Noncanonical Quantization of Gravity. I. Foundations of Affine Quantum Gravity

The nature of the classical canonical phase-space variables for gravity suggests that the associated quantum field operators should obey affine commutation relations rather than canonical commutation relations. Prior to the introduction of constraints, a primary kinematical representation is derived in the form of a reproducing kernel and its associated reproducing kernel Hilbert space. Constraints are introduced following the projection operator method which involves no gauge fixing, no complicated moduli space, nor any auxiliary fields. The result, which is only qualitatively sketched in the present paper, involves another reproducing kernel with which inner products are defined for the physical Hilbert space and which is obtained through a reduction of the original reproducing kernel. Several of the steps involved in this general analysis are illustrated by means of analogous steps applied to one-dimensional quantum mechanical models. These toy models help in motivating and understanding the analysis in the case of gravity.Comment: minor changes, LaTeX, 37 pages, no figure

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

Aluminum (Al) compounds are neurotoxic and have been shown to induce experimental neurodegeneration although the mechanism of this effect is unclear. In order to study this neurotoxic effect of Al, we have developed an in vitro model system using Al maltolate and human NT2 cells. Al maltolate at 500 mM caused significant cell death with a 24-h incubation and this toxicity was even more evident after 48 h. Lower doses of Al maltolate were also effective, but required a longer incubation for cell death. Nuclear fragmentation suggestive of apoptosis was observed as early as three hours and increased substantially through 24 h. Chromatin condensation and nuclear fragmentation were confirmed by electron microscopy. In addition, TUNEL positive nuclei were also observed. The release of cytochrome c was demonstrated with Western blot analysis. This in vitro model using human cells adds to our understanding of Al neurotoxicity and could provide insight into the neurodegenerative processes in human disease

Co-involvement of Mitochondria and Endoplasmic Reticulum in Regulation of Apoptosis: Changes in Cytochrome c, Bcl-2 and Bax in the Hippocampus of Aluminum-treated Rabbits

Neurodegenerative diseases, including Alzheimer’s disease, are characterized by a progressive and selective loss of neurons. Apoptosis under mitochondrial control has been implicated in this neuronal death process, involving the release of cytochrome c into the cytoplasm and initiation of the apoptosis cascade. However, a growing body of evidence suggests an active role for the endoplasmic reticulum in regulating apoptosis, either independent of mitochondrial, or in concert with mitochondrial-initiated pathways. Members of the Bcl-2 family of proteins have been shown to either inhibit apoptosis, as is the case with Bcl-2, or to promote it, in the case of Bax. Investigations in our laboratory have focused on neuronal injury resulting from the intracisternal administration of aluminum maltolate to New Zealand white rabbits, an animal system relevant to a study of human disease in that it reflects many of the histological and biochemical changes associated with Alzheimer’s disease. Here we report that treatment of young adult rabbits with aluminum maltolate induces both cytochrome c translocation into brain cytosol, and caspase-3 activation. Furthermore, as assessed by Western blot analysis, these effects are accompanied by a decrease in Bcl-2 and an increase in Bax reactivity in the endoplasmic reticulum

Determinants of Time to Fatigue during Non-Motorized Treadmill Exercise

Treadmill exercise is commonly used for aerobic and anaerobic conditioning. During non-motorized treadmill exercise, the subject must provide the power necessary to drive the treadmill belt. The purpose of this study was to determine what factors affected the time to fatigue on a pair of non-motorized treadmills. Twenty subjects (10 males/10 females) attempted to complete five minutes of locomotion during separate trials at 3.22, 4.83, 6.44, 8.05, 9.66, and 11.27 km (raised dot) h(sup -1). Total exercise time (less than or equal to 5 min) was recorded. Exercise time was converted to the amount of 15 second intervals completed. Peak oxygen uptake (VO2) was measured using a graded exercise test on a standard treadmill, and anthropometric measures were collected from each subject before entering into the study. A Cox proportional hazards regression model was used to determine significant predictive factors in a multivariate analysis. Non-motorized treadmill speed and absolute peak VO2 were found to be significant predictors of exercise time, but there was no effect of anthropometric characteristics. Gender was found to be a predictor of treadmill time, but this was likely due to a higher peak VO2 in males than in females. These results were not affected by the type of treadmill tested in this study. Coaches and therapists should consider the cardiovascular fitness of an athlete or client when prescribing target speed since these factors are related to the total exercise time than can be achieved on a non-motorized treadmill

Note and Comment

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Endoscopic ultrasound characteristics of pancreatic lymphoepithelial cysts: A case series from a large referral center.

BACKGROUND AND OBJECTIVES: Lymphoepithelial cysts (LECs) of the pancreas are benign lesions that can mimic cystic neoplasms on imaging. Endoscopic ultrasound (EUS) features have not been well described. We aimed to describe the clinical and EUS characteristics of LECs and the present outcomes of management at a high-volume referral center. MATERIALS AND METHODS: We identified patients who underwent EUS and were found to have LECs based on fine-needle aspiration (FNA) cytology or surgical pathology from existing databases. EUS features, imaging characteristics, and pathology results were described. RESULTS: Sixteen patients were found to have 17 LECs. The mean size was 33 mm ± 15 mm. Locations within the pancreas included 10 lesions in the tail, 3 in the body, 1 in the uncinate process; the remaining 3 were exophytic. Six lesions were anechoic, 6 were hypoechoic, and 5 had mixed echogenicity. Nine lesions had mixed solid/cystic components, 7 were purely cystic, and 1 was solid. Cyst fluid was thick or viscous in six cases and thin in three. Eleven patients had diagnostic cytopathology. Six patients ultimately underwent surgery due to symptoms, nondiagnostic FNA, or other clinical concerns for malignancy. CONCLUSIONS: Pancreatic LECs have variable morphology and echogenicity on EUS, but the appearance of a cyst with variable solid and cystic components combined with the appearance of thick, turbid, and viscous aspirate should raise suspicion for an LEC. The majority of patients with LECs at our center avoided surgery for LECs on the basis of diagnostic EUS-FNA

Peri-nuclear Clustering of Mitochondria is Triggered during Aluminum Maltolate Induced Apoptosis

Synapse loss and neuronal death are key features of Alzheimer’s disease pathology. Disrupted axonal transport of mitochondria is a potential mechanism that could contribute to both. As the major producer of ATP in the cell, transport of mitochondria to the synapse is required for synapse maintenance. However, mitochondria also play an important role in the regulation of apoptosis. Investigation of aluminum (Al) maltolate induced apoptosis in human NT2 cells led us to explore the relationship between apoptosis related changes and the disruption of mitochondrial transport. Similar to that observed with tau over expression, NT2 cells exhibit peri-nuclear clustering of mitochondria following treatment with Al maltolate. Neuritic processes largely lacked mitochondria, except in axonal swellings. Similar, but more rapid results were observed following staurosporine administration, indicating that the clustering effect was not specific to Al maltolate. Organelle clustering and transport disruption preceded apoptosis. Incubation with the caspase inhibitor zVAD-FMK effectively blocked apoptosis, however failed to prevent organelle clustering. Thus, transport disruption is associated with the initiation, but not necessarily the completion of apoptosis. These results, together with observed transport defects and apoptosis related changes in Alzheimer disease brain suggest that mitochondrial transport disruption may play a significant role in synapse loss and thus the pathogenesis or Alzheimer’s disease

Metabolic Rate and Ground Reaction Force During Motorized and Non-Motorized Treadmill Exercise

PURPOSE: To measure vertical ground reaction force (vGRF) and oxygen consumption (VO2) at several velocities during exercise using a ground-based version of the ISS treadmill in the M and NM modes. METHODS: Subjects (n = 20) walked or ran at 0.89, 1.34, 1.79, 2.24, 2.68, and 3.12 m/s while VO2 and vGRF data were collected. VO2 was measured using open-circuit spirometry (TrueOne 2400, Parvo-Medics). Data were averaged over the last 2 min of each 5-min stage. vGRF was measured in separate 15-s bouts at 125 Hz using custom-fitted pressure-sensing insoles (F-Scan Sport Sensors, Tekscan, Inc). A repeated-measures ANOVA was used to test for differences in VO2 and vGRF between M and NM and across speeds. Significance was set at P < 0.05. RESULTS: Most subjects were unable to exercise for 5 min at treadmill speeds above 1.79 m/s in the NM mode; however, vGRF data were obtained for all subjects at each speed in both modes. VO2 was approx.40% higher during NM than M exercise across treadmill speeds. vGRF increased with treadmill speed but was not different between modes. CONCLUSION: Higher VO2 with no change in vGRF suggests that the additional metabolic cost associated with NM treadmill exercise is accounted for in the horizontal forces required to move the treadmill belt. Although this may limit the exercise duration at faster speeds, high-intensity NM exercise activates the hamstrings and plantarflexors, which are not specifically targeted or well protected by other in-flight countermeasures

Management of Branch‐duct Intraductal Papillary Mucinous Neoplasms: A Large Single Center Study to Assess Predictors of Malignancy and Long Term Outcomes

Background and Aims Management of branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging. We determined factors associated with malignancy in BD-IPMNs and long-term outcomes. Methods This retrospective cohort study included all patients with established BD-IPMNs by the International Consensus Guidelines (ICG) 2012 and/or pathologically confirmed BD-IPMNs in a tertiary care referral center between 2001 and 2013. Main outcome measures were the association between high-risk stigmata (HRS)/worrisome features (WFs) of the ICG 2012 and malignant BD-IPMNs, performance characteristics of EUS-FNA for the diagnosis of malignant BD-IPMNs, and recurrence and long-term outcomes of BD-IPMN patients undergoing surgery or imaging surveillance. Results Of 364 BD-IPMN patients, 229 underwent imaging surveillance and 135 underwent surgery. Among the 135 resected BD-IPMNs, HRS/WFs on CT/magnetic resonance imaging (MRI) were similar between the benign and malignant groups, but main pancreatic duct (MPD) dilation (5-9 mm) was more frequently identified in malignant lesions. On EUS-FNA, mural nodules, MPD features suspicious for involvement, and suspicious/positive malignant cytology were more frequently detected in the malignant group with a sensitivity, specificity, and accuracy of 33%, 94%, and 86%; 42%, 91%, and 83%; and 33% 91%, and 82%, respectively. Mural nodules identified by EUS were missed by CT/MRI in 28% in the malignant group. Patients with malignant lesions had a higher risk of any IPMN recurrence during a mean follow-up period of 131 months (P = .01). Conclusions Among HRS and WFs of the ICG 2012, an MPD size of 5 to 9 mm on CT/MRI was associated with malignant BD-IPMNs. EUS features including mural nodules, MPD features suspicious for involvement, and suspicious/malignant cytology were accurate and highly specific for malignant BD-IPMNs. Our study highlights the incremental value of EUS-FNA over imaging in identifying malignant BD-IPMNs, particularly in patients without WFs and those with smaller cysts. Benign IPMN recurrence was observed in some patients up to 8 years after resection

Clinical Study Bedside Endoscopic Ultrasound in Critically Ill patients

Background. The aim of this study was to evaluate the role and impact of EUS in the management of critically ill patients. Methods. We retrospectively identified all patients at our institution over a 68-month period in whom bedside inpatient EUS was performed. EUS was considered to have a significant impact if a new diagnosis was established and/or the findings altered subsequent clinical management. Results. Fifteen patients (9 male; mean age 58 ± 15 years) underwent bedside EUS without complications. EUS-FNA (median 4 passes; range 2–7) performed in 12 (80%) demonstrated a malignant mediastinal mass/lymph node (5), pancreatic abscess (1), excluded a pelvic abscess (1), established enlarged gastric folds as benign (1) and excluded malignancy in enlarged mediastinal (1) and porta hepatis adenopathy (1). In two patients, EUS-FNA failed to diagnose mediastinal histoplasmosis (1) and a hemorrhagic pancreatic pseudocyst (1). In three diagnostic exams without FNA, EUS correctly excluded choledocholithaisis (n = 1) and cholangiocarcinoma (1), and found gastric varices successfully thrombosed after previous cyanoacrylate injection (1). EUS was considered to have an impact in 13/15 (87%) patients. Conclusions. In this series, bedside EUS in critically ill patients was technically feasible, safe and had a major impact on the majority of patients. 1