A Whole-Brain and Cross-Diagnostic Perspective on Functional Brain Network Dysfunction.

A wide variety of mental disorders have been associated with resting-state functional network alterations, which are thought to contribute to the cognitive changes underlying mental illness. These observations appear to support theories postulating large-scale disruptions of brain systems in mental illness. However, existing approaches isolate differences in network organization without putting those differences in a broad, whole-brain perspective. Using a graph distance approach-connectome-wide similarity-we found that whole-brain resting-state functional network organization is highly similar across groups of individuals with and without a variety of mental diseases. This similarity was observed across autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. Nonetheless, subtle differences in network graph distance were predictive of diagnosis, suggesting that while functional connectomes differ little across health and disease, those differences are informative. These results suggest a need to reevaluate neurocognitive theories of mental illness, with a role for subtle functional brain network changes in the production of an array of mental diseases. Such small network alterations suggest the possibility that small, well-targeted alterations to brain network organization may provide meaningful improvements for a variety of mental disorders.

Mapping the human brain's cortical-subcortical functional network organization.

Understanding complex systems such as the human brain requires characterization of the system's architecture across multiple levels of organization - from neurons, to local circuits, to brain regions, and ultimately large-scale brain networks. Here we focus on characterizing the human brain's large-scale network organization, as it provides an overall framework for the organization of all other levels. We developed a highly principled approach to identify cortical network communities at the level of functional systems, calibrating our community detection algorithm using extremely well-established sensory and motor systems as guides. Building on previous network partitions, we replicated and expanded upon well-known and recently-identified networks, including several higher-order cognitive networks such as a left-lateralized language network. We expanded these cortical networks to subcortex, revealing 358 highly-organized subcortical parcels that take part in forming whole-brain functional networks. Notably, the identified subcortical parcels are similar in number to a recent estimate of the number of cortical parcels (360). This whole-brain network atlas - released as an open resource for the neuroscience community - places all brain structures across both cortex and subcortex into a single large-scale functional framework, with the potential to facilitate a variety of studies investigating large-scale functional networks in health and disease.

Preparation and characterization of maghemite nanoparticles from mild steel for magnetically guided drug therapy.

Maghemite (γ-Fe 2 O 3) nanoparticles for therapeutic applications are prepared from mild steel but the existing synthesis technique is very cumbersome. The entire process takes around 100 days with multiple steps which lack proper understanding. In the current work, maghemite nanoparticles of cuboidal and spheroidal morphologies were prepared from mild steel chips by a novel cost effective oil reduction technique for magnetically guided intravascular drug delivery. The technique developed in this work yields isometric sized γ-Fe 2 O 3 nanoparticles in 6 h with higher saturation magnetization as compared to the existing similar solid state synthesis route. Mass and heat flow kinetics during the heating and quenching steps were studied with the help of Finite element simulations. Qualitative and quantitative analysis of the γ-Fe 2 O 3 phase is performed with the help of x-ray diffraction, transmission electron microscope and x-ray photoelectron spectroscopy. Mechanism for the α-Fe 2 O 3 (haematite) to γ-Fe 2 O 3 (maghemite) phase evolution during the synthesis process is also investigated. Maghemite (γ-Fe2O3) nanoparticles were prepared bya novel cost effective oil reduction technique as mentioned below in the figure. The raw materials included mild steel chips which is one of the most abundant engineering materials. These particles can be used as ideal nanocarriers for targeted drug delivery through the vascular network.

Human Substantia Nigra Neurons Encode Reward Expectations.

Dopamine (DA) signals originating from substantia nigra (SN) neurons are centrally involved in the regulation of motor and reward processing. DA signals behaviorally relevant events where reward outcomes differ from expectations (reward prediction errors, RPEs). RPEs play a crucial role in learning optimal courses of action and in determining response vigor when an agent expects rewards. Nevertheless, how reward expectations, crucial for RPE calculations, are conveyed to and represented in the dopaminergic system is not fully understood, especially in the human brain where the activity of DA neurons is difficult to study. One possibility, suggested by evidence from animal models, is that DA neurons explicitly encode reward expectations. Alternatively, they may receive RPE information directly from upstream brain regions. To address whether SN neuron activity directly reflects reward expectation information, we directly examined the encoding of reward expectation signals in human putative DA neurons by performing single-unit recordings from the SN of patients undergoing neurosurgery. Patients played a two-armed bandit decision-making task in which they attempted to maximize reward. We show that neuronal firing rates (FR) of putative DA neurons during the reward expectation period explicitly encode reward expectations. First, activity in these neurons was modulated by previous trial outcomes, such that FR were greater after positive outcomes than after neutral or negative outcome trials. Second, this increase in FR was associated with shorter reaction times, consistent with an invigorating effect of DA neuron activity during expectation. These results suggest that human DA neurons explicitly encode reward expectations, providing a neurophysiological substrate for a signal critical for reward learning.

Longing to act: Bayesian inference as a framework for craving in behavioral addiction.

Traditionally, craving is considered a defining feature of drug addiction. Accumulating evidence suggests that craving can also exist in behavioral addictions (e.g., gambling disorder) without drug-induced effects. However, the degree to which mechanisms of craving overlap between classic substance use disorders and behavioral addictions remains unclear. There is, therefore, an urgent need to develop an overarching theory of craving that conceptually integrates findings across behavioral and drug addictions. In this review, we will first synthesize existing theories and empirical findings related to craving in both drug-dependent and -independent addictive disorders. Building on the Bayesian brain hypothesis and previous work on interoceptive inference, we will then propose a computational theory for craving in behavioral addiction, where the target of craving is execution of an action (e.g., gambling) rather than a drug. Specifically, we conceptualize craving in behavioral addiction as a subjective belief about physiological states of the body associated with action completion and is updated based on both a prior belief ("I need to act to feel good") and sensory evidence ("I cannot act"). We conclude by briefly discussing the therapeutic implications of this framework. In summary, this unified Bayesian computational framework for craving generalizes across addictive disorders, provides explanatory power for ostensibly conflicting empirical findings, and generates strong hypotheses for future empirical studies. The disambiguation of the computational components underlying domain-general craving using this framework will lead to a deeper understanding of, and effective treatment targets for, behavioral and drug addictions.

Awareness and attitude about mental illness in the rural population of India: A mixed method study.

Context: Recent systematic review and meta-analysis of public attitudes have shown that despite improvements in mental health literacy, public attitudes and desire for social distance with mental illnesses have remained stable over time. Aims: To assess the awareness and attitude of the rural community towards mental disorders using the CAMI scale. Materials and Methods: This mixed method study was conducted under the ICMR-STS grant scheme after IEC approval. It included administration of a pre-tested questionnaire adapted from CAMI scale on 196 adults aged 18-60 years from an adopted village in the field practice area of medical college along with 8 in-depth interviews of key people in the same community. Thematic analysis was done for the qualitative part whereas for the quantitative part, Pearson's correlation coefficient, independent t-test, ANOVA and Kruskall-wallis test were used. Results: Age was positively correlated with the attitude of authoritarianism, social restrictiveness, CMHI and showed a negative correlation with attitude of benevolence. Females showed higher scores for authoritarianism and social restrictiveness. There was a statistically significant difference between APL and BPL groups for authoritarianism attitude towards the mentally ill (P value = 0.02) and CMHI (P value = 0.033). It was observed that with increase in the education levels there was a rise in the mean score of the values for the attitude of benevolence but the difference wasn't statistically significant (P > 0.05). Thematic analysis of the key informant interviews suggested various perceptions of the community regarding mental illness, available options for management, current practices of the community and what can be done further to improve facilities for mental health. Conclusions: People in the community have a varied perspective to mental illnesses which has changed for the better over time but community still approaches quacks first which warrants the need for more awareness. For this, feasibility and effectiveness of increasing involvement of females from the community in health-related decisions can be explored further. We recommend further awareness generation in the younger generation with community-based research on perceptions of the community about mental health. This will provide more practical and feasible solutions to complement the national mental health program.

Neural patterns differentiate traumatic from sad autobiographical memories in PTSD.

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of 'regular' negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type from hippocampal multivoxel patterns. Finally, individual symptom severity modulated semantic representation of the traumatic narratives in the posterior cingulate cortex. Taken together, these findings suggest that traumatic memories are an alternative cognitive entity that deviates from memory per se.

An Interpretable and Predictive Connectivity-Based Neural Signature for Chronic Cannabis Use.

BACKGROUND: Cannabis is one of the most widely used substances in the world, with usage trending upward in recent years. However, although the psychiatric burden associated with maladaptive cannabis use has been well established, reliable and interpretable biomarkers associated with chronic use remain elusive. In this study, we combine large-scale functional magnetic resonance imaging with machine learning and network analysis and develop an interpretable decoding model that offers both accurate prediction and novel insights into chronic cannabis use. METHODS: Chronic cannabis users (n = 166) and nonusing healthy control subjects (n = 124) completed a cue-elicited craving task during functional magnetic resonance imaging. Linear machine learning methods were used to classify individuals into chronic users and nonusers based on whole-brain functional connectivity. Network analysis was used to identify the most predictive regions and communities. RESULTS: We obtained high (∼80% out-of-sample) accuracy across 4 different classification models, demonstrating that task-evoked connectivity can successfully differentiate chronic cannabis users from nonusers. We also identified key predictive regions implicating motor, sensory, attention, and craving-related areas, as well as a core set of brain networks that contributed to successful classification. The most predictive networks also strongly correlated with cannabis craving within the chronic user group. CONCLUSIONS: This novel approach produced a neural signature of chronic cannabis use that is both accurate in terms of out-of-sample prediction and interpretable in terms of predictive networks and their relation to cannabis craving.

Variations in the Anatomy of Spinal Accessory Nerve and its Landmarks for Identification in Neck Dissection: A Clinical Study.

PURPOSE: To assess the anatomy of the spinal accessory nerve (SAN), its variations and the landmark of level II B lymph nodes. METHODS: Prospective study included 50 patients from 2016 to 2018.The predictor variables were drawn from demographic details of the patients; SAN was analyzed intraoperatively with the parameters like the nerve relationship with the IJV, SCM muscle, contributions of cervical plexus and a new parameter of length from midpoint of clavicle to entry of nerve in the trapezius muscle in the lower part of neck which was studied for the first time and forms the prime identification landmark to preserve the nerve. Outcome variables were details of anatomic variations and branches and utility of these landmarks in prevention of nerve injury. RESULTS: Sample consisted of 38 (76%) male and 12 (24%) female patients. The SAN with respect to the IJV was dorsal in 42% patients and ventral in 58%. In 54% cases, SAN gave a branch to the SCM without penetrating the muscle and in 46% gave a branch to the SCM penetrating the muscle. SAN received contributions from the C2 root of the cervical plexus in 68%, both C2 and C3 in 54% and C3 in 50% cases. Mean length from measurements recorded between mid-line of clavicle to insertion of SAN to trapezius muscle and entry of SAN into trapezius muscle was 59 mm with variations recorded in gender and short/long neck. CONCLUSION: The result of this study suggests that parameters used are simple clinical tools for identification of the SAN and its variations resulting in no nerve injury. It is prudent for the surgeon to have knowledge of sound anatomical landmarks with the variations in the SAN course which avoids morbidity and improves the quality of life.

Emotional adaptation during a crisis: decline in anxiety and depression after the initial weeks of COVID-19 in the United States.

Crises such as the COVID-19 pandemic are known to exacerbate depression and anxiety, though their temporal trajectories remain under-investigated. The present study aims to investigate fluctuations in depression and anxiety using the COVID-19 pandemic as a model crisis. A total of 1512 adults living in the United States enrolled in this online study beginning April 2, 2020 and were assessed weekly for 10 weeks (until June 4, 2020). We measured depression and anxiety using the Zung Self-Rating Depression scale and State-Trait Anxiety Inventory (state subscale), respectively, along with demographic and COVID-related surveys. Linear mixed-effects models were used to examine factors contributing to longitudinal changes in depression and anxiety. We found that depression and anxiety levels were high in early April, but declined over time. Being female, younger age, lower-income, and previous psychiatric diagnosis correlated with higher overall levels of anxiety and depression; being married additionally correlated with lower overall levels of depression, but not anxiety. Importantly, worsening of COVID-related economic impact and increase in projected pandemic duration exacerbated both depression and anxiety over time. Finally, increasing levels of informedness correlated with decreasing levels of depression, while increased COVID-19 severity (i.e., 7-day change in cases) and social media use were positively associated with anxiety over time. These findings not only provide evidence for overall emotional adaptation during the initial weeks of the pandemic, but also provide insight into overlapping, yet distinct, factors contributing to depression and anxiety throughout the first wave of the pandemic.

Containment of COVID-19: Simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

Efficient contact tracing and testing are fundamental tools to contain the transmission of SARS-CoV-2. We used multi-agent simulations to estimate the daily testing capacity required to find and isolate a number of infected agents sufficient to break the chain of transmission of SARS-CoV-2, so decreasing the risk of new waves of infections. Depending on the non-pharmaceutical mitigation policies in place, the size of secondary infection clusters allowed or the percentage of asymptomatic and paucisymptomatic (i.e., subclinical) infections, we estimated that the daily testing capacity required to contain the disease varies between 0.7 and 9.1 tests per thousand agents in the population. However, we also found that if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of new daily infections did not always decrease and could even increase exponentially, irrespective of the testing capacity. Under these conditions, we show that population-level information about geographical distribution and travel behaviour could inform sampling policies to aid a successful containment, while avoiding concerns about government-controlled mass surveillance.

Containment of future waves of COVID-19: simulating the impact of different policies and testing capacities for contact tracing, testing, and isolation.

We used multi-agent simulations to estimate the testing capacity required to find and isolate a number of infections sufficient to break the chain of transmission of SARS-CoV-2. Depending on the mitigation policies in place, a daily capacity between 0.7 to 3.6 tests per thousand was required to contain the disease. However, if contact tracing and testing efficacy dropped below 60% (e.g. due to false negatives or reduced tracing capability), the number of infections kept growing exponentially, irrespective of any testing capacity. Under these conditions, the population's geographical distribution and travel behaviour could inform sampling policies to aid a successful containment.

Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells.

BACKGROUND: Epidemiological and laboratory studies support the hypothesis that several plant components influence prostate carcinogenesis and holds promise for disease prevention. Previously we reported that Nexrutine (bark extract from Phellodendron amurense) inhibits proliferation of prostate cancer cells and prostate tumor development in the transgenic adenocarcinoma of mouse prostate (TRAMP) model through modulation of Akt signaling pathway. In the present investigation we conducted studies to further define the mechanism of action of Nexrutine and to identify the active component associated with its biological activity. METHODS: Androgen-responsive, androgen-independent human prostate cancer cell lines and tissues from TRAMP mice fed Nexrutine(R) were used in these studies. Activity guided fractionation identified butanol fraction recapitulating the activities of Nexrutine assessed by proliferation assays, apoptotic assays (DAPI and TUNEL staining), transient transfections, gel shift assays and Western blotting. In addition ultra-performance liquid chromatography (UPLC) of butanol fraction was used to identify active component of Nexrutine. RESULTS: Butanol fraction recapitulated the activities of Nexrutine in (i) inhibiting proliferation; (ii) inducing apoptosis; and (iii) modulating transcriptional activity of NFkappaB in prostate cancer cells. Our data also indicates that both Nexrutine and butanol fraction modulates NFkappaB transcriptional activity by inhibiting IkappaBalpha phosphorylation. Expression of p65 and phosphorylated IkappaBalpha are high in tumors from TRAMP mice. In contrast dietary administration of Nexrutine reduced expression of p65 and phosphorylated IkappaBalpha in prostate from TRAMP mice. In addition using UPLC, we have identified berberine or closely related compound in the butanol fraction. CONCLUSION: The results suggest that berberine or closely related component of butanol fraction may be responsible for the observed biological activities and induce apoptosis in prostate cancer cells by targeting critical cell survival signaling pathways both in vitro and in vivo.

Disposition of flavonoids via enteric recycling: UDP-glucuronosyltransferase (UGT) 1As deficiency in Gunn rats is compensated by increases in UGT2Bs activities.

Flavonoids have poor bioavailabilities largely because of metabolism via UDP-glucuronosyltransferases (UGTs). This study aims to further understand the functions of UGT in metabolizing genistein and apigenin, two compounds metabolized more extensively in the gut than in the liver. Because Gunn rats are deficient in UGT1As, we determined whether this deficiency would result in less flavonoid glucuronidation, using rat intestinal perfusion model and microsomes prepared from rat liver and intestine. In yeast-expressed rat UGT isoforms, rat UGT1A isoforms (especially UGT1A7) were mainly responsible for flavonoid metabolism. In perfusion studies, the two flavonoids were rapidly absorbed at comparable rates, but the intestinal excretions of glucuronides in Gunn rats compared with Wistar rats were not only comparable for genistein but also were higher (p < 0.05) for apigenin, suggesting up-regulation of UGT isoforms in Gunn rats. To determine the possible compensatory UGT isoforms, we first verified that UGT1A activities were significantly lower (p < 0.05) in Gunn rats by using UGT1A-specific probes 7-ethyl-10-hydroxycamptothecin (SN-38) and prunetin. We then demonstrated using UGT2B probes testosterone, ezetimibe, and indomethacin that UGT2B activities were usually significantly higher in Gunn rats. In addition, testosterone was metabolized much faster in liver microsomes than in intestinal microsomes, and in microsomes prepared from Gunn rats compared with Wistar rats. In conclusion, flavonoids are efficiently metabolized by UGT1A-deficient Gunn rats because of compensatory up-regulation of intestinal UGT2Bs and hepatic anion efflux transporters, which increases their disposition and limits their oral bioavailabilities.

Regulation of [3H] D-aspartate release from mammalian isolated retinae by hydrogen sulfide.

Hydrogen sulfide (H(2)S), can produce pharmacological effects on neural and non-neural tissues from several mammalian species. The present study investigates the pharmacological action of H(2)S, (using sodium hydrosulfide, NaHS, and/or sodium sulfide, Na(2)S as donors) on amino acid neurotransmission (using [(3)H] D: -aspartate as a marker for glutamate) from isolated, superfused bovine and porcine retinae. Isolated neural retinae were incubated in Krebs solution containing [(3)H] D: -aspartate at 37 degrees C. Release of [(3)H] D: -aspartate was elicited by high potassium (K(+) 50 mM) pulse. Both NaHS and Na(2)S donors caused an inhibition of K(+)-evoked [(3)H] D: -aspartate release from isolated bovine retinae without affecting basal [(3)H] D: -aspartate efflux yielding IC(50) values of 0.006 and 6 microm, respectively. Furthermore, NaHS inhibited depolarization-evoked release of [(3)H] D: -aspartate from isolated porcine retinae with an IC(50) value of 8 microM. The inhibitory action of NaHS on [(3)H] D: -aspartate release from porcine retinae was blocked by propargyglycine, a selective inhibitor of cystathionine gamma-lyase (CSE). Our results indicate that H(2)S donors can inhibit amino acid neurotransmission from both isolated bovine and porcine retinae, an effect that is dependent, at least in part, on intramural biosynthesis of H(2)S.

Effect of hydrogen sulfide on sympathetic neurotransmission and catecholamine levels in isolated porcine iris-ciliary body.

In the present study, we investigated the pharmacological action of hydrogen sulfide (H2S, using sodium hydrosulfide, NaHS, and/or sodium sulfide, Na2S as donors) on sympathetic neurotransmission from isolated, superfused porcine iris-ciliary bodies. We also examined the effect of H2S on norepinephrine (NE), dopamine and epinephrine concentrations in isolated porcine anterior uvea. Release of [3H]NE was triggered by electrical field stimulation and basal catecholamine concentrations was measured by high performance liquid chromatography (HPLC). Both NaHS and Na2S caused a concentration-dependent inhibition of electrically evoked [3H]NE release from porcine iris-ciliary body without affecting basal [3H]NE efflux. The inhibitory action of H2S donors on NE release was attenuated by aminooxyacetic acid (AOA) and propargyglycine (PAG), inhibitors of cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), respectively. With the exception of dopamine, NaHS caused a concentration-dependent reduction in endogenous NE and epinephrine concentrations in isolated iris-ciliary bodies. We conclude that H2S can inhibit sympathetic neurotransmission from isolated porcine anterior uvea, an effect that is dependent, at least in part, on intramural biosynthesis of this gas. Furthermore, the observed action of H2S donors on sympathetic transmission may be due to a direct action of this gas on neurotransmitter pools.

Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.

The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon, and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides.

Clinical outcomes of endoscopic vs retromandibular approach for the treatment of condylar fractures-a randomized clinical trial.

OBJECTIVE: Condylar fractures remain the most controversial topic in maxillofacial trauma. Open reduction and internal fixation (ORIF) with use of an extraoral approach has certain benefits over the nonsurgical treatment. Concerns, however, remain about the risk of facial nerve injury, postoperative facial nerve weakness, and facial scarring when operating in this region despite the various extraoral approaches that have been developed. The recently popularized endoscope-assisted open reduction and internal fixation (EAORIF) is claimed to provide better results because it is minimally invasive, provides excellent visibility, and eliminates surgical scarring and the risk of facial nerve injury. This study, therefore, aims to compare the retromandibular (extraoral) approach and EAORIF for the treatment of condylar fractures. STUDY DESIGN: A prospective analysis of 32 cases of condylar fractures that reported to the SDM Craniofacial Centre (Dharwad, India) was carried out. Sixteen patients had been treated with the retromandibular (RM) approach, and 16 had undergone EAORIF in the period from 2012-2017. Patients were evaluated for clinical parameters, such as fracture site, displacement, and surgical duration, as well as for functional parameters, such as occlusion, maximum interincisal opening, deviation of mouth on lateral movements, temporomandibular joint (TMJ) pain and clicking, and facial nerve weakness. Statistical significance was elicited with P < .05. RESULTS: The patients subjected to either approach had suffered fractures of the low condylar neck and the subcondyle. Maximum interincisal opening, mandibular deviation, occlusion, and TMJ function at postoperative month 6 were comparable between the groups. Although no permanent facial nerve injury was seen in this study, the incidence of transient facial nerve weakness was higher in the RM group (56.25%) compared with the EAORIF group (6.25%) (P = .036). The surgical time was longer in the EAORIF group (RM: 107+/- 19.7 minutes and EAORIF: 155 +/- 18.2 minutes) (P = .04). The rest of the parameters were comparable between both groups. CONCLUSIONS: Although there is consensus on closed reduction in pediatric and adult condylar head fractures, the role of a surgical approach to treatment of displaced condylar neck and subcondylar fractures remains controversial. In our study, both surgical approaches were found to be suitable for the treatment of these fractures.

Inhibitory action of hydrogen sulfide on muscarinic receptor-induced contraction of isolated porcine irides.

We investigated the pharmacological actions of hydrogen sulfide (H(2)S) using sodium hydrosulfide (NaHS) and sodium sulfide (Na(2)S) as donors on isolated porcine irides in the presence of tone induced by muscarinic receptor stimulation. Furthermore, we also investigated the mechanism of action of H(2)S in this smooth muscle. Isolated porcine iris muscle strips were set up in organ baths and prepared for measurement of longitudinal isometric tension. The relaxant action of NaHS or Na(2)S on carbachol-induced tone was studied in the absence and presence of a K(+)-channel inhibitor and inhibitors/activators of enzymes of the biosynthetic pathways for H(2)S, prostanoid and nitric oxide production. In the concentration range, 10 nM to 100 microM, NaHS produced a concentration-dependent relaxation of carbachol-induced tone reaching a maximum of inhibition of 28% at 30 microM. The cyclooxygenase inhibitor, flurbiprofen (1 microM), enhanced relaxations induced by both NaHS and Na(2)S yielding IC(50) values of 7 microM and 70 microM, respectively. With exception of l-NAME (300 muM) inhibitors of cystathionine gamma-lyase, propargylglycine, (PAG) (1 mM) and beta-cyanoalanine, (BCA) (1 mM) and inhibitors of cystathionine beta-synthase, aminooxyacetic acid (AOA) (30 microM) and hydroxylamine (HOA) (30 microM) caused significant (P < 0.001) rightward shifts in the concentration-response curves to NaHS. An activator of cystathionine beta-synthase, SAM (100 microM), enhanced relaxations elicited by low concentrations of NaHS but attenuated responses caused by the higher concentrations of this H(2)S donor. The inhibitor of K(ATP) channel, glibenclamide (100 and 300 microM), blocked relaxations induced by NaHS. We conclude that the observed inhibitory action of NaHS and Na(2)S in isolated porcine irides is dependent on endogenous production of prostanoids and the biosynthesis of H(2)S by cystathionine gamma-lyase and cystathionine beta-synthase. Furthermore, relaxation induced by H(2)S is mediated, at least in part, by K(ATP) channels. Nitric oxide is not involved in the relaxation induced by this gas in the isolated porcine irides.

The Human Brain Traverses a Common Activation-Pattern State Space Across Task and Rest.

Much of our lives are spent in unconstrained rest states, yet cognitive brain processes are primarily investigated using task-constrained states. It may be possible to utilize the insights gained from experimental control of task processes as reference points for investigating unconstrained rest. To facilitate comparison of rest and task functional magnetic resonance imaging data, we focused on activation amplitude patterns, commonly used for task but not rest analyses. During rest, we identified spontaneous changes in temporally extended whole-brain activation-pattern states. This revealed a hierarchical organization of rest states. The top consisted of two competing states consistent with previously identified "task-positive" and "task-negative" activation patterns. These states were composed of more specific states that repeated over time and across individuals. Contrasting with the view that rest consists of only task-negative states, task-positive states occurred 40% of the time while individuals "rested," suggesting task-focused activity may occur during rest. Together our results suggest that brain activation dynamics form a general hierarchy across task and rest, with a small number of dominant general states reflecting basic functional modes and a variety of specific states potentially reflecting a wide variety of cognitive processes.