St. John's Hospital

BACKGROUND: We previously reported that, in a randomized trial, carotid stenting with the use of an emboli-protection device is not inferior to carotid endarterectomy for the treatment of carotid artery disease at 30 days and at 1 year. We now report the 3-year results. METHODS: The trial evaluated carotid artery stenting with the use of an emboli-protection device as compared with endarterectomy in 334 patients at increased risk for complications from endarterectomy who had either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%. The prespecified major secondary end point at 3 years was a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1080 days (3 years). RESULTS: At 3 years, data were available for 260 patients (77.8%), including 85.6% of patients in the stenting group and 70.1% of those in the endarterectomy group. The prespecified major secondary end point occurred in 41 patients in the stenting group (cumulative incidence, 24.6%; Kaplan-Meier estimate, 26.2%) and 45 patients in the endarterectomy group (cumulative incidence, 26.9%; Kaplan-Meier estimate, 30.3%) (absolute difference in cumulative incidence for the stenting group, -2.3%; 95% confidence interval, -11.8 to 7.0). There were 15 strokes in each of the two groups, of which 11 in the stenting group and 9 in the endarterectomy group were ipsilateral. CONCLUSIONS: In our trial of patients with severe carotid artery stenosis and increased surgical risk, no significant difference could be shown in long-term outcomes between patients who underwent carotid artery stenting with an emboli-protection device and those who underwent endarterectomy. (ClinicalTrials.gov number, NCT00231270 [ClinicalTrials.gov].).

BACKGROUND: The treatment of peripheral artery disease with percutaneous transluminal angioplasty is limited by the occurrence of vessel recoil and restenosis. Drug-coated angioplasty balloons deliver antiproliferative agents directly to the artery, potentially improving vessel patency by reducing restenosis. METHODS: In this single-blind, randomized trial conducted at 54 sites, we assigned, in a 2:1 ratio, 476 patients with symptomatic intermittent claudication or ischemic pain while at rest and angiographically significant atherosclerotic lesions to angioplasty with a paclitaxel-coated balloon or to standard angioplasty. The primary efficacy end point was primary patency of the target lesion at 12 months (defined as freedom from binary restenosis or from the need for target-lesion revascularization). The primary safety end point was a composite of freedom from perioperative death from any cause and freedom at 12 months from limb-related death (i.e., death from a medical complication related to a limb), amputation, and reintervention. RESULTS: The two groups were well matched at baseline; 42.9% of the patients had diabetes, and 34.7% were current smokers. At 12 months, the rate of primary patency among patients who had undergone angioplasty with the drug-coated balloon was superior to that among patients who had undergone conventional angioplasty (65.2% vs. 52.6%, P=0.02). The proportion of patients free from primary safety events was 83.9% with the drug-coated balloon and 79.0% with standard angioplasty (P=0.005 for noninferiority). There were no significant between-group differences in functional outcomes or in the rates of death, amputation, thrombosis, or reintervention. CONCLUSIONS: Among patients with symptomatic femoropopliteal peripheral artery disease, percutaneous transluminal angioplasty with a paclitaxel-coated balloon resulted in a rate of primary patency at 12 months that was higher than the rate with angioplasty with a standard balloon. The drug-coated balloon was noninferior to the standard balloon with respect to safety. (Funded by Lutonix-Bard; LEVANT 2 ClinicalTrials.gov number, NCT01412541.).

Vascular calcification (VC), particularly medial (Mönckeberg's medial sclerosis) arterial calcification, is common in patients with diabetes mellitus and chronic kidney disease and is associated with increased cardiovascular morbidity and mortality. Although, the underlying pathophysiological mechanisms and genetic pathways of VC are not fully known, hypocalcemia, hyperphosphatemia, and the suppression of parathyroid hormone activity are central to the development of vessel mineralization and, consequently, bone demineralization. In addition to preventive measures, such as the modification of atherosclerotic cardiovascular risk factors, current treatment strategies include the use of calcium-free phosphate binders, vitamin D analogs, and calcium mimetics that have shown promising results, albeit in small patient cohorts. The impact of intimal and medial VC on the safety and effectiveness of endovascular devices to treat symptomatic peripheral arterial disease (PAD) remains poorly defined. The absence of a generally accepted, validated vascular calcium grading scale hampers clinical progress in assessing the safety and utility of various endovascular devices (e.g., atherectomy) in treating calcified vessels. Accordingly, we propose the peripheral arterial calcium scoring system (PACSS) and a method for its clinical validation. A better understanding of the pathogenesis of vascular calcification and the development of optimal medical and endovascular treatment strategies are crucial as the population ages and presents with more chronic comorbidities.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

BACKGROUND: The objective was to evaluate the effect of preoperative administration of newer chemotherapeutic agents (irinotecan and oxaliplatin) on development of steatohepatitis, which could limit surgical options. STUDY DESIGN: Thirty-seven patients were referred for resection of hepatic colorectal metastases. Thirteen patients received no neoadjuvant therapy (NO CHEMO group); 10 received neoadjuvant 5-fluorouracil only (5-FU group), and 14 received neoadjuvant irinotecan (n = 12), or oxaliplatin, or both (n = 4), in conjunction with 5-FU (IRI-OXALI group). Specimens were graded for the presence of nonalcoholic steatohepatitis (NASH) according to established criteria. Specimens were also evaluated by a nine-criteria liver injury score (LIS). RESULTS: Mean biopsy scores were: NO CHEMO: NASH, 1.2, LIS, 5.2; 5-FU only: NASH, 1.1, LIS 5.7; and IRI-OXALI: NASH, 1.9, LIS, 9.4. Biopsy scores were significantly worse for IRI-OXALI compared with NO CHEMO or 5-FU only for NASH score, p = 0.003, and close to significantly worse for LIS score, p = 0.057. A multivariate analysis showed that both being in the IRI-OXALI group and body mass index were independent risk factors for developing this type of steatohepatitis. CONCLUSIONS: Severe steatohepatitis can be associated with preoperative administration of irinotecan or oxaliplatin, especially in the obese. It can affect the ability to perform large liver resections. Consideration should be given to performing resections before commencing these agents and to obtaining preoperative biopsy in those who have received these agents.

The emergence of Coronavirus disease 2019 (COVID-19) has affected health-care workers' psychological and mental health. Few studies have been conducted examining the psychological effect of COVID-19 on health-care worker psychological health in Jordan. Therefore, the present study aims to assess the respective levels of fear, anxiety, depression, stress, social support, and the associated factors, experienced by Jordanian health-care workers during the COVID-19 Pandemic. This study adopted a cross-sectional, correlational design to collect data from 365 health-care workers in Amman, Jordan, from August 16th to 23rd, 2020. Along with collecting sociodemographic characteristics, the Fear of COVID-19 Scale, the Depression, Anxiety, Stress Scale, and the Multidimensional Scale of Perceived Social Support electronically administered to participants. The majority of the participants (69.3%) were registered nurses. The mean overall score for the Fear of COVID-19 scale was 23.64 (SD + 6.85) which again exceeded the mid-point for the total score range (21), indicating elevated level fear of the COVID-19 pandemic. Participants had displayed extremely severe depression 40%, extremely severe anxiety 60%, and 35% severely distressed. Scores for depression (21.30 ± 10.86), anxiety (20.37 ± 10.80), stress (23.33 ± 10.87) were also high. Factors determined to be associated with psychological distress were being male, married, aged 40 years and older, and having more clinical experience. Assessment of social support indicated moderate-to-high levels of perceived support for all dimensions (significant other: 5.17 ± 1.28, family: 5.03 ± 1.30, friends: 5.05 ± 1.30). Weak significant correlations were found between social support and the other study variables (r < 0.22), indicating a weak association with fear, depression, anxiety, and stress, respectively. Overall, Jordanian health-care workers sample reported fear, depression, anxiety, and stress. The associated factors were being male, married, aged 40 years and older, and having more clinical experience. Regarding social support, participants primarily relied on support from their families, followed by support from friends.

BACKGROUND AND OBJECTIVES: The relationship of contrast-induced nephropathy (CIN) to long-term adverse events (AEs) is controversial. Although an association with AEs has been previously reported, it is unclear whether CIN is causally related to these AEs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We obtained long-term (> or =1 yr) follow-up on 294 patients who participated in a randomized, double-blind comparison of two prevention strategies for CIN (iopamidol versus iodixanol). A difference in the incidence of AEs between patients who had developed CIN and those who had not was performed using a chi(2) test and Poisson regression analysis. A similar statistical approach was used for the differences in AEs between those who received iopamidol or iodixanol. Multiple definitions of CIN were used to strengthen and validate the results and conclusions. RESULTS: The rate of long-term AEs was higher in individuals with CIN (all definitions of CIN). After adjustment for baseline comorbidities and risk factors, the adjusted incidence rate ratio for AEs was twice as high in those with CIN. Randomization to iopamidol reduced both the incidence of CIN and AEs. CONCLUSIONS: The parallel decrease in the incidence of CIN and AEs in one arm of this randomized trial supports a causal role for CIN.

OBJECTIVES: The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. BACKGROUND: To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. METHODS: DEFINITIVE LE (Determination of EFfectiveness of the SilverHawk(®) PerIpheral Plaque ExcisioN System (SIlverHawk Device) for the Treatment of Infrainguinal VEssels / Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. RESULTS: A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. CONCLUSIONS: The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246).

This paper discusses the evolving concept of atrial myopathy by presenting how it develops and how it affects the properties of the atria. It also reviews the complex relationships among atrial myopathy, atrial fibrillation (AF), and stroke. Finally, it discusses how to apply the concept of atrial myopathy in the clinical setting-to identify patients with atrial myopathy and to be more selective in anticoagulation in a subset of patients with AF. An apparent lack of a temporal relationship between episodes of paroxysmal AF and stroke in patients with cardiac implantable electronic devices has led investigators to search for additional factors that are responsible for AF-related strokes. Multiple animal models and human studies have revealed a close interplay of atrial myopathy, AF, and stroke via various mechanisms (e.g., aging, inflammation, oxidative stress, and stretch), which, in turn, lead to fibrosis, electrical and autonomic remodeling, and a pro-thrombotic state. The complex interplay among these mechanisms creates a vicious cycle of ever-worsening atrial myopathy and a higher risk of more sustained AF and strokes. By highlighting the importance of atrial myopathy and the risk of strokes independent of AF, this paper reviews the methods to identify patients with atrial myopathy and proposes a way to incorporate the concept of atrial myopathy to guide anticoagulation in patients with AF.

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

The dynamic signal intensity changes at magnetic resonance (MR) imaging in active and chronic wallerian degeneration in the corticospinal tract were evaluated. Forty-three patients with wallerian degeneration seen on MR images after cerebral infarction were studied. When possible, patients with acute stroke were examined with MR imaging prospectively at the onset of symptoms and then at weekly intervals for several months. Focal infarction without distal axonal degeneration is demonstrated for the 1st month following onset of clinical symptoms. At 4 weeks, a well-defined band of hypointense signal appears on T2-weighted images in the topographic distribution of the corticospinal tract. After 10-14 weeks, the signal becomes permanently hyperintense. Over several years, accompanying ipsilateral brain stem shrinkage occurs. The dark signal intensity observed on T2-weighted images between 4 and 14 weeks is believed to result primarily from transitory increased lipid-protein ratio.

OBJECTIVES: The purpose of this study was to assess the diagnostic accuracy of the instantaneous wave-free ratio (iFR) to characterize, outside of a pre-specified range of values, stenosis severity, as defined by fractional flow reserve (FFR) ≤0.80, in a prospective, independent, controlled, core laboratory-based environment. BACKGROUND: Studies with methodological heterogeneity have reported some discrepancies in the classification agreement between iFR and FFR. The ADVISE II (ADenosine Vasodilator Independent Stenosis Evaluation II) study was designed to overcome limitations of previous iFR versus FFR comparisons. METHODS: A total of 919 intermediate coronary stenoses were investigated during baseline and hyperemia. From these, 690 pressure recordings (n = 598 patients) met core laboratory physiology criteria and are included in this report. RESULTS: The pre-specified iFR cut-off of 0.89 was optimal for the study and correctly classified 82.5% of the stenoses, with a sensitivity of 73.0% and specificity of 87.8% (C statistic: 0.90 [95% confidence interval (CI): 0.88 to 0.92, p < 0.001]). The proportion of stenoses properly classified by iFR outside of the pre-specified treatment (≤0.85) and deferral (≥0.94) values was 91.6% (95% CI: 88.8% to 93.9%). When combined with FFR use within these cut-offs, the percent of stenoses properly classified by such a pre-specified hybrid iFR-FFR approach was 94.2% (95% CI: 92.2% to 95.8%). The hybrid iFR-FFR approach obviated vasodilators from 65.1% (95% CI: 61.1% to 68.9%) of patients and 69.1% (95% CI: 65.5% to 72.6%) of stenoses. CONCLUSIONS: The ADVISE II study supports, on the basis rigorous methodology, the diagnostic value of iFR in establishing the functional significance of coronary stenoses, and highlights its complementariness with FFR when used in a hybrid iFR-FFR approach. (ADenosine Vasodilator Independent Stenosis Evaluation II-ADVISE II; NCT01740895).

OBJECTIVES: To determine if a ventilator available in an emergency department could quickly be modified to provide ventilation for four adults simultaneously. METHODS: Using lung simulators, readily available plastic tubing, and ventilators (840 Series Ventilator; Puritan-Bennett), human lung simulators were added in parallel until the ventilator was ventilating the equivalent of four adults. Data collected included peak pressure, positive end-expiratory pressure, total tidal volume, and total minute ventilation. Any obvious asymmetry in the delivery of gas to the lung simulators was also documented. The ventilator was run for almost 12 consecutive hours (5.5 hours of pressure control and more than six hours of volume control). RESULTS: Using readily available plastic tubing set up to minimize dead space volume, the four lung simulators were easily ventilated for 12 hours using one ventilator. In pressure control (set at 25 mm H2O), the mean tidal volume was 1,884 mL (approximately 471 mL/lung simulator) with an average minute ventilation of 30.2 L/min (or 7.5 L/min/lung simulator). In volume control (set at 2 L), the mean peak pressure was 28 cm H2O and the minute ventilation was 32.5 L/min total (8.1 L/min/lung simulator). CONCLUSIONS: A single ventilator may be quickly modified to ventilate four simulated adults for a limited time. The volumes delivered in this simulation should be able to sustain four 70-kg individuals. While further study is necessary, this pilot study suggests significant potential for the expanded use of a single ventilator during cases of disaster surge involving multiple casualties with respiratory failure.

A published case report and anecdotal experience suggested that topical imiquimod is an effective treatment for stage 0 melanoma (lentigo maligna). To gauge the efficacy of this therapy, we undertook a trial of topical imiquimod in 30 subjects with histologically confirmed lentigo maligna. Thirty subjects with lentigo maligna were recruited for an open-labelled efficacy trial with daily topical application of imiquimod 5% cream for 3 months. Study subjects were enrolled from the Dermatology service of the University of Oklahoma, the Oklahoma City Veteran's Administration Hospital Dermatology service and from referrals for the study from other practitioners. In order to determine an initial response rate, a four-quadrant biopsy was carried out on all patients 1 month after cessation of treatment, targeting the most clinically and dermatoscopically suspicious areas. Of 28 evaluable subjects who have completed the 3-month treatment phase, 26 (93%) were complete responders and two were treatment failures at the time of the 4-quadrant biopsy. Over 80% of the 28 subjects that completed treatment have been followed for more than 1 year with no relapses. The results of this study demonstrate that topical imiquimod produces a high complete response rate in lentigo maligna when applied daily for 3 months.

Importance: Transcatheter aortic valve replacement (TAVR) is established for selected patients with severe aortic stenosis. However, limitations such as suboptimal deployment, conduction disturbances, and paravalvular leak occur. Objective: To evaluate if a mechanically expanded valve (MEV) is noninferior to an approved self-expanding valve (SEV) in high-risk patients with aortic stenosis undergoing TAVR. Design, Setting, and Participants: The REPRISE III trial was conducted in 912 patients with high or extreme risk and severe, symptomatic aortic stenosis at 55 centers in North America, Europe, and Australia between September 22, 2014, and December 24, 2015, with final follow-up on March 8, 2017. Interventions: Participants were randomized in a 2:1 ratio to receive either an MEV (n = 607) or an SEV (n = 305). Main Outcomes and Measures: The primary safety end point was the 30-day composite of all-cause mortality, stroke, life-threatening or major bleeding, stage 2/3 acute kidney injury, and major vascular complications tested for noninferiority (margin, 10.5%). The primary effectiveness end point was the 1-year composite of all-cause mortality, disabling stroke, and moderate or greater paravalvular leak tested for noninferiority (margin, 9.5%). If noninferiority criteria were met, the secondary end point of 1-year moderate or greater paravalvular leak was tested for superiority in the full analysis data set. Results: Among 912 randomized patients (mean age, 82.8 [SD, 7.3] years; 463 [51%] women; predicted risk of mortality, 6.8%), 874 (96%) were evaluable at 1 year. The primary safety composite end point at 30 days occurred in 20.3% of MEV patients and 17.2% of SEV patients (difference, 3.1%; Farrington-Manning 97.5% CI, -∞ to 8.3%; P = .003 for noninferiority). At 1 year, the primary effectiveness composite end point occurred in 15.4% with the MEV and 25.5% with the SEV (difference, -10.1%; Farrington-Manning 97.5% CI, -∞ to -4.4%; P<.001 for noninferiority). The 1-year rates of moderate or severe paravalvular leak were 0.9% for the MEV and 6.8% for the SEV (difference, -6.1%; 95% CI, -9.6% to -2.6%; P < .001). The superiority analysis for primary effectiveness was statistically significant (difference, -10.2%; 95% CI, -16.3% to -4.0%; P < .001). The MEV had higher rates of new pacemaker implants (35.5% vs 19.6%; P < .001) and valve thrombosis (1.5% vs 0%) but lower rates of repeat procedures (0.2% vs 2.0%), valve-in-valve deployments (0% vs 3.7%), and valve malpositioning (0% vs 2.7%). Conclusions and Relevance: Among high-risk patients with aortic stenosis, use of the MEV compared with the SEV did not result in inferior outcomes for the primary safety end point or the primary effectiveness end point. These findings suggest that the MEV may be a useful addition for TAVR in high-risk patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02202434.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Clostridium difficile is a leading cause of antibiotic-associated diarrhea, and a significant etiologic agent of healthcare-associated infections. The mechanisms of attachment and host colonization of C. difficile are not well defined. We hypothesize that non-toxin bacterial factors, especially those facilitating the interaction of C. difficile with the host gut, contribute to the initiation of C. difficile infection. In this work, we optimized a completely anaerobic, quantitative, epithelial-cell adherence assay for vegetative C. difficile cells, determined adherence proficiency under multiple conditions, and investigated C. difficile surface protein variation via immunological and DNA sequencing approaches focused on Surface-Layer Protein A (SlpA). In total, thirty-six epidemic-associated and non-epidemic associated C. difficile clinical isolates were tested in this study, and displayed intra- and inter-clade differences in attachment that were unrelated to toxin production. SlpA was a major contributor to bacterial adherence, and individual subunits of the protein (varying in sequence between strains) mediated host-cell attachment to different extents. Pre-treatment of host cells with crude or purified SlpA subunits, or incubation of vegetative bacteria with anti-SlpA antisera significantly reduced C. difficile attachment. SlpA-mediated adherence-interference correlated with the attachment efficiency of the strain from which the protein was derived, with maximal blockage observed when SlpA was derived from highly adherent strains. In addition, SlpA-containing preparations from a non-toxigenic strain effectively blocked adherence of a phylogenetically distant, epidemic-associated strain, and vice-versa. Taken together, these results suggest that SlpA plays a major role in C. difficile infection, and that it may represent an attractive target for interventions aimed at abrogating gut colonization by this pathogen.

BACKGROUND: Metaplastic carcinoma is a rare form of breast carcinoma that often is confused with other benign and malignant entities. The diagnosis can be difficult to establish on both a clinical and conventional histopathologic basis. One report recently described clinical and mammographic features dissimilar to the authors' experience but to the authors' knowledge no other reports have been published. Therefore a review of three cases was undertaken; all patients had undergone mammography to identify and report the mammographic features of this disease, suggesting that imaging may add to the proper diagnosis of this entity. METHODS: Three clinical cases in which the diagnosis of metaplastic carcinoma was confirmed and for which mammography was performed were reviewed retrospectively. Follow-up on all three patients was available. RESULTS: Metaplastic carcinoma may be manifest as a well circumscribed mass or an irregular or spiculated mass. The latter always is highly suspicious for malignancy and the former incurs suspicion if it grows, although in this series the smooth mass was biopsied immediately. The spiculated masses were associated with delayed diagnosis and poorer prognosis because immunohistochemical studies were not performed on the original excisional biopsy specimens. CONCLUSIONS: Although spiculated masses usually are associated with invasive ductal and lobular carcinoma, they also may represent metaplastic carcinoma and immunohistochemical studies often are required to establish this diagnosis and avoid delay in proper treatment. Well circumscribed masses representing this disease may suggest benign disease but metaplastic carcinoma should be included in the differential diagnosis, especially if the mass enlarges.

BACKGROUND: Gastroparesis, a chronic disorder of abnormal gastric motility, is common in patients with diabetes mellitus. A synthetic, selective ghrelin receptor agonist, TZP-101, is in clinical development for treatment of gastroparesis. This double-blind, randomized, placebo-controlled study evaluated the safety and efficacy of multiple TZP-101 doses in patients with moderate to severe symptomatic diabetic gastroparesis. METHODS: Patients were admitted to the hospital and adaptively randomized to receive a single 30-min intravenous infusion of 20, 40, 80, 160, 320, or 600 μg kg(-1) TZP-101, (n = 57) or placebo, (n = 19) for four consecutive days. Symptoms were evaluated daily with the patient-rated Gastroparesis Cardinal Symptom Index (GCSI) and Gastroparesis Symptom Assessment (GSA). Clinicians rated gastroparesis symptoms on treatment day 4. KEY RESULTS: The 80 μg kg(-1) dose was identified as the most effective dose. On day 4, there was statistically significant improvement compared with placebo in the severity of GCSI Loss of Appetite and Vomiting scores for that dose group (P = 0.034 and P = 0.006). In addition, at the 80 μg kg(-1) dose, the proportion of patients with at least 50% improvement in vomiting score was significantly different (P = 0.019) compared with placebo. Meal-related GSA scores for Postprandial fullness were significantly improved in the 80 μg kg(-1) TZP-101 group compared with placebo (P = 0.012). Clinicians rated the 80 μg kg(-1) group better improved than placebo for overall symptom assessment (P = 0.047). Safety profiles were similar in the placebo and TZP-101 groups and all doses were well-tolerated. CONCLUSIONS & INFERENCES: TZP-101 appears to be safe, well-tolerated, and effective at acutely addressing several gastroparesis symptoms.

BACKGROUND: Galectin-3 is a carbohydrate-binding protein whose level of expression has been shown to be correlated with metastatic potential in a number of different tumor types. The purpose of this investigation was to examine galectin-3 expression in several tumorigenic and nontumorigenic prostate cell lines and prostate tissue samples. METHODS: The expression of galectin-3 in cell lines and tissue samples was evaluated by tissue immunohistochemistry and Western blot analysis. RESULTS: Human cell lines PC-3M, PC-3, DU-145, PrEC-1, and MCF10A demonstrated the presence of galectin-3. Galectin-3 was not detected in TSU-pr1 and LNCaP by Western blot analysis. We furthered our studies by examining a series of human prostate tissue samples for expression of galectin-3. Overall, approximately 60-70% of the normal tissue examined demonstrated heterogenous expression of galectin-3. In stage II tumors, however, there was a dramatic decrease in galectin-3 expression in both PIN and tumor sections, with only 10.5% (2/19) of these samples expressing this protein. Stage III tumors also demonstrated a decreased expression of galectin-3, although this downregulation was not as dramatic, with 35% of PIN samples and 52% of tumor tissue expressing galectin-3 (P < 0.01). CONCLUSIONS: These data demonstrate that galectin-3 is downregulated in prostate cancer. The altered downregulation pattern of galectin-3 observed between tumor stages suggests different roles for galectin-3 in the progression of prostate cancer.