concern for 2013. Quality, HIT, and safety leaders are very concerned about technology performance risks as addressed in the Health Information Technology and Patient Safety report of the Institute of Medicine; and these are being addressed by the Office of the National Coordinator of HIT of the U.S. Dept. of Human Services in their proposed plans. We describe the evolution of postdeployment testing of HIT performance, including the results of national deployment of Texas Medical Institute of Technology's electronic health record computer prescriber order entry (TMIT EHR-CPOE) Flight Simulator verification test that is addressed in these 2 reports, and the safety hazards of concern to leaders., Results: A global webinar for health-care leaders addressed the top patient safety hazards in the areas of leadership, practices, and technologies. A poll of 76 of the 221 organizations participating in the webinar revealed that HIT hazards were the participants' greatest concern of all 30 hazards presented. Of those polled, 89% rated HIT patient/data mismatches in EHRs and HIT systems as a 9 or 10 on a scale of 1 to 10 as a hazard of great concern. Review of a key study of postdeployment testing of the safety performance of operational EHR systems with CPOE implemented in 62 hospitals, using the TMIT EHR-CPOE simulation tool, showed that only 53% of the medication orders that could have resulted in fatalities were detected. The study also showed significant variability in the performance of specific EHR vendor systems, with the same vendor product scoring as high as a 75% detection score in one health-care organization, and the same vendor system scoring below 10% in another health-care organization., Conclusions: HIT safety hazards should be taken very seriously, and the need for proven, robust, and regular postdeployment performance verification measurement of EHR system operations in every health-care organization is critical to ensure that these systems are safe for every patient. The TMIT EHR-CPOE flight simulator is a well-tested and scalable tool that can be used to identify performance gaps in EHR and other HIT systems. It is critical that suppliers, providers, and purchasers of health-care partner with HIT stakeholders and leverage the existing body of work, as well as expert teams and collaborative networks to make care safer; and public-private partnerships to accelerate safety in HIT. A global collaborative is already underway incorporating a "trust but verify" philosophy.

Quantifying the effect size of acute exercise on insulin sensitivity (SI(exercise)) and simultaneous measurement of glucose disappearance (R(d)), endogenous glucose production (EGP), and meal glucose appearance in the postprandial state has not been developed in humans. To do so, we studied 12 healthy subjects [5 men, age 37.1 ± 3.1 yr, body mass index 24.1 ± 1.1 kg/m², fat-free mass (FFM) 50.9 ± 3.9 kg] during moderate exercise at 50% V(O₂max) for 75 min, 120-195 min after a triple-tracer mixed meal consumed at time 0. Tracer infusion rates were adjusted to achieve constant tracer-to-tracee ratio and minimize non-steady-state errors. Glucose turnover was estimated by accounting for the nonstationary kinetics introduced by exercise. Insulin sensitivity index was calculated in each subject both in the absence [time (t) = 0-120 min, SI(rest)] and presence (t = 0-360 min, SI(exercise)) of physical activity. EGP at t = 0 min (13.4 ± 1.1 μM·kg FFM⁻¹·min⁻¹) fell at t = 120 min (2.4 ± 0.4 μM·kg FFM⁻¹·min⁻¹) and then rapidly rose almost eightfold at t = 180 min (18.2 ± 2.6 μM·kg FFM⁻¹·min⁻¹) before gradually falling at t = 360 min (10.6 ± 0.9 μM·kg FFM⁻¹·min⁻¹). R(d) rapidly peaked at t = 120 min at the start of exercise (89.5 ± 11.6 μM·kg FFM⁻¹·min⁻¹) and then gradually declined at t = 195 min (26.4 ± 3.3 μM·kg FFM⁻¹·min⁻¹) before returning to baseline at t = 360 min. SI(exercise) was significantly higher than SI(rest) (21.6 ± 3.7 vs. 12.5 ± 2.0 10⁻⁴ dl·kg⁻¹·min⁻¹ per μU/ml, P < 0.0005). Glucose turnover was estimated for the first time during exercise with the triple-tracer technique. Our results, applying state-of-the-art techniques, show that moderate exercise almost doubles postprandial insulin sensitivity index in healthy subjects.

In the past 30 years, composite microvascular free tissue transfer has become a popular and highly successful option for the reconstruction of defects in the head and neck region. However, inherent shortcomings exist with free tissue transfer in that the imported tissue often fails to adequately replicate the characteristics of the native tissues. This can lead to difficulties when attempting reconstruction from a surgical and prosthetic standpoint. Endosseous implants are often required to adequately retain prostheses, and management of the peri-implant soft tissues represents a critical challenge for the oral and maxillofacial surgeon. This report describes a novel technique for controlling the implant-abutment-soft tissue interface and the advantages of this technique as it pertains to orofacial reconstruction., (Copyright © 2013 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Takotsubo syndrome, also called apical ballooning syndrome, is a clinical entity characterized by transient hypokinesis, akinesis, or dyskinesis of the left ventricular mid and apical segments without flow limiting obstructive coronary lesions. There have been many reported morphologic variants of apical ballooning syndrome based upon distribution of segment involvement including traditional apical, midventricular, and basilar. We present a patient who demonstrated sequential transition of mid-basilar type to classical apical ballooning type. < Learning objective: Takotsubo syndrome mimics acute coronary syndrome and is accompanied by reversible left ventricular apical ballooning in the absence of angiographically significant coronary artery stenosis. Many morphological presentations can present, hence increased awareness may help practitioners identify and properly treat this condition. This is the first reported case of a sequential transition between variants.>.

Evaluation of the existence of a diurnal pattern of glucose tolerance after mixed meals is important to inform a closed-loop system of treatment for insulin requiring diabetes. We studied 20 healthy volunteers with normal fasting glucose (4.8 ± 0.1 mmol/L) and HbA(1c) (5.2 ± 0.0%) to determine such a pattern in nondiabetic individuals. Identical mixed meals were ingested during breakfast, lunch, or dinner at 0700, 1300, and 1900 h in randomized Latin square order on 3 consecutive days. Physical activity was the same on all days. Postprandial glucose turnover was measured using the triple tracer technique. Postprandial glucose excursion was significantly lower (P < 0.01) at breakfast than lunch and dinner. β-Cell responsivity to glucose and disposition index was higher (P < 0.01) at breakfast than lunch and dinner. Hepatic insulin extraction was lower (P < 0.01) at breakfast than dinner. Although meal glucose appearance did not differ between meals, suppression of endogenous glucose production tended to be lower (P < 0.01) and insulin sensitivity tended to be higher (P < 0.01) at breakfast than at lunch or dinner. Our results suggest a diurnal pattern to glucose tolerance in healthy humans, and if present in type 1 diabetes, it will need to be incorporated into artificial pancreas systems.

Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder.

Background: Functional tricuspid regurgitation (FTR) with structurally normal valve is of poorly defined mechanisms. Prevalence and clinical context of idiopathic FTR (Id-FTR) (without overt TR cause) are unknown., Methods and Results: To investigate prevalence, clinical context, and mechanisms specific to FTR types, Id-FTR versus pulmonary hypertension-related (PHTN-FTR, systolic pulmonary pressure ≥50 mm Hg), we analyzed 1161 patients with prospectively quantified TR. Id-FTR (prevalence 12%) was associated with aging and atrial fibrillation. For mechanistic purposes, we measured valvular and right ventricular (RV) remodeling in 141 Id-FTR matched to 140 PHTN-FTR and to 99 controls with trivial TR for age, sex, atrial fibrillation, and ejection fraction. PHTN-FTR and Id-FTR were also matched for TR effective-regurgitant-orifice (ERO). Id-FTR valvular alterations (versus controls) were largest annular area (3.53±0.6 versus 2.74±0.4 cm(2), P<0.0001) and lowest valvular/annular coverage ratio (1.06±0.1 versus 1.45±0.2, P<0.0001) but normal valve tenting height. PHTN-FTR had mild annular enlargement but excessive valve tenting height (0.8±0.3 versus 0.35±0.1 cm, P<0.0001). Valvular changes were linked to specific RV changes, largest basal dilatation, and normal length (RV conical deformation) in Id-FTR versus longest RV with elliptical/spherical deformation in PHTN-FTR. With increasing FTR severity (ERO ≥40 mm(2)), changes specific to each FTR type were accentuated, and RV function (index of myocardial performance) was consistently reduced., Conclusions: Id-FTR is frequent, linked to aging and atrial fibrillation, can be severe, and is of unique mechanism. In Id-FTR, excess annular and RV-basal enlargement exhausts valvular/annular coverage reserve, and RV conical deformation does not cause notable valvular tenting. Conversely, PHTN-FTR is determined by valvular tethering with tenting linked to RV elongation and elliptical/spherical deformation. These specific FTR-mechanisms may be important in considering surgical correction in FTR.

Incidentally discovered pituitary lesions are commonly encountered in the current era of ever-increasing imaging. Individualizing a particular approach implies a thorough analysis of existing evidence and balancing it against different patient expectations. We will illustrate the application of principles of Evidence-Based Medicine to a case of a pituitary incidentaloma by formulating questions that are important to patient care and finding related evidence. Our objective is to reflect the opportunities and the challenges that an evidence-based clinical approach offers to clinicians and patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Unlabelled: TREAT (Targeted RE-sequencing Annotation Tool) is a tool for facile navigation and mining of the variants from both targeted resequencing and whole exome sequencing. It provides a rich integration of publicly available as well as in-house developed annotations and visualizations for variants, variant-hosting genes and host-gene pathways., Availability and Implementation: TREAT is freely available to non-commercial users as either a stand-alone annotation and visualization tool, or as a comprehensive workflow integrating sequencing alignment and variant calling. The executables, instructions and the Amazon Cloud Images of TREAT can be downloaded at the website: http://ndc.mayo.edu/mayo/research/biostat/stand-alone-packages.cfm.

Key Points: 1. Our increasing understanding of the signaling pathways and cellular interactions in transplant immunobiology has facilitated targeted strategies using novel immunosuppressive agents. 2. The pattern of immunosuppressive drug use in the United States continues to change, and the changes include the use of antibody induction therapy and the agents used in maintenance therapy. 3. The driving forces behind the development of new immunosuppressive regimens are the long-term complications of current immunosuppressive regimens (particularly renal dysfunction and metabolic disturbances)., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Mitral regurgitation (MR), currently the most frequent valvular heart disease, is mostly degenerative, linked to aging and of increasing prevalence. Indications of mitral surgery, the only current approved treatment of MR, are disputed. Coherent cumulative evidence obtained worldwide show that early surgery in asymptomatic patients is the preferred approach. Waiting for symptoms or left ventricular dysfunction is a failed strategy in that these characteristics are insensitive markers of risk, are often unrecognized in a timely manner and, even after successful surgery, are associated with poor outcome. Furthermore, in patients with severe organic MR, surgery is almost unavoidable and early mitral repair before the appearance of symptoms or overt LV dysfunction may restore life expectancy as long as valve repair is performed. New objective markers of adverse outcome under medical management have recently been described, allowing selection of patients for performance of restorative surgery that reestablishes life expectancy. This approach of early surgery provides improved outcomes in observational studies and is conceivable in centers that provide low risk, high repair rates, high quality of repairs and of Doppler-Echocardiographic assessment., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: We sought to determine if higher resolution 3 Tesla (T) magnetic resonance imaging (MRI) with or without ovine corticotropin releasing hormone (o-CRH) stimulation would increase the sensitivity for detection of pituitary microadenomas in ACTH-dependent Cushing's syndrome (CS)., Design and Patients: We prospectively identified 23 patients over a 2-year period with clinical and biochemical evidence of ACTH-dependent CS with no lesion (n = 11) or equivocal lesion (n = 10) on 1.5T MRI. Subsequently, two additional MRIs were performed in random order: 3T nonstimulated MRI or 3T MRI with o-CRH in all patients. Three neuroradiologists reviewed all examinations in a randomized blinded fashion. Patients were divided into four groups, depending on the outcome of their evaluation and treatment for CS. Two patients had to be excluded, and so we report on 21 subjects., Measurements and Results: Both 3T MRI without (P < 0.016) and with o-CRH stimulation (P < 0.013) was significantly more sensitive for detection of pituitary microadenomas than 1.5T MRI for Group 1 (definitive proof of Cushing's disease, n = 10). Group 2 (those in group 1, plus three patients where dynamic/invasive testing suggested pituitary source) also showed a significant (P < 0.012) advantage for 3T. There was no difference between the 3T and the 3T o-CRH examinations for any of the pulse sequences. We did not observe a statistically significant difference in other patient groups [patients with recurrent CD (n = 6) and patients with ectopic CS (n = 2)]., Conclusions: The results of our prospective blinded studies suggest that 3T MRI of pituitary gland should be considered in evaluation of patients with ACTH-dependent CD when 1.5T imaging is negative or equivocal.

Background: Primary lateral sclerosis (PLS) is a progressive upper motor neuron neurodegenerative condition. The diagnosis is made using clinical history, objective neurological assessment, and exclusion of other neurodegenerative disorders., Objective: To evaluate the role of fluorodeoxyglucose F18 positron emission tomography and 3-dimensional stereotactic surface projection in the diagnosis of PLS., Design: Case series., Setting: Outpatient neurology clinic. Patients Three cases of probable PLS. Intervention Fluorodeoxyglucose F18 positron emission tomography in 3 patients with PLS., Results: Three patients (2 male and 1 female; mean age, 65 years) were identified with a clinical diagnosis of PLS. Fluorodeoxyglucose F18 positron emission tomography demonstrated varying degrees of primary motor cortex hypometabolism., Conclusion: Fluorodeoxyglucose F18 positron emission tomography and 3-dimensional stereotactic surface projection provide a useful diagnostic method to support a clinical diagnosis of PLS.

Background: Postoperative Rhabdomyolysis (RM) is rare after neurosurgical procedures. Furthermore, it has not been observed after transnasal approaches. The authors report a case of idiopathic RM occurring after transnasal resection of a sincipital encephalocele., Case Description: A 32-year-old woman underwent a transnasal resection of a sincipital encephalocele after 6 years of intermittent clear nasal drainage. Postoperatively, she experienced severe back pain, peripheral neuropathy, associated with a markedly elevated creatinine kinase, and severe RM. The patient was treated with hydration and forced urine alkalization and treated symptomatically for her pain and neuropathy. She ultimately made a full recovery without complication., Conclusion: Rhabdomyolysis is a rare but known complication of neurosurgical procedures. We report the first known case report of RM after a transnasal procedure. Furthermore, a review of documented postneurosurgical cases of RM is presented and reveals that the causes and risk factors for this complication after neurosurgery are similar to those in other surgical subspecialties., (Copyright 2009 Elsevier Inc. All rights reserved.)

We describe two cases of trisomy 2. The first case is a child with mosaic trisomy 2 who presented with mental retardation, multiple congenital anomalies, and dysmorphic findings similar to Pallister-Killian syndrome. The second case was an acardiac and acranial fetus with complete trisomy 2. We review the phenotypic spectrum associated with trisomy 2.

Peripheral T-cell lymphomas (PTCLs) are malignancies of immunologically mature T-cells that arise in peripheral lymphoid tissues such as lymph nodes, spleen, gastrointestinal tract, and skin. These lymphomas are uncommon as compared with the incidence of B-cell lymphomas, and they comprise only 5% to 10% of non-Hodgkin lymphomas in North America and Western Europe. A variety of specific disease entities have been recognized among PTCLs, and they tend to have lymph node, extranodal/cutaneous, or mixed leukemic/lymphomatous presentations. Most PTCLs have an aggressive clinical course. The clinicopathologic features of the various PTCLs are described herein.

Objective: To assess the incidence, severity, and spectrum of neurologic toxic effects associated with administration of amiodarone hydrochloride., Design: Retrospective medical record analysis of cardiac patients treated with amiodarone between January 1, 1996, and July 31, 2008., Setting: Residents of Olmsted County, Minnesota, treated at the Mayo Clinic., Patients: The Mayo Clinic medical records of all adult Olmsted County residents prescribed amiodarone between January 1, 1996, and July 31, 2008, were reviewed and all possible neurologic adverse effects that might be attributable to amiodarone were tabulated., Main Outcome Measures: Risk factors and clinical characteristics of patients developing neurologic problems were compared with those who did not., Results: Over the 151 months of analysis, 707 patients were treated with amiodarone. Among these patients, the cumulative incidence of likely amiodarone neurotoxic effects was 2.8%; 1.6% of all amiodarone-treated patients were referred to Neurology for a neurotoxic reaction. Neurologic problems included tremor, gait ataxia, peripheral neuropathy, and cognitive impairment. The primary risk factor for amiodarone neurotoxic effects was duration of treatment, not age, drug dose, sex, or indication for therapy. Where this could be assessed, the adverse effects were usually but not always reversible., Conclusions: Amiodarone infrequently causes clinically significant neurologic toxic effects. Substantially higher estimates of neurotoxic effects in the early amiodarone era may be related to a much higher daily dose.

Background: Despite a nonobstructive coronary angiogram, many patients may still have an abnormal coronary vasomotor response to provocation and to myocardial demand during stress. The ability of noninvasive stress tests to predict coronary vasomotor dysfunction in patients with nonobstructive coronary artery disease is unknown., Methods and Results: All patients with nonobstructive coronary artery disease who had invasive coronary vasomotor assessment and a noninvasive stress test (exercise ECG, stress echocardiography, or stress nuclear imaging) within 6 months of the cardiac catheterization with provocation at our institution were identified (n=376). Coronary vasomotor dysfunction was defined as a percentage increase in coronary blood flow of

Objective: To determine if 3 months of preoperative gonadotropin-releasing hormone agonist (GnRH-a) treatment decreases postoperative uterine adhesions after open abdominal surgery for the removal of uterine fibroids., Design: Prospective, randomized, clinical study., Setting: A tertiary care medical center., Patient(s): Women of reproductive age with symptomatic uterine fibroids not amenable to hysteroscopic removal., Intervention(s): Twenty patients underwent an initial abdominal myomectomy followed by a second-look laparoscopy for evaluating uterine adhesions after random allocation to groups receiving either GnRH analog or placebo for 3 months before the initial surgery., Main Outcome Measure(s): Adhesion formation between treatment groups and by incision number and aggregate length., Result(s): Presurgical GnRH-a treatment did not decrease adhesion formation compared with placebo. For every additional centimeter of incision length, the total adhesion area over the uterine serosal surface increased by 0.55 cm(2). The number of myomas removed and the number of incisions were positively correlated with total adhesion area., Conclusion(s): Preoperative treatment with GnRH-a for 3 months before open abdominal myomectomy did not decrease postoperative uterine adhesions. Following the standards of good surgical technique, adhesions are minimized with fewer and smaller incisions.

The Exeter universal stem implanted with contemporary cementing technique has shown an excellent survivorship at 15 years. The technique used for implantation calls for prolonged pressurization preventing blood from the femur exiting into the femoral canal, but this technique is not accepted widely as some surgeons believe it is associated with significant morbidity. This concern prompted this review. From 1988 to 2005, 9082 primary total hip arthroplasty (THA) were implanted. We identified all patients who died within 30 days from surgery. When available, the postmortem results were reviewed. Twenty-one patients died within 30 days from their primary THA (prevalence, 0.23%). There was one intraoperative death (prevalence, 0.01%). The postmortem report was consistent with fat embolism. Two additional patients died the same day of surgery from cardiac processes. No other deaths could be linked to cement. Sudden death during cemented THA with a current contemporary cementing technique and a specialized anesthetic protocol is nearly zero.

Objective and Importance: Intraprocedural three-dimensional (3D) axial tomography reconstructions have improved aneurysm detection, pedicle screw placement and more, resulting in less morbidity and improved outcomes. Currently, relative to balloon compression for trigeminal neuralgia, we are dependent upon lateral 2-dimensional imaging for the classic 'pear shape' imaging to determine correct positioning., Clinical Presentation: Our patient was a 97-year-old woman with a 4-year history of V2 and V3 intermittent severe pain with typical features of trigeminal neuralgia., Intervention: After induction of anesthesia on the Dyna-CT (Siemens) angiogram table, Meckl's cave was accessed as guided by fluoroscopy, a 4-French Fogarty catheter was introduced, and its balloon was inflated tightly for 90 s with soluble contrast agent to compress the gasserian ganglion. As would be done for 3D angiogram, the Dyna-CT was used to perform image acquisition for image reconstruction. Two additional cases are supplied to show the variability of volume filling of the balloon compression., Conclusion: We speculate that 3D reconstructions of percutaneous balloon compression of the trigeminal ganglion may aid in the identification of an ideal balloon configuration of a volume which could impact the outcome, or perhaps reduce complications such as masseter weakness or dysesthesias. Here we show the first clinical images available demonstrating volumetric reconstruction of a balloon compression for trigeminal neuralgia utilizing Dyna-CT., (Copyright 2009 S. Karger AG, Basel.)

Photodynamic therapy was the first treatment to have been shown to significantly decrease high-grade dysplasia and cancer in patients with Barrett's esophagus. However, its use has been limited, primarily because of the side effects, which include esophageal strictures, cutaneous photosensitivity, chest pain, and nausea and vomiting. The tolerability aspects of photodynamic therapy, as well as the dosimetry, though, can be improved with existing technologies to further develop this therapy into truly a widely applicable therapy. Studies have recently been done to help identify patients more likely to suffer stricture after photodynamic therapy. In addition there has been evidence to suggest that the efficacy of photodynamic therapy also can be limited by genetic abnormalities in the mucosa. By combining knowledge of tissue biology, optical properties of the tissue, and dosimetry issues with ablation, photodynamic therapy can still have a potentially bright future.

Objectives: Our purpose was to compare outcomes of patients treated for obstructive sleep apnea (OSA) versus patients with untreated OSA, all of whom had undergone percutaneous coronary intervention (PCI)., Background: Obstructive sleep apnea has been associated with increases in fatal and nonfatal cardiovascular events. It is not known whether treatment of OSA in patients who have had PCI results in a better outcome., Methods: In a retrospective cohort study, a group of patients with OSA diagnosed with polysomnography between 1992 and 2004 (apnea-hypopnea index > or =15) who subsequently underwent a PCI (n = 371) were stratified according to whether they were treated for OSA (n = 175) or not (n = 196). Main outcome measures were cardiac death, general mortality, major adverse cardiac events (MACE) (severe angina, myocardial infarction, PCI, coronary artery bypass grafting, or death), and major adverse cardiac or cerebrovascular events (MACCE)., Results: Patients treated for OSA had a statistically significant decreased number of cardiac deaths on follow-up when compared with untreated OSA patients (3% [95% confidence interval (CI) 0% to 6%] vs. 10% [95% CI 5% to 14%] after 5 years, p = 0.027), as well as a trend toward decreased all-cause mortality (p = 0.058). There was no difference in the number of MACE or MACCE between the 2 groups (p = 0.91 and 0.96, respectively)., Conclusions: Treatment of OSA is associated with a reduction in the number of cardiac deaths, but not in MACE or MACCE, after PCI. Screening for and treating OSA in patients with coronary artery disease who may undergo PCI may result in decreased cardiac death.

Blockade of the lateral femoral cutaneous nerve (LFCN) is performed for therapeutic management of meralgia paresthetica and as a regional anesthetic technique. The conventional technique is associated with high failure rates secondary to variable LFCN anatomy. We describe a technique for blockade of the LFCN using ultrasound guidance. A cross-sectional view of the LFCN was obtained by identifying the anterior superior iliac spine, then moving a 14-to-7MHz linear array ultrasound probe in a medial caudal direction until the nerve was encountered. The needle was advanced to the LFCN under ultrasound guidance via a lateral to medial approach. Injection using dynamic ultrasound demonstrated excellent perineural spread. Ten subjects underwent successful blockade of the LFCN with this technique. Five subjects were obese. Use of ultrasound for precise needle placement allowed low injection volumes to be utilized. Theref were no complications. Ultrasound guidance can facilitate blockade of the LFCN for diagnostic and therapeutic purposes and may be particularly beneficial with patients with challenging surface anatomic landmarks, or when low volume injections are desired.

Background: Smoking is a major risk factor for cardiovascular events. One of the potential mechanisms may be related to both coronary endothelial dysfunction and increased inflammatory response. The present study was designed to test the hypothesis that smoking is associated with epicardial coronary endothelial dysfunction and inflammation., Methods and Results: Coronary endothelial function in response to acetylcholine was assessed in 881 patients (115 current smokers and 766 nonsmokers, including 314 previous smokers). Smokers were significantly younger than nonsmokers (43+/-1 versus 51+/-1 years, P<0.0001), had more epicardial vasoconstriction in response to intracoronary acetylcholine (-19+/-2% versus -14+/-1% change in coronary artery diameter, P=0.03), and were more likely than nonsmokers to have epicardial endothelial dysfunction (46% versus 35%, P=0.005), but their microvascular endothelial function was intact. Smokers had higher white blood cell counts than nonsmokers (7.7+/-0.2 versus 6.6+/-0.1x10(9)/L, P<0.0001), higher myeloperoxidase (156+/-19 versus 89+/-8 ng/mL), higher lipoprotein-associated phospholipase A2 (242+/-12 versus 215+/-5 ng/mL), and higher levels of intracellular adhesion molecule (283+/-14 versus 252+/-5 ng/mL). There were no differences in the levels of C-reactive protein, fibrinogen, or vascular cell adhesion molecule between the groups., Conclusions: Young smokers are characterized by epicardial coronary endothelial dysfunction, preserved microvascular endothelial function, and increased levels of inflammatory biomarkers and oxidative stress. The present study provides further information regarding the potential mechanisms by which smoking contributes to cardiovascular events.

We aimed to define the dose of pirfenidone in children and adolescents with neurofibromatosis 1 and plexiform neurofibromas that is pharmacokinetically comparable to the active adult dose. Pirfenidone was administered orally on a continuous dosing schedule. The starting dose level was 250 mg/m2/dose. The second dose level (500 mg/m2/dose) corresponded to the adult dose that previously showed activity in sclerosing conditions. A dose was considered pharmacokinetically comparable if the drug exposure in children was <1 standard deviation below the drug exposure in adults treated with 800 mg three times a day. Pharmacokinetic sampling was performed for 24 hours after the first dose. Response to treatment was evaluated using automated volumetric magnetic resonance imaging analysis; quality of life was evaluated using the Impact of Pediatric Illness Scale. Sixteen patients were entered and evaluated for toxicity. Dose-limiting toxicities were observed in 2 of 12 patients receiving 500 mg/m2 three times a day. The plasma pharmacokinetics of pirfenidone were highly variable, but not age dependent. The second dose level was the pharmacokinetically comparable dose and is being used in an ongoing phase II trial of pirfenidone for children with neurofibromatosis 1 and progressive plexiform neurofibroma.

The purpose of this study was to determine the association between depression and coronary endothelial function and cardiac risk factors in men and women without obstructive coronary artery disease. Patients with no significant coronary artery disease who underwent invasive coronary endothelial function assessment with acetylcholine were studied. Men and women were divided into 2 groups: those with depression and those without. Endothelial function and risk factor profiles were compared between the 2 groups. Seven hundred fifty-nine patients were studied, 603 (79%) without depression and 156 (21%) with depression. Patients with depression were more likely to be women (71% vs 60%, p = 0.02), have greater body mass indexes (29.9 +/- 6.7 vs 28.2 +/- 5.9 kg/m(2), p = 0.002), and be diabetic (12% vs 6%, p = 0.02). Depressed patients also had higher levels of C-reactive protein (0.35 vs 0.30 mg/dl, p = 0.02). There was no difference in the change in coronary blood flow or diameter in response to acetylcholine between the 2 groups in men and women. In conclusion, the results of this study demonstrate that depression is not associated with coronary endothelial dysfunction in men and women without significant coronary artery disease. It is, however, associated with a cluster of cardiac risk factors that are linked to the progression of atherosclerotic disease.

We investigated whether markers of inflammation, including a cytokine (IL-6), acute-phase reactants [C-reactive protein (CRP) and fibrinogen], and white blood cell (WBC) count are associated with maximal O(2) consumption (Vo(2 max)) in men without coronary heart disease (CHD). In asymptomatic men (n = 172, 51 +/- 9.3 yr old), Vo(2 max) was measured during a symptom-limited graded treadmill exercise test. Physical activity level was assessed by a standardized questionnaire. IL-6 and CRP were measured by immunoassays, fibrinogen by the Clauss method, and WBC count with a Coulter counter. IL-6 and CRP were logarithmically transformed to reduce skewness. Multivariable regression was used to assess whether markers of inflammation were associated with Vo(2 max) after adjustment for age, body mass index, CHD risk factors, and lifestyle variables (physical activity level, percent body fat, and alcohol intake). Vo(2 max) was 34.5 ml.kg(-1).min(-1) (SD 6.1). Log IL-6 (r = -0.38, P < 0.001), log CRP (r = -0.40, P < 0.001), fibrinogen (r = -0.42, P < 0.001), and WBC count (r = -0.22, P = 0.004) were each correlated with Vo(2 max). In separate multivariable linear regression models that adjusted for age, body mass index, CHD risk factors, and lifestyle variables, log IL-6 [beta-coeff = -1.66 +/- 0.63 (SE), P = 0.010], log CRP [beta-coeff = -0.99 +/- 0.33 (SE), P = 0.003], fibrinogen [beta-coeff = -1.51 +/- 0.44 (SE), P = 0.001], and WBC count [beta-coeff = -0.52 +/- 0.30 (SE), P = 0.088] were each inversely associated with Vo(2 max). In conclusion, higher circulating levels of IL-6, CRP, and fibrinogen are independently associated with lower Vo(2 max) in asymptomatic men.

In a 1991 editorial in The FASEB Journal, Robert W. Krauss commented on a recent report of the Presidential Advisory Committee on the Future of the U.S. Space Program (Augustine report). He concluded that, although a manned mission to Mars with life sciences as the priority was endorsed by the Committee, it failed to deal realistically with one huge gap; biological sciences have never been given high priority. According to Krauss, this left a void that will cripple, perhaps fatally, any early effort to ensure long-term survival on any mission of extended duration. The gap included insufficient flight time for fundamental biological space research and insufficient funds. Krauss expressed his opinions 15 years ago. Have we better knowledge of space biology now? This question becomes more acute now that President George W. Bush recently proposed a manned return to the moon by 2015 or 2020, with the moon to become our staging post for manned missions to Mars. Will we be ready so soon? A review of the progress in the last 15 years suggests that we will not. Because of the Columbia disaster, flight opportunities for biological sciences in shuttle spacelabs and in Space Station laboratories compete with time for engineering problems and construction. Thus, research on gravity, radiation, and isolation loses out to problems deemed to be of higher priority. Radiation in deep space and graded gravity in space with on board centrifuges are areas that must be studied before we undertake prolonged space voyages. Very recent budgetary changes within National Aeronautics and Space Administration threaten to greatly reduce the fundamental space biology funds. Are we ready for a trip to Mars? Like Krauss 15 years ago, I think not for some time.

Chronic ulcerative colitis (CUC) is associated with extraintestinal manifestations such as primary sclerosing cholangitis (PSC). The onset of PSC can precede the diagnosis of CUC, and require liver transplantation in some patients. Surgical management of CUC posttransplant has traditionally been open total proctocolectomy and ileal pouch-anal anastomosis. Herein, we present a case of a woman with a previous liver transplant for PSC who subsequently developed CUC with dysplasia, successfully treated with hand-assisted laparoscopic total proctocolectomy and ileal pouch-anal anastomosis. Hand-assisted laparoscopic surgery is an excellent option for patients with previous complex abdominal surgery. It can be performed safely and expediently, providing the benefits of reduced hospital stay and early return of bowel function.

Background: Although few studies have been performed recently, several have suggested that some practitioners are not well able to detect preset anesthesia machine faults., Methods: We performed a prospective study to determine whether there is a correlation between duration of anesthesia practice and the ability to detect anesthesia machine faults. Our hypothesis was that more anesthesia practice would increase the ability to detect anesthesia machine faults. This study was performed during a nationally attended anesthesia meeting held at a large academic medical center, where 87 anesthesia providers were observed performing anesthesia machine checkouts. The participants were asked to individually check out an anesthesia machine with an unspecified number of preset faults. The primary outcome measures were the written listing of faults detected during an anesthesia machine checkout., Results: Of the five faults preset into the test machine, participants with 0-2 yr experience detected a mean of 3.7 faults, participants with 2-7 yr experience detected a mean of 3.6 faults, and participants with more than 7 yr experience detected a mean of 2.3 faults (P < 0.001)., Conclusions: Our prospective study demonstrated that anesthesia machine checkout continues to be a problem.

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.

Endoscopic ultrasound fine needle aspiration (EUS FNA) provides high diagnostic accuracy in most settings. However, limitations associated with pancreatic EUS FNA reduce accuracy. These limitations most significantly impact patients with autoimmune and nonspecific pancreatitis, but also cystic pancreatic tumors, vascular tumors, and less so ductal carcinoma. The EUS trucut biopsy (TCB) needle design overcomes many of the shortcomings of EUS FNA by acquiring larger tissue samples to allow histologic examination. However, these techniques should be considered complimentary as technical or interpretive failure with one device often indicates a need for biopsy with the alternate method. The suggested role of EUS TCB in pancreatic disease is based on limited data and personal experience. As such, further study is needed to determine if this experience is widely applicable. Issues of safety, accuracy, and cost must also be clarified and considered before establishing the role of EUS TCB relative to EUS FNA., ((c) 2007 S. Karger AG, Basel and IAP.)

Objective: Colon cancers with high frequency microsatellite instability (MSI-H) are preferentially located in the proximal colon. Given that 15-20% of sporadic colon cancers are MSI-H, we determined whether tumor site-specific differences in clinicopathological variables, biomarkers, and prognosis are due to inclusion of MSI-H cases., Methods: TNM stage II and III primary colon carcinomas (N = 528) from patients enrolled in 5-fluorouracil-based adjuvant trials were analyzed for MSI using 11 microsatellite markers. Immunostaining for DNA mismatch repair (hMLH1, hMSH2, hMSH6) and p53 proteins was performed. DNA ploidy (diploid vs aneuploid/tetraploid) and proliferative indices (PI: S-phase + G(2)M) were analyzed by flow cytometry., Results: MSI-H was found in 95 (18%) colon cancers. Proximal tumors (N = 286) were associated with MSI-H, older age (>65 yr), poor differentiation, and diploid DNA content compared with distal tumors (all P< or = 0.016). Nuclear p53 staining was more frequent in distal tumors (P= 0.002); PI was unrelated to tumor site. When MSI-H tumors were excluded, no tumor site-related differences were found except for age, which remained associated with proximal cancers (P= 0.030). Proximal site was associated with improved disease-free survival in all patients (P= 0.042), but not when MSI-H cases were excluded (P= 0.236). MSI-H status or loss of mismatch repair proteins, diploidy, and lower PI were associated with improved survival rates., Conclusions: Tumor site-related differences in clinicopathological variables, biomarkers, and prognosis of sporadic colon cancers can be explained by the inclusion of MSI-H cases. Older age, however, is associated with proximal tumor site independent of MSI status.

Computational methods designed to predict and visualize ligand protein binding interactions were used to characterize volatile anesthetic (VA) binding sites and unoccupied pockets within the known structures of VAs bound to serum albumin, luciferase, and apoferritin. We found that both the number of protein atoms and methyl hydrogen, which are within approximately 8 A of a potential ligand binding site, are significantly greater in protein pockets where VAs bind. This computational approach was applied to structures of calmodulin (CaM), which have not been determined in complex with a VA. It predicted that VAs bind to [Ca(2+)](4)-CaM, but not to apo-CaM, which we confirmed with isothermal titration calorimetry. The VA binding sites predicted for the structures of [Ca(2+)](4)-CaM are located in hydrophobic pockets that form when the Ca(2+) binding sites in CaM are saturated. The binding of VAs to these hydrophobic pockets is supported by evidence that halothane predominantly makes contact with aliphatic resonances in [Ca(2+)](4)-CaM (nuclear Overhauser effect) and increases the Ca(2+) affinity of CaM (fluorescence spectroscopy). Our computational analysis and experiments indicate that binding of VA to proteins is consistent with the hydrophobic effect and the Meyer-Overton rule.

The putative association between pesticide exposures and Parkinson's disease (PD) remains controversial. We identified all subjects who developed PD in Olmsted County, Minnesota, from 1976 through 1995, and matched them by age (+/- 1 year) and sex to general population controls. We assessed exposures to chemical products by means of telephone interview with cases, controls, or their proxies (149 cases; 129 controls). Exposure to pesticides related or unrelated to farming was associated with PD in men (odds ratio, 2.4; 95% confidence interval, 1.1-5.4; P = 0.04). The association remained significant after adjustment for education or smoking. Analyses for the other six categories of industrial and household chemicals were all nonsignificant. This population-based study suggests a link between pesticides use and PD that is restricted to men. Pesticides may interact with other genetic or nongenetic factors that are different in men and women.

Background: In 2002, a U.S. Multi-Society Task Force on Colorectal Cancer recommended that the withdrawal phase for colonoscopy should average at least 6-10 min. This was based on 10 consecutive colonoscopies by two endoscopists with different adenoma miss rates., Aims: To characterize the relationship between endoscopist withdrawal time and polyp detection at colonoscopy, and to determine the withdrawal time that corresponds to the median polyp detection rate., Design: Procedural data from out-patient colonoscopies performed at the Mayo Clinic, Rochester during 2003 were reviewed. Endoscopists were characterized by their mean withdrawal time for a negative procedure and individual polyp detection rate., Results: A total of 10 955 colonoscopies performed by 43 endoscopists were analysed. Median withdrawal time was 6.3 min (range: 4.2-11.9); polyp detection rate was 44.0% (all polyps), 29.8% (< or = 5 mm), 5.9% (6-9 mm), 6.7% (10-19 mm), 2.1% (> or = 20 mm). Longer withdrawal time was associated with higher polyp detection rate (r = 0.76; P < 0.0001); this relationship weakened for larger polyps (r = 0.19 for polyps 6-9 mm, r = 0.28 for polyps 10-19 mm, r = 0.02 for polyps > or = 20 mm). Overall median polyp detection rate corresponded to a withdrawal time of 6.7 min., Conclusion: Our findings support a colonoscopy withdrawal time of at least 7 min, which correlates with higher colon polyp detection rates.

Objectives: This study was designed to evaluate prevalence, determinants, and clinical outcome implications of reduced functional capacity (FC) in patients with organic mitral regurgitation (MR)., Background: Evaluation of FC by exercise testing is rarely performed in MR because little is known about the clinical determinants and outcome implications of FC., Methods: Cardiopulmonary exercise testing (CPET) was prospectively performed in 134 asymptomatic patients with organic MR to assess FC (peak oxygen consumption [VO2]) simultaneously to Doppler-echocardiographic quantitation of MR (effective regurgitant orifice [ERO]) and left ventricular (LV) systolic and diastolic function., Results: Peak VO2 was 26 +/- 6 ml/kg/min (96 +/- 16% of age-predicted), but varied widely (57% to 145% of predicted) and was markedly reduced (< or =84% of predicted) in 19% of patients. Although ERO of MR was univariately associated with reduced FC (26 vs. 9% with ERO > or =40 vs. <40 mm2), independent determinants of reduced FC were LV diastolic function (higher E/E' ratio, p = 0.006), atrial fibrillation (p = 0.01), and lower forward stroke volume (p = 0.03). Clinical events (death, heart failure, new atrial fibrillation) and clinical events or surgery were more frequent with than without reduced FC (3 years, 36 +/- 14% vs. 13 +/- 4%, p = 0.02; and 66 +/- 11% vs. 29 +/- 5%, p = 0.001, respectively), even adjusting (risk ratios 1.80 and 1.54 respectively, both p < or = 0.03) for age and ERO., Conclusions: In asymptomatic organic MR, FC quantitatively assessed by CPET is unexpectedly markedly reduced in one out of every four to five patients. Reduced FC is independently determined by consequences rather than severity of MR and predicts increased subsequent clinical events. Therefore, CPET frequently reveals functional limitations not detected clinically and is an important tool in managing patients with organic MR.

Background: We and others have previously shown that plasminogen activators generate endogenous angiogenesis inhibitors and induce antiangiogenic activity. Here we assessed the effects of plasminogen activator overexpression on tumor progression in a syngeneic mammary cancer model., Methods: Genes encoding murine tissue plasminogen activator (tPA), urokinase (uPA), and vector controls were stably transfected into 4T1 murine mammary cancer cells, and cell proliferation in vitro was analyzed. Cells were also implanted into female BALB/c mice (n = 12 per group), and tumor growth, lung metastases, and survival were compared. Tumor cell proliferation and microvessel formation were analyzed by immunohistochemistry using antibodies to proliferating cell nuclear antigen and CD31, respectively. 4T1 cells transfected with proteolytically inactive uPA mutants (A and B) were assayed for proliferation in vitro and tumor growth in vivo by using the same syngeneic model (eight to 10 mice per group). All statistical tests were two-sided., Results: In vitro growth of uPA- and tPA-overexpressing and control 4T1 cells was similar. In vivo, however, inhibition of tumor growth and lung metastasis were inhibited in the mice carrying tPA- and uPA-overexpressing tumors, compared with controls (tumor weight at day 34: control, mean = 1760 mg, 95% confidence interval [CI] = 1434 to 2087 mg; tPA, mean = 921, 95% CI = 624 to 1217 mg; P < .001; uPA, mean = 395 mg, 95% CI = 161 to 629 mg; P < .001; number of lung metastases at day 34: control, mean = 117, 95% CI = 74 to 159; tPA, mean = 33, 95% CI = 13 to 52; uPA, mean = 15, 95% CI = 4 to 25; P < .001). Median survival was 42 (95% CI = 36 to 44), 55 (95% CI = 48 to 61), and 73 (95% CI = 51 to 86) days in the control, tPA, and uPA groups, respectively (P < .001). uPA- and tPA-expressing tumors had reduced angiogenesis and cell proliferation compared with controls. Tumors overexpressing uPA mutants grew faster than tumors expressing wild-type uPA (tumor volume at day 30: wild-type uPA, mean = 203, 95% CI = 121 to 285 mm3; control, mean = 534, 95% CI = 460 to 608 mm3; P < .001; mutant A, mean = 600, 95% CI = 520 to 679 mm3; P < .001; and mutant B, mean = 435, 95% CI = 358.9 to 511 mm3; P = .005)., Conclusions: In this mouse model, uPA expression delayed tumor progression and had antiangiogenic and antiproliferative effects that may be mediated by uPA's protease activity. These results challenge the current dogma of proteases being exclusively tumor promoting and provide further rationale for exploring plasminogen activators as antitumor agents.

Purpose: This paper presents a project whose main goal is to construct a corpus of clinical text manually annotated for part-of-speech (POS) information. We describe and discuss the process of training three domain experts to perform linguistic annotation., Methods: Three domain experts were trained to perform manual annotation of a corpus of clinical notes. A part of this corpus was combined with the Penn Treebank corpus of general purpose English text and another part was set aside for testing. The corpora were then used for training and testing statistical part-of-speech taggers. We list some of the challenges as well as encouraging results pertaining to inter-rater agreement and consistency of annotation., Results: We used the Trigrams'n'Tags (TnT) [T. Brants, TnT-a statistical part-of-speech tagger, In: Proceedings of NAACL/ANLP-2000 Symposium, 2000] tagger trained on general English data to achieve 89.79% correctness. The same tagger trained on a portion of the medical data annotated for this project improved the performance to 94.69%. Furthermore, we find that discriminating between different types of discourse represented by different sections of clinical text may be very beneficial to improve correctness of POS tagging., Conclusion: Our preliminary experimental results indicate the necessity for adapting state-of-the-art POS taggers to the sublanguage domain of clinical text.

Purpose: Colon cancer cells with high-frequency microsatellite instability (MSI-H) display resistance to 5-fluorouracil (5-FU) that can be reversed by restoring DNA mismatch repair (MMR) proficiency. Given that thymidylate synthase (TS) is inhibited by 5-FU, we studied the relationship between MSI and TS expression, and the prognostic effect of these and other markers (i.e., p53 and 17p allelic imbalance)., Experimental Design: Dukes' stage B2 and C colon carcinomas (n = 320) from participants in 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p allelic imbalance. Expression of MMR (hMLH1, hMSH2), TS, and p53 proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival were determined., Results: Of 320 cancers studied, 60 (19%) were MSI-H. TS expression variables were similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) cancers, and unrelated to MMR proteins. MSI-H tumors had lower stage (P = 0.0007), fewer metastatic lymph nodes (P = 0.004), and improved overall survival (P = 0.01). Loss of MMR proteins was also associated with better overall survival (P = 0.006). None of the TS variables were prognostic. Histologic grade (P = 0.0008) and nodal status (P = 0.0002) were associated with overall survival, in contrast to 17p allelic imbalance or p53. Only MSI status or loss of MMR proteins, histologic grade, and tumor stage were independent markers for overall survival., Conclusions: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers.

PS-341 (bortezomib) is a potent and reversible proteosome inhibitor that functions to degrade intracellular polyubiquitinated proteins. PS-341 induces apoptosis and has shown broad antitumor activity with selectivity for transformed cells. We studied the effect of PS-341 on lysosomal and mitochondrial permeabilization, including the role of caspase-2 activation in apoptosis induction in the BxPC-3 human pancreatic carcinoma cell line. PS-341 induced a dose-dependent apoptosis in association with reactive oxygen species generation and cleavage of caspase-2 to its 33- and 14-kDa fragments. PS-341 disrupted lysosomes with redistribution of cathepsin B to the cytosol, as shown using fluorescence confocal microscopy, that was blocked by the free radical scavenger tiron but not by a caspase-2 inhibitor (benzyloxycarbonyl (Z)-VDVAD-fluoromethyl ketone (FMK)). PS-341-induced caspase-2 activation was attenuated by a selective pharmacological inhibitor of cathepsin B (R-3032), suggesting that cathepsin B release occurs upstream of caspase-2. PS-341-induced mitochondrial depolarization was attenuated by Z-VDVAD-FMK, tiron, and an inhibitor of the mitochondrial permeability transition pore (bongkrekic acid). Regulation of mitochondrial permeability by caspase-2 was confirmed using caspase-2 small interfering RNA. PS-341-induced cytochrome c release and phosphatidylserine externalization were attenuated by Z-VDVAD-FMK and partially by R-3032. PS-341 activated the BH3-only proteins Bik and Bim and down-regulated Bcl-2 and Bcl-xL mRNA and protein expression. Taken together, PS-341 induces lysosomal cathepsin B redistribution upstream of caspase-2. Caspase-2 activation regulates PS-341-induced mitochondrial depolarization and apoptosis, suggesting that caspase-2 can serve as a link between lysosomal and mitochondrial permeabilization.