Restructuring Reward Mechanisms in Nicotine Addiction: A Pilot fMRI Study of Mindfulness-Oriented Recovery Enhancement for Cigarette Smokers.

The primary goal of this pilot feasibility study was to examine the effects of Mindfulness-Oriented Recovery Enhancement (MORE), a behavioral treatment grounded in dual-process models derived from cognitive science, on frontostriatal reward processes among cigarette smokers. Healthy adult (N = 13; mean (SD) age 49 ± 12.2) smokers provided informed consent to participate in a 10-week study testing MORE versus a comparison group (CG). All participants underwent two fMRI scans: pre-tx and after 8-weeks of MORE. Emotion regulation (ER), smoking cue reactivity (CR), and resting-state functional connectivity (rsFC) were assessed at each fMRI visit; smoking and mood were assessed throughout. As compared to the CG, MORE significantly reduced smoking (d = 2.06) and increased positive affect (d = 2.02). MORE participants evidenced decreased CR-BOLD response in ventral striatum (VS; d = 1.57) and ventral prefrontal cortex (vPFC; d = 1.7) and increased positive ER-BOLD in VS (dVS = 2.13) and vPFC (dvmPFC = 2.66). Importantly, ER was correlated with smoking reduction (r's = .68 to .91) and increased positive affect (r's = .52 to .61). These findings provide preliminary evidence that MORE may facilitate the restructuring of reward processes and play a role in treating the pathophysiology of nicotine addiction.

The effects of N-Acetylcysteine on frontostriatal resting-state functional connectivity, withdrawal symptoms and smoking abstinence: A double-blind, placebo-controlled fMRI pilot study.

BACKGROUND: Chronic exposure to drugs of abuse disrupts frontostriatal glutamate transmission, which in turn meditates drug seeking. In animal models, N-Acetylcysteine normalizes dysregulated frontostriatal glutamatergic neurotransmission and prevents reinstated drug seeking; however, the effects of N-Acetylcysteine on human frontostriatal circuitry function and maintaining smoking abstinence is unknown. Thus, the current study tested the hypothesis that N-Acetylcysteine would be associated with stronger frontostriatal resting-state functional connectivity (rsFC), attenuated nicotine withdrawal and would help smokers to maintain abstinence over the study period. METHODS: The present study examined the effects of N-Acetylcysteine on frontostriatal rsFC, nicotine-withdrawal symptoms and maintaining abstinence. Healthy adult, non-treatment seeking smokers (N=16; mean (SD) age 36.5±11.9; cigs/day 15.8±6.1; years/smoking 15.7±8.9) were randomized to a double-blind course of 2400mg N-Acetylcysteine (1200mg b.i.d.) or placebo over the course of 3½ days of monetary-incentivized smoking abstinence. On each abstinent day, measures of mood and craving were collected and participants attended a lab visit in order to assess smoking (i.e., expired-air carbon monoxide [CO]). On day 4, participants underwent fMRI scanning. RESULTS: As compared to placebo (n=8), smokers in the N-Acetylcysteine group (n=8) maintained abstinence, reported less craving and higher positive affect (all p's<.01), and concomitantly exhibited stronger rsFC between ventral striatal nodes, medial prefrontal cortex and precuneus-key default mode network nodes, and the cerebellum [p<.025; FWE]). CONCLUSIONS: Taken together, these findings suggest that N-Acetylcysteine may positively affect dysregulated corticostriatal connectivity, help to restructure reward processing, and help to maintain abstinence immediately following a quit attempt.

The anatomy of the subscapular nerves: a new nomenclature.

We propose a new nomenclature for the consistent, additional nerves that branch from the posterior cord of the brachial plexus. We hope this will aid the plexus surgeon and the evolution of plexus reconstruction for both obstetric and adult cases of injury.

Recombinant activated protein C usage in Scotland: a comparison with published guidelines and a survey of attitudes.

Severe sepsis is a common cause of admission to the intensive care unit and is associated with a high hospital mortality. This audit explored the current use of, and attitudes towards, recombinant activated protein C therapy across Scotland, and compared these with current guidance. Patients with severe sepsis were followed for three days. Consideration and/or usage of recombinant activated protein C were compared with two different guidelines. Ninety-seven patients were admitted to the intensive care unit over the audit period. Recombinant activated protein C was used in nine of these patients. Depending on the criteria used, between 50% and 81% of the patients who qualified for recombinant activated protein C therapy did not receive it. Subsequent to the audit, a survey was performed to study intensive care unit consultants' attitudes to recombinant activated protein C therapy. A total of 125 consultants responded to the survey (77%). Of these, 104 (83%) stated that they used recombinant activated protein C in their clinical practice, 56 (52%) of whom prescribed it to patients with two-organ failures and an Acute Physiology and Chronic Health Evaluation II score of ≥ 25. Thirty-nine respondents (38%) stated that two-organ failures alone would be an adequate trigger for therapy. We conclude that recombinant activated protein C is potentially under-used to treat severe sepsis. Many consultants seem to reserve the drug for the most severely ill sub group of patients.

The right inferior phrenic artery: path of its ascending branch at the vena caval foramen.

The ascending branch of the right inferior phrenic artery is generally understood to pass to the lateral side of the vena caval foramen, on the inferior surface of the diaphragm. A study of 16 cadavers shows that the artery may pass through the vena caval foramen to run on the superior surface of the diaphragm, before returning to the inferior surface by passing through the muscle of the diaphragm.

Trends in the management of esophageal carcinoma based on provider volume: treatment practices of 618 esophageal surgeons.

Controversy exists regarding optimal treatment practices for esophageal cancer. Esophagectomy has received focus as one of the index procedures for both hospital and surgical quality despite a relative paucity of controlled trials to define best practices. A survey was created to determine the degree of heterogeneity in the treatment of esophageal cancer among a diverse group of surgeons and to use high-volume (HV) (>/=15 cases/year) and low-volume (LV) (<15 cases/year) designations to discern specific differences in the management of esophageal cancer from the surgeon's perspective. Based on society rosters, surgeons (n = 4000) in the USA and 15 countries were contacted via mail and queried regarding their treatment practices for esophageal cancer using a 50-item survey instrument addressing demographics, utilization of neoadjuvant chemoradiotherapy, and choice of surgical approach for esophageal resection and palliation. There were 618 esophageal surgeons among respondents (n = 1447), of which 77 (12.5%) were considered HV. The majority of HV surgeons (87%) practiced in an academic setting and had cardiothoracic training, while most LV surgeons were general surgeons in private practice (52.3%). Both HV and LV surgeons favored the hand-sewn cervical anastomosis and the stomach conduit. Minimally invasive esophagectomy is performed more frequently by HV surgeons when compared with LV surgeons (P = 0.045). Most HV surgeons use neoadjuvant therapy for patients with nodal involvement, while LV surgeons are more likely to leave the decision to the oncologist. With a few notable exceptions, substantial heterogeneity exists among surgeons' management strategies for esophageal cancer, particularly when grouped and analyzed by case volume. These results highlight the need for controlled trials to determine best practices in the treatment of this complex patient population.

A framework for integrating the songbird brain.

Biological systems by default involve complex components with complex relationships. To decipher how biological systems work, we assume that one needs to integrate information over multiple levels of complexity. The songbird vocal communication system is ideal for such integration due to many years of ethological investigation and a discreet dedicated brain network. Here we announce the beginnings of a songbird brain integrative project that involves high-throughput, molecular, anatomical, electrophysiological and behavioral levels of analysis. We first formed a rationale for inclusion of specific biological levels of analysis, then developed high-throughput molecular technologies on songbird brains, developed technologies for combined analysis of electrophysiological activity and gene regulation in awake behaving animals, and developed bioinformatic tools that predict causal interactions within and between biological levels of organization. This integrative brain project is fitting for the interdisciplinary approaches taken in the current songbird issue of the Journal of Comparative Physiology A and is expected to be conducive to deciphering how brains generate and perceive complex behaviors.

Coronary and myocardial effects of acetaminophen: protection during ischemia-reperfusion.

Acetaminophen is a phenol with antioxidant properties, but little is known about its actions on the mammalian myocardium and coronary circulation. We studied isolated, perfused guinea pig hearts, and tested the hypothesis that acetaminophen-treated hearts would be protected during ischemia-reperfusion. Acetaminophen concentrations in the range of 0.3-0.6 mmol/l caused modest but significant (P < 0.05) coronary vasoconstriction and positive inotropy. The effects were more brisk during constant pressure perfusion than during constant flow. During 20 min of low-flow, global myocardial ischemia and 40 min of reperfusion, hearts treated with acetaminophen retained or recovered a greater percentage of left ventricular function than hearts treated with vehicle. Myofibrillar ultrastructure appeared to be preserved in the reperfused myocardium with acetaminophen. By using chemiluminescence and spin-trap methodologies, we investigated acetaminophen-mediated antioxidant mechanisms to help explain the cardioprotection. The burst of hydroxyl radicals seen between 0 and 10 min of reperfusion was significantly attenuated (P < 0.05) by acetaminophen but not by vehicle. The 3-morpholinosydnominine (SIN-1) generation of peroxynitrite and its oxidative interaction with luminol to produce blue light during ischemia-reperfusion was also blocked by acetaminophen. Our results show that acetaminophen provides significant functional and structural protection to the ischemic-reperfused myocardium, and the mechanism of cardioprotection seems to involve attenuation of the production of both hydroxyl radicals and peroxynitrite.

Variations in the normal anatomy of the collateral ligaments of the human elbow joint.

The variations which occur in the medial and lateral ligament complexes of the elbow were investigated. These occurred frequently with the standard appearances occurring in no more than half the specimens on the medial side and one quarter of those on the lateral side. Surgeons who regularly perform elbow arthroplasty must be aware of these considerations, especially with the introduction of unconstrained prostheses which rely upon the ligament complex for their postoperative stability.

Stereoselective binding of an enantiomeric pair of stromelysin-1 inhibitors caused by conformational entropy factors.

Isothermal titration calorimetry was used to analyze the binding of an enantiomeric pair of inhibitors to the stromelysin-1 catalytic domain. Differences in binding affinity are attributable to different conformational entropy penalties suffered upon binding. Two possible explanations for these differences are proposed.

Chronic endothelin blockade in dogs with pacing-induced heart failure: possible modulation of sympathoexcitation.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide elaborated by many cell types. Plasma ET-1 levels are significantly augmented in patients and experimental animals with heart failure. Enhanced levels of ET-1 may contribute to myocardial depression and alterations in sympathetic nerve activity in the setting of chronic heart failure. The effects of chronic blockade of endothelin A (ET(A)) receptors on the development and severity of experimental heart failure and sympathoexcitation were evaluated in these experiments using the specific ET(A) antagonist, PD156707. METHODS AND RESULTS: Four groups of conscious, chronically instrumented mongrel dogs were administered either PD156707 (750 mg orally thrice daily) or a placebo starting 1 day before ventricular pacing or a sham (nonpaced) period. Before pacing or the sham period, baseline hemodynamic and plasma norepinephrine (NE) measurements were made. Hemodynamic and NE measurements were made every 3 to 4 days for the next 28 days. All parameters were relatively stable in nonpaced dogs administered placebo. Paced placebo dogs showed classic hemodynamic and sympathoexcitatory changes indicative of heart failure. Nonpaced dogs administered PD156707 showed a significant decrease in mean arterial pressure and total peripheral resistance beginning 3 days after drug administration. Myocardial function was not affected by PD156707 in nonpaced dogs. In paced dogs, PD156707 also reduced arterial pressure and peripheral resistance. Changes in myocardial function were small and insignificant. Paced dogs administered PD156707 showed an approximately 50% lower increase in plasma NE level from days 10 to 24 compared with paced dogs administered placebo (941.8 +/- 122.8 vs 501.1 +/- 92.6 pg/mL at 17 days; P < .01). CONCLUSIONS: These data suggest that ET-1 contributes to the maintenance of arterial pressure in both sham dogs and dogs paced into heart failure. ET-1 does not appear to have a potent effect on inotropic state, but the data strongly suggest that ET-1 may contribute to the progressive deterioration of circulatory function in heart failure by mediating sympathoexcitation and enhancing plasma NE concentration.

Green tea extract and its polyphenols markedly inhibit luminol-dependent chemiluminescence activated by peroxynitrite or SIN-1.

This study is based on a simple chemical interaction of peroxynitrite (OONO-) and luminol, which produces blue light upon oxidation. Since peroxynitrite has a half-life of less than 1 s, a drug known as SIN-1 is used as a peroxynitrite generator. In addition peroxynitrite itself was used directly with a fast injection-mixing system to ascertain whether there are differences between it and the peroxynitrite-generating system (SIN-1) which mimics the natural production of (OONO-). Peroxynitrite is a potent oxidizing compound (1000 times more active than equidose hydrogen peroxide) and it can oxidize carbohydrates, lipids, proteins and nucleic acids. Upon stimulation by inflammation and/or infection, macrophages and neutrophils can be activated to produce large amounts of peroxynitrite. We are interested in simple chemicals that are non-toxic that could inhibit or destroy peroxynitrite, which might otherwise cause inappropriate damage to blood and tissues. Green tea is a complex mixture containing several potent major antioxidant constituents, eg flavins and/or polyphenols. The constituents in green tea may react directly or indirectly with peroxynitrite or its constituents through the process of antioxidation to inhibit light. Alternatively, compounds could produce superoxide which, when reacted with nitric oxide, could produce more peroxynitrite and hence more light with luminol. Therefore, as the tea or antioxidants from tea are diluted, while the peroxynitrite or its precursors are kept at a constant concentration, one can observe unusual behaviour regarding light emission. Initially, at high doses of tea or antioxidant, one observes clear inhibition of the light generated from the reaction of peroxynitrite and luminol. However, at dilute concentrations of antioxidants, one can often observe stimulation of light. Possible reasons for these observations are discussed.

A new method of recording clinical forensic evidence.

Digital photography is a practical tool, useful for the recording of clinical forensic evidence.

Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption.

Our objective was to determine the precise role of endothelial nitric oxide synthase (eNOS) as a modulator of cardiac O2 consumption and to further examine the role of nitric oxide (NO) in the control of mitochondrial respiration. Left ventricle O2 consumption in mice with defects in the expression of eNOS [eNOS (-/-)] and inducible NOS [iNOS (-/-)] was measured with a Clark-type O2 electrode. The rate of decreases in O2 concentration was expressed as a percentage of the baseline. Baseline O2 consumption was not significantly different between groups of mice. Bradykinin (10(-4) mol/L) induced significant decreases in O2 consumption in tissues taken from iNOS (-/-) (-28+/-4%), wild-type eNOS (+/+) (-22+/-4%), and heterozygous eNOS(+/-) (-22+/-5%) but not homozygous eNOS (-/-) (-3+/-4%) mice. Responses to bradykinin in iNOS (-/-) and both wild-type and heterozygous eNOS mice were attenuated after NOS blockade with N-nitro-L-arginine methyl ester (L-NAME) (-2+/-5%, -3+/-2%, and -6+/-5%, respectively, P<0.05). In contrast, S-nitroso-N-acetyl-penicillamine (SNAP, 10(-4) mol/L), which releases NO spontaneously, induced decreases in myocardial O2 consumption in all groups of mice, and such responses were not affected by L-NAME. In addition, pretreatment with bacterial endotoxin elicited a reduction in basal O2 consumption in tissues taken from normal but not iNOS (-/-)-deficient mice. Our results indicate that the pivotal role of eNOS in the control of myocardial O2 consumption and modulation of mitochondrial respiration by NO may have an important role in pathological conditions such as endotoxemia in which the production of NO is altered.

Regulatory effects of endogenous protease inhibitors in acute lung inflammatory injury.

Inflammatory lung injury is probably regulated by the balance between proteases and protease inhibitors together with oxidants and antioxidants, and proinflammatory and anti-inflammatory cytokines. Rat tissue inhibitor of metalloprotease-2 (TIMP-2) and secreted leukoprotease inhibitor (SLPI) were cloned, expressed, and shown to be up-regulated at the levels of mRNA and protein during lung inflammation in rats induced by deposition of IgG immune complexes. Using immunoaffinity techniques, endogenous TIMP-2 in the inflamed lung was shown to exist as a complex with 72- and 92-kDa metalloproteinases (MMP-2 and MMP-9). In inflamed lung both TIMP-2 and SLPI appeared to exist as enzyme inhibitor complexes. Lung expression of both TIMP-2 and SLPI appeared to involve endothelial and epithelial cells as well as macrophages. To assess how these endogenous inhibitors might affect the lung inflammatory response, animals were treated with polyclonal rabbit Abs to rat TIMP-2 or SLPI. This intervention resulted in significant intensification of lung injury (as revealed by extravascular leak of albumin) and substantially increased neutrophil accumulation, as determined by cell content in bronchoalveolar lavage (BAL) fluids. These events were correlated with increased levels of C5a-related chemotactic activity in BAL fluids, while BAL levels of TNF-alpha and chemokines were not affected by treatment with anti-TIMP-2 or anti-SLPI. The data suggest that endogenous TIMP-2 and SLPI dynamically regulate the intensity of lung inflammatory injury, doing so at least in part by affecting the generation of the inflammatory mediator, C5a.

Nitric oxide controls cardiac substrate utilization in the conscious dog.

OBJECTIVES: The aim of this study was to determine whether the acute inhibition of nitric oxide (NO) synthase causes changes in cardiac substrate utilization which can be reversed by a NO donor. METHODS: NO synthase was blocked by giving 30 mg/kg of nitro-L-arginine (NLA) i.v. to 15 chronically instrumented dogs. Hemodynamics and blood samples from aorta and coronary sinus were taken at control and at 1 and 2 h after NLA. In five dogs, 0.4 mg/kg of the NO donor 3754 was given i.v. 1 h after NLA. In six dogs, angiotensin II was infused over 2 h (20-40 ng/kg/min) to mimic the hemodynamic effects of NLA. RESULTS: Two h after NLA: mean arterial pressure was 153 +/- 4 mmHg; MVO2 increased by 38%; cardiac uptake of lactate and glucose increased, respectively, from 20.0 +/- 5.0 to 41.0 +/- 9.3 mumol/min and from 1.1 +/- 0.7 to 6.8 +/- 1.5 mg/min (all P < 0.05 vs. control). Cardiac uptake of free fatty acids decreased by 43% after 1 h (P < 0.05) and returned to control values at 2 h. Cardiac respiratory quotient increased from 0.76 +/- 0.03 to 1.05 +/- 0.07, indicating a shift to carbohydrate oxidation. All these changes were reversed by the NO donor. In the dogs receiving angiotensin II infusion, MVO2 increased by 28% and lactate uptake doubled (both P < 0.05), but no other metabolic changes where observed. CONCLUSIONS: The acute inhibition of NO synthase by NLA causes a switch from fatty acids to lactate and glucose utilization by the heart which can be reversed by a NO donor, suggesting an important regulatory action of NO on cardiac metabolism.

Application of electrospray ionization mass spectrometry for studying human immunodeficiency virus protein complexes.

Mass spectrometry (MS) with electrospray ionization (ESI) has shown utility for studying noncovalent protein complexes, as it offers advantages in sensitivity, speed, and mass accuracy. The stoichiometry of the binding partners can be easily deduced from the molecular weight measurement. In many examples of protein complexes, the gas phase-based measurement is consistent with the expected solution phase binding characteristics. This quality suggests the utility of ESI-MS for investigating solution phase molecular interactions. Complexes composed of proteins from the human immunodeficiency virus (HIV) have been studied using ESI-MS. Multiply charged protein dimers from HIV integrase catalytic core (F185K) and HIV protease have been observed. Furthermore, the ternary complex between HIV protease dimer and inhibitor pepstatin A was studied as a function of solution pH. Zinc binding to zinc finger-containing nucleocapsid protein (NCp7) and the NCp7-psi RNA 1:1 stoichiometry complex was also studied by ESI-MS. No protein-RNA complex was observed in the absence of zinc, consistent with the role of the zinc finger motifs for RNA binding.