Associations of nature contact with emotional ill-being and well-being: the role of emotion regulation.

Nature contact has associations with emotional ill-being and well-being. However, the mechanisms underlying these associations are not fully understood. We hypothesised that increased adaptive and decreased maladaptive emotion regulation strategies would be a pathway linking nature contact to ill-being and well-being. Using data from a survey of 600 U.S.-based adults administered online in 2022, we conducted structural equation modelling to test our hypotheses. We found that (1) frequency of nature contact was significantly associated with lesser emotional ill-being and greater emotional well-being, (2) effective emotion regulation was significantly associated with lesser emotional ill-being and greater emotional well-being, and (3) the associations of higher frequency of nature contact with these benefits were partly explained via emotion regulation. Moreover, we found a nonlinear relationship for the associations of duration of nature contact with some outcomes, with a rise in benefits up to certain amounts of time, and a levelling off after these points. These findings support and extend previous work that demonstrates that the associations of nature contact with emotional ill-being and well-being may be partly explained by changes in emotion regulation.

Chronic alcohol use primes bronchial cells for altered inflammatory response and barrier dysfunction during SARS-CoV-2 infection.

Alcohol use disorder (AUD) is a significant public health concern and people with AUD are more likely to develop severe acute respiratory distress syndrome (ARDS) in response to respiratory infections. To examine whether AUD was a risk factor for more severe outcome in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we examined early responses to infection using cultured differentiated bronchial epithelial cells derived from brushings obtained from people with AUD or without AUD. RNA-seq analysis of uninfected cells determined that AUD cells were enriched for expression of epidermal genes as compared with non-AUD cells. Bronchial epithelial cells from patients with AUD showed a significant decrease in barrier function 72 h postinfection, as determined by transepithelial electrical resistance. In contrast, barrier function of non-AUD cells was enhanced 72 h after SARS-CoV-2 infection. AUD cells showed claudin-7 that did not colocalize with zonula occludens-1 (ZO-1), indicative of disorganized tight junctions. However, both AUD and non-AUD cells showed decreased ß-catenin expression following SARS-CoV-2 infection. To determine the impact of AUD on the inflammatory response to SARS-CoV-2 infection, cytokine secretion was measured by multiplex analysis. SARS-CoV-2-infected AUD bronchial cells had enhanced secretion of multiple proinflammatory cytokines including TNFα, IL-1ß, and IFNγ as opposed to non-AUD cells. In contrast, secretion of the barrier-protective cytokines epidermal growth factor (EGF) and granulocyte macrophage-colony stimulating factor (GM-CSF) was enhanced for non-AUD bronchial cells. Taken together, these data support the hypothesis that AUD is a risk factor for COVID-19, where alcohol primes airway epithelial cells for increased inflammation and increased barrier dysfunction and increased inflammation in response to infection by SARS-CoV-2.NEW & NOTEWORTHY Alcohol use disorder (AUD) is a significant risk factor for severe acute respiratory distress syndrome. We found that AUD causes a phenotypic shift in gene expression in human bronchial epithelial cells, enhancing expression of epidermal genes. AUD cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had higher levels of proinflammatory cytokine secretion and barrier dysfunction not present in infected non-AUD cells, consistent with increased early COVID-19 severity due to AUD.

Pioglitazone Reverses Alcohol-Induced Alveolar Macrophage Phagocytic Dysfunction.

Alcohol use disorders (AUD) increase susceptibility to respiratory infections by 2- to 4-fold in part because of impaired alveolar macrophage (AM) immune function. Alcohol causes AM oxidative stress, diminishing AM phagocytic capacity and clearance of microbes from the alveolar space. Alcohol increases AM NADPH oxidases (Noxes), primary sources of AM oxidative stress, and reduces peroxisome proliferator-activated receptor γ (PPARγ) expression, a critical regulator of AM immune function. To investigate the underlying mechanisms of these alcohol-induced AM derangements, we hypothesized that alcohol stimulates CCAAT/enhancer-binding protein ß (C/EBPß) to suppress Nox-related microRNAs (miRs), thereby enhancing AM Nox expression, oxidative stress, and phagocytic dysfunction. Furthermore, we postulated that pharmacologic PPARγ activation with pioglitazone would inhibit C/EBPß and attenuate alcohol-induced AM dysfunction. AM isolated from human AUD subjects or otherwise healthy control subjects were examined. Compared with control AM, alcohol activated AM C/EBPß, decreased Nox1-related miR-1264 and Nox2-related miR-107, and increased Nox1, Nox2, and Nox4 expression and activity. These alcohol-induced AM derangements were abrogated by inhibition of C/EBPß, overexpression of miR-1264 or miR-107, or pioglitazone treatment. These findings define novel molecular mechanisms of alcohol-induced AM dysfunction mediated by C/EBPß and Nox-related miRs that are amenable to therapeutic targeting with PPARγ ligands. These results demonstrate that PPARγ ligands provide a novel and rapidly translatable strategy to mitigate susceptibility to respiratory infections and related morbidity in individuals with AUD.

Use of Baricitinib in Patients With Moderate to Severe Coronavirus Disease 2019.

Hyperinflammation is associated with increased mortality in coronavirus disease 2019 (COVID-19). In this retrospective, uncontrolled patient cohort with moderate -severe COVID-19, treatment with baricitinib plus hydroxychloroquine was associated with recovery in 11 of 15 patients. Baricitinib for the treatment of COVID-19 should be further investigated in randomized, controlled clinical trials.

Acceptability and Effectiveness of Artificial Intelligence Therapy for Anxiety and Depression (Youper): Longitudinal Observational Study.

BACKGROUND: Youper is a widely used, commercially available mobile app that uses artificial intelligence therapy for the treatment of anxiety and depression. OBJECTIVE: Our study examined the acceptability and effectiveness of Youper. Further, we tested the cumulative regulation hypothesis, which posits that cumulative emotion regulation successes with repeated intervention engagement will predict longer-term anxiety and depression symptom reduction. METHODS: We examined data from paying Youper users (N=4517) who allowed their data to be used for research. To characterize the acceptability of Youper, we asked users to rate the app on a 5-star scale and measured retention statistics for users' first 4 weeks of subscription. To examine effectiveness, we examined longitudinal measures of anxiety and depression symptoms. To test the cumulative regulation hypothesis, we used the proportion of successful emotion regulation attempts to predict symptom reduction. RESULTS: Youper users rated the app highly (mean 4.36 stars, SD 0.84), and 42.66% (1927/4517) of users were retained by week 4. Symptoms decreased in the first 2 weeks of app use (anxiety: d=0.57; depression: d=0.46). Anxiety improvements were maintained in the subsequent 2 weeks, but depression symptoms increased slightly with a very small effect size (d=0.05). A higher proportion of successful emotion regulation attempts significantly predicted greater anxiety and depression symptom reduction. CONCLUSIONS: Youper is a low-cost, completely self-guided treatment that is accessible to users who may not otherwise access mental health care. Our findings demonstrate the acceptability and effectiveness of Youper as a treatment for anxiety and depression symptoms and support continued study of Youper in a randomized clinical trial.

Predictors of length of hospital stay among preterm infants admitted to neonatal intensive care unit: Data from a multicentre collaborative network from India (INNC: Indian National Neonatal Collaborative).

AIM: Prediction of length of stay (LOS) among preterm neonates is important for counselling of parents and for assessing neonatal intensive care unit (NICU) census and economic burden. The aim of this study is to evaluate perinatal and postnatal factors that influence LOS in preterm infants (25-33 weeks of gestation) admitted to participating NICUs of Indian National Neonatal Collaborative (INNC). METHODS: From the INNC database, the data which were prospectively entered using uniformed pre-defined criteria were analysed. RESULTS: A total of 3095 infants were included from 12 centres. Every week decrease in gestation increased LOS by 9 days. The median LOS for infants with gestational age of 25, 26, 27, 28, 29, 30, 31, 32 and 33 weeks were 86, 70, 62, 52, 40, 30, 23, 16 and 10 days, respectively. On multivariate analysis, abnormal antenatal umbilical artery doppler, severe small for gestational age (SGA), requirement of resuscitation, respiratory distress syndrome (RDS), seizures, sepsis, necrotising enterocolitis (NEC), major malformations and bronchopulmonary dysplasia (BPD) increased LOS by 5.4 (3.5-7.4), 21.6 (19-23.9), 4.7 (3.3-6.1), 3 (1.7-4.3), 15.2 (8.5-22.1), 11.2 (9.1-13.2), 9.8 (5.2-14.4), 8.8 (4.4-13.3) and 5.6 (0.5-10.7) days, respectively. CONCLUSIONS: Apart from lower gestation and birth weight, abnormal antenatal umbilical artery doppler, severe SGA, resuscitation need, major malformations, RDS, seizures, sepsis, NEC and BPD influenced LOS in preterm infants. In comparison with other networks or data from developed countries, LOS in our network was comparatively less for similar gestational age infants.

The regulation of recurrent negative emotion in the aftermath of a lost election.

For some American voters, the news of Mr. Trump's victory in the 2016 presidential election caused recurrent emotions that were negative, persistent, and intense enough to elicit repeated attempts at emotion regulation. This afforded a rare opportunity to analyse the regulation of recurrent emotions in a natural, non-laboratory context. The regulation of recurrent emotion involves additional considerations relative to single-instance emotion, such as representations of past and future encounters with the emotion-eliciting variables, ongoing consequences of each regulatory episode, and a tendency to repeatedly deploy emotion regulation strategies that one is most familiar with in the context of the particular recurrent emotion. Despite the ubiquitous nature of recurrent emotions, its associated regulatory processes have been infrequently examined and are not well-understood. Over eight days (11/10/16-11/18/16), we administered four surveys to 202 participants who voted against Mr. Trump. We examined the determinants and outcomes of regulatory strategies in the context of recurrent emotion. We found that (1) reappraisal (compared to distraction and acceptance) was associated with greater decline in emotion intensity, (2) high-intensity emotions were more likely to be distracted, whereas low-intensity emotions were more likely to be reappraised, and (3) strategy variability was associated with greater affective adaptation.

Identification of a targeted and testable antiarrhythmic therapy for long-QT syndrome type 2 using a patient-specific cellular model.

Aims: Loss-of-function mutations in the hERG gene causes long-QT syndrome type 2 (LQT2), a condition associated with reduced IKr current. Four different mutation classes define the molecular mechanisms impairing hERG. Among them, Class 2 mutations determine hERG trafficking defects. Lumacaftor (LUM) is a drug acting on channel trafficking already successfully tested for cystic fibrosis and its safety profile is well known. We hypothesize that LUM might rescue also hERG trafficking defects in LQT2 and exert anti-arrhythmic effects. Methods and results: From five LQT2 patients, we generated lines of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) harbouring Class 1 and 2 mutations. The effects of LUM on corrected field potential durations (cFPD) and calcium-handling irregularities were verified by multi electrode array and by calcium transients imaging, respectively. Molecular analysis was performed to clarify the mechanism of action of LUM on hERG trafficking and calcium handling. Long-QT syndrome type 2 induced pluripotent stem cell-derived cardiomyocytes mimicked the clinical phenotypes and showed both prolonged cFPD (grossly equivalent to the QT interval) and increased arrhythmias. Lumacaftor significantly shortened cFPD in Class 2 iPSC-CMs by correcting the hERG trafficking defect. Furthermore, LUM seemed to act also on calcium handling by reducing RyR2S2808 phosphorylation in both Class 1 and 2 iPSC-CMs. Conclusion: Lumacaftor, a drug already in clinical use, can rescue the pathological phenotype of LQT2 iPSC-CMs, particularly those derived from Class 2 mutated patients. Our results suggest that the use of LUM in LQT2 patients not protected by ß-blockers is feasible and may represent a novel therapeutic option.

Acetylated Signal Transducer and Activator of Transcription 3 Functions as Molecular Adaptor Independent of Transcriptional Activity During Human Cardiogenesis.

Activation of signal transducer and activator of transcription 3 (STAT3) is imperative for mammalian development, specifically cardiogenesis. STAT3 phosphorylation and acetylation are key post-translational modifications that regulate its transcriptional activity. Significance of such modifications during human cardiogenesis remains elusive. Using human pluripotent stem cells to recapitulate cardiogenesis, two independently modified STAT3α (92 kDa) isoforms (phosphorylated and acetylated), which perform divergent functions were identified during cardiomyocyte (CM) formation. Phosphorylated STAT3α functioned as the canonical transcriptional activator, while acetylated STAT3α underwent caspase-3-mediated cleavage to generate a novel STAT3ζ fragment (∼45 kDa), which acted as a molecular adaptor integral to the ErbB4-p38γ signaling cascade in driving CM formation. While STAT3α knockdown perturbed cardiogenesis by eliminating both post-translationally modified STAT3α isoforms, caspase-3 knockdown specifically abrogates the function of acetylated STAT3α, resulting in limited STAT3ζ formation thereby preventing nuclear translocation of key cardiac transcription factor Nkx2-5 that disrupted CM formation. Our findings show the coexistence of two post-translationally modified STAT3α isoforms with distinct functions and define a new role for STAT3 as a molecular adaptor that functions independently of its canonical transcriptional activity during human cardiogenesis. Stem Cells 2017;35:2129-2137.

Alteration in cognitive behaviour, brain antioxidant enzyme activity and their gene expression in F1 generation mice, following Cd exposure during the late gestation period: modulation by quercetin.

We investigated whether in-utero Cd(II) chloride exposure of the dams between 14th to 21st day of gestation affects memory and learning, oxidative stress, antioxidant enzyme activity and their gene expression in brain of the pups in their adulthood. In the Morris water maze, cadmium (Cd) exposure impaired spatial memory which was reversed following co-treatment with quercetin (100 mg/kg). In the passive avoidance paradigm, retention memory was adversely affected but was significantly reversed by co treatment with quercetin (25, 50, 100 mg/kg). The malondialdehyde and catalase (CAT) levels and glutathione-S-transferase (GST) activity were increased significantly in Cd-treated group, but were reversed by quercetin (all doses). The gene expression for CAT and GST in brain tissue of Cd treated animals also increased many folds as compared to the control, and this effect was decreased on co-treatment with quercetin (all doses), thus matching with the respective enzyme activities. Quercetin (25 mg/kg) when co-treated with Cd caused a decrease in GST activity compared to control, which points towards a complex interplay with oxidative free radicals and promoters and transcription factors. Thus, Cd exposure during late gestation causes impaired spatial and retention memory in the next generation which may be due to alteration of activity as well as gene expression of the antioxidant enzymes, CAT and GST. Quercetin may offer some protection of memory impairment probably by modulating these effects.

ErbB4 Activated p38γ MAPK Isoform Mediates Early Cardiogenesis Through NKx2.5 in Human Pluripotent Stem Cells.

Activation of ErbB4 receptor signaling is instrumental in heart development, lack of which results in embryonic lethality. However, mechanism governing its intracellular signaling remains elusive. Using human pluripotent stem cells, we show that ErbB4 is critical for cardiogenesis whereby its genetic knockdown results in loss of cardiomyocytes. Phospho-proteome profiling and Western blot studies attribute this loss to inactivation of p38γ MAPK isoform which physically interacts with NKx2.5 and GATA4 transcription factors. Post-cardiomyocyte formation p38γ/NKx2.5 downregulation is followed by p38α/MEF2c upregulation suggesting stage-specific developmental roles of p38 MAPK isoforms. Knockdown of p38γ MAPK similarly disrupts cardiomyocyte formation in spite of the presence of NKx2.5. Cell fractionation and NKx2.5 phosphorylation studies suggest inhibition of ErbB4-p38γ signaling hinders NKx2.5 nuclear translocation during early cardiogenesis. This study reveals a novel pathway that directly links ErbB4 and p38γ to the transcriptional machinery of NKx2.5-GATA4 complex which is critical for cardiomyocyte formation during mammalian heart development.

ErbB Receptor Tyrosine Kinase: A Molecular Switch Between Cardiac and Neuroectoderm Specification in Human Pluripotent Stem Cells.

Mechanisms determining intrinsic differentiation bias inherent to human pluripotent stem cells (hPSCs) toward cardiogenic fate remain elusive. We evaluated the interplay between ErbB4 and Epidemal growth factor receptor (EGFR or ErbB1) in determining cardiac differentiation in vitro as these receptor tyrosine kinases are key to heart and brain development in vivo. Our results demonstrate that during cardiac differentiation, cell fate biases exist in hPSCs due to cardiac/neuroectoderm divergence post cardiac mesoderm stage. Stage-specific up-regulation of EGFR in concert with persistent Wnt3a signaling post cardiac mesoderm favors commitment toward neural progenitor cells (NPCs). Inhibition of EGFR abrogates these effects with enhanced (>twofold) cardiac differentiation efficiencies by increasing proliferation of Nkx2-5 expressing cardiac progenitors while reducing proliferation of Sox2 expressing NPCs. Forced overexpression of ErbB4 rescued cardiac commitment by augmenting Wnt11 signaling. Convergence between EGFR/ErbB4 and canonical/noncanonical Wnt signaling determines cardiogenic fate in hPSCs. Stem Cells 2016;34:2461-2470.

Peroxisome Proliferator-Activated Receptor γ Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction.

Peroxisome proliferator-activated receptor (PPAR) γ is critical for alveolar macrophage (AM) function. Chronic alcohol abuse causes AM phagocytic dysfunction and susceptibility to respiratory infections by stimulating nicotinamide adenine dinucleotide oxidases (Nox), transforming growth factor-ß1, and oxidative stress in the AM. Because PPARγ inhibits Nox expression, we hypothesized that alcohol reduces PPARγ, stimulating AM dysfunction. AMs were examined from: (1) patients with alcoholism or control patients; (2) a mouse model of chronic ethanol consumption; (3) PPARγ knockout mice; or (4) MH-S cells exposed to ethanol in vitro. Alcohol reduced AM PPARγ levels and increased Nox1, -2, and -4, transforming growth factor-ß1, oxidative stress, and phagocytic dysfunction. Genetic loss of PPARγ recapitulated, whereas stimulating PPARγ activity attenuated alcohol-mediated alterations in gene expression and phagocytic function, supporting the importance of PPARγ in alcohol-induced AM derangements. Similarly, PPARγ activation in vivo reduced alcohol-mediated impairments in lung bacterial clearance. Alcohol increased levels of microRNA-130a/-301a, which bind to the PPARγ 3' untranslated region to reduce PPARγ expression. MicroRNA-130a/-301a inhibition attenuated alcohol-mediated PPARγ reductions and derangements in AM gene expression and function. Alcohol-induced Toll-like receptor 4 endocytosis was reversed by PPARγ activation. These findings demonstrate that targeting PPARγ provides a novel therapeutic approach for mitigating alcohol-induced AM derangements and susceptibility to lung infection.

iPSC-derived human cardiac progenitor cells improve ventricular remodelling via angiogenesis and interstitial networking of infarcted myocardium.

We investigate the effects of myocardial transplantation of human induced pluripotent stem cell (iPSC)-derived progenitors and cardiomyocytes into acutely infarcted myocardium in severe combined immune deficiency mice. A total of 2 × 10(5) progenitors, cardiomyocytes or cell-free saline were injected into peri-infarcted anterior free wall. Sham-operated animals received no injection. Myocardial function was assessed at 2-week and 4-week post-infarction by using echocardiography and pressure-volume catheterization. Early myocardial remodelling was observed at 2-week with echocardiography derived stroke volume (SV) in saline (20.45 ± 7.36 µl, P < 0.05) and cardiomyocyte (19.52 ± 3.97 µl, P < 0.05) groups, but not in progenitor group (25.65 ± 3.61 µl), significantly deteriorated as compared to sham control group (28.41 ± 4.41 µl). Consistently, pressure-volume haemodynamic measurements showed worsening chamber dilation in saline (EDV: 23.24 ± 5.01 µl, P < 0.05; ESV: 17.08 ± 5.82 µl, P < 0.05) and cardiomyocyte (EDV: 26.45 ± 5.69 µl, P < 0.05; ESV: 18.03 ± 6.58 µl, P < 0.05) groups by 4-week post-infarction as compared to control (EDV: 15.26 ± 2.96 µl; ESV: 8.41 ± 2.94 µl). In contrast, cardiac progenitors (EDV: 20.09 ± 7.76 µl; ESV: 13.98 ± 6.74 µl) persistently protected chamber geometry against negative cardiac remodelling. Similarly, as compared to sham control (54.64 ± 11.37%), LV ejection fraction was preserved in progenitor group from 2-(38.68 ± 7.34%) to 4-week (39.56 ± 13.26%) while cardiomyocyte (36.52 ± 11.39%, P < 0.05) and saline (35.34 ± 11.86%, P < 0.05) groups deteriorated early at 2-week. Improvements of myocardial function in the progenitor group corresponded to increased vascularization (16.12 ± 1.49/mm(2) to 25.48 ± 2.08/mm(2) myocardial tissue, P < 0.05) and coincided with augmented networking of cardiac telocytes in the interstitial space of infarcted zone.

Cadmium exposure during lactation causes learning and memory-impairment in F1 generation mice: amelioration by quercetin.

Cadmium (Cd) is a known pollutant present in the environment at low levels and is reported to affect reproduction in many ways. The present study was undertaken to explore the effect of Cd in F1 generation mice on cognitive parameters, and to further investigate whether quercetin could modulate these effects. In this study, female lactating mice were exposed to cadmium for seven days just after delivery. The new born pups in their adulthood were tested for learning and memory parameters by passive avoidance task and Morris water maze (MWM) test. It was observed that pups exposed to Cd showed significant impairment of memory in step down latency test, which was reversed by quercetin (100 mg/kg). In MWM test for spatial memory, animals exposed to Cd exhibited increased escape latency, which was reversed by quercetin (50 mg/kg) significantly. Quercetin alone (50 and 100 mg/kg) also demonstrated improved spatial memory, and showed improved retention memory in the passive avoidance paradigm at dose 50 mg/kg. On testing oxidative stress parameters, we observed significantly increased malondialdehyde (MDA) levels in brain tissue of Cd-treated mice. Moreover, co-treatment with quercetin (50 mg/kg) and Cd significantly reduced these MDA levels. The other doses (25 and 100 mg/kg) also showed reduction in MDA levels as compared to the group exposed to Cd alone, though the difference was not statistically significant. Hence, this study highlights the possibility of cognitive impairment in adulthood if there is Cd exposure during lactation and oxidative stress could possibly attribute to this effect.

Phasic modulation of Wnt signaling enhances cardiac differentiation in human pluripotent stem cells by recapitulating developmental ontogeny.

Cardiomyocytes (CMs) derived from human pluripotent stem cells (hPSCs) offer immense value in studying cardiovascular regenerative medicine. However, intrinsic biases and differential responsiveness of hPSCs towards cardiac differentiation pose significant technical and logistic hurdles that hamper human cardiomyocyte studies. Tandem modulation of canonical and non-canonical Wnt signaling pathways may play a crucial role in cardiac development that can efficiently generate cardiomyocytes from pluripotent stem cells. Our Wnt signaling expression profiles revealed that phasic modulation of canonical/non-canonical axis enabled orderly recapitulation of cardiac developmental ontogeny. Moreover, evaluation of 8 hPSC lines showed marked commitment towards cardiac-mesoderm during the early phase of differentiation, with elevated levels of canonical Wnts (Wnt3 and 3a) and Mesp1. Whereas continued activation of canonical Wnts was counterproductive, its discrete inhibition during the later phase of cardiac differentiation was accompanied by significant up-regulation of non-canonical Wnt expression (Wnt5a and 11) and enhanced Nkx2.5(+) (up to 98%) populations. These Nkx2.5(+) populations transited to contracting cardiac troponin T-positive CMs with up to 80% efficiency. Our results suggest that timely modulation of Wnt pathways would transcend intrinsic differentiation biases of hPSCs to consistently generate functional CMs that could facilitate their scalable production for meaningful clinical translation towards personalized regenerative medicine.

Commiphora mukul attenuates peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

OBJECTIVE: The management of neuropathic pain remains unsatisfactory till date, despite immense advances in the therapeutic strategies. Commiphora mukul (CM), also known as Commiphora wightii, is well known in the traditional Indian system of medicine, and has been used to treat ailments such as obesity, bone fractures, arthritis, inflammation, cardiovascular diseases, and lipid disorders. The present study was performed to investigate the effect of CM on peripheral neuropathic pain in rats. METHODS: Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, CM was orally administered for 2 weeks in doses of 50, 100, and 200 mg/kg, and pain assessment was performed by employing the behavioral tests for thermal hyperalgesia (hot-plate and tail-flick tests) and cold allodynia (acetone test). RESULTS: Following the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of CM (50 mg/kg) did not have any effect on the hot-plate and tail-flick tests, but significant anti-allodynic effect was observed in the acetone test. Furthermore, administration of CM (100 mg/kg) caused significant decrease in pain as observed on the tail-flick and acetone tests, but not in the hot-plate test. CM in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot-plate and tail-flick latencies, and decreased paw withdrawal duration (in acetone test). DISCUSSION: Therefore, the present study suggests that CM may be used in future as a treatment option for neuropathic pain.

Analgesic effect of piracetam on peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.

Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction.

RATIONALE: Alcohol use disorders cause oxidative stress in the lower airways and increase susceptibility to pneumonia and lung injury. Currently, no therapeutic options exist to mitigate the pulmonary consequences of alcoholism. OBJECTIVES: We recently determined in an animal model that alcohol ingestion impairs pulmonary zinc metabolism and causes alveolar macrophage immune dysfunction. The objective of this research is to determine the effects of alcoholism on zinc bioavailability and alveolar macrophage function in human subjects. METHODS: We recruited otherwise healthy alcoholics (n = 17) and matched control subjects (n = 17) who underwent bronchoscopy for isolation of alveolar macrophages, which were analyzed for intracellular zinc, phagocytic function, and surface expression of granulocyte-macrophage colony-stimulating factor receptor; all three of these indices are decreased in experimental models. MEASUREMENTS AND MAIN RESULTS: Alcoholic subjects had normal serum zinc, but significantly decreased alveolar macrophage intracellular zinc levels (adjusted means [SE], 718 [41] vs. 948 [25] RFU/cell; P < 0.0001); bacterial phagocytosis (adjusted means [SE], 1,027 [48] vs. 1,509 [76] RFU/cell; P < 0.0001); and expression of granulocyte-macrophage colony-stimulating factor receptor ß subunit (adjusted means [SE], 1,471 [42] vs. 2,114 [35] RFU/cell; P < 0.0001]. Treating alveolar macrophages with zinc acetate and glutathione in vitro increased intracellular zinc levels and improved their phagocytic function. CONCLUSIONS: These novel clinical findings provide evidence that alcohol abuse is associated with significant zinc deficiency and immune dysfunction within the alveolar space and suggest that dietary supplementation with zinc and glutathione precursors could enhance airway innate immunity and decrease the risk for pneumonia or lung injury in these vulnerable individuals.