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Long Fragment Polymerase Chain Reaction.

Methods Mol Biol. 2017;1620:65-74

Authors: Chua EW, Maggo S, Kennedy MA

Abstract
Polymerase chain reaction (PCR) is an oft-used preparatory technique in amplifying specific DNA regions for downstream analysis. The size of an amplicon was initially limited by errors in nucleotide polymerization and template deterioration during thermal cycling. A variant of PCR, designated long-range PCR, was devised to counter these drawbacks and enable the amplification of large fragments exceeding a few kb. In this chapter we describe a protocol for long-range PCR, which we have adopted to obtain products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples.

PMID: 28540699 [PubMed - in process]

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Correlation of HAMP gene polymorphisms and expression with the susceptibility and length of hospital stays in Taiwanese children with Kawasaki disease.

Oncotarget. 2017 May 08;:

Authors: Huang YH, Yang KD, Hsu YW, Lu HF, Wong HS, Yu HR, Kuo HC, Huang FC, Lo MH, Hsieh KS, Chen SF, Chang WC, Kuo HC

Abstract
Kawasaki disease (KD) is a form of systemic vasculitis. Regarding its pathogenesis, HAMP gene encoding hepcidin, which is significant for iron metabolism, has a vital function. In this study, we recruited a total of 381 KD patients for genotyping. Data from 997 subjects (500 subjects from cohort 1; 497 subjects from cohort 2) were used for analysis. Using TaqMan allelic discrimination, we determined five tag SNPs (rs916145, rs10421768, rs3817623, rs7251432, and rs2293689). Treatment outcome data related to such clinical phenotypes as coronary artery lesions (CAL), coronary artery aneurysms (CAA), and intravenous immunoglobulin (IVIG) effects were also collected. Furthermore, we measured plasma hepcidin levels with an enzyme-linked immunosorbent assay. We found that HAMP gene polymorphism (rs7251432, and rs2293689) was significantly correlated with KD risk and that plasma hepcidin levels both before and after IVIG treatment had a significantly positive correlation with length of hospital stays (R = 0.217, p = 0.046 and R = 0.381, p < 0.0001, respectively). In contrast, plasma hepcidin levels has a negative correlation with KD patients' albumin levels (R = -0.27, p < 0.001) prior to IVIG treatment. This study's findings indicate that HAMP might have a role in the disease susceptibility, as well as its expressions correlated length of hospital stays, and albumin levels in Taiwanese children with KD.

PMID: 28538210 [PubMed - as supplied by publisher]

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UHPLC-MS/MS method with sample dilution to test therapeutic adherence through quantification of ten antihypertensive drugs in urine samples.

J Pharm Biomed Anal. 2017 May 13;142:279-285

Authors: De Nicolò A, Avataneo V, Rabbia F, Sciandra M, Tosello F, Cusato J, Perlo E, Mulatero P, Veglio F, Di Perri G, D'Avolio A

Abstract
Nowadays, hypertension represents an important health problem, particularly in developed countries. In some cases the standard therapeutic approaches are not able to reestablish the normal blood pressure values: this condition is called "resistant hypertension". However, a fraction of cases of resistant hypertension are actually due to poor adherence to the prescribed therapy. Therapeutic Drug Monitoring could represent a direct and useful tool to correctly identify non-compliant patients. Nevertheless, high throughput methods for the simultaneous monitoring of a wide panel of drugs in the same analysis are lacking and, furthermore, there is not a generally acknowledged "standard" matrix for this test (plasma or urine). In this work, we validated a UHPLC-MS/MS assay to quantify ten among the most used antihypertensive agents in urine samples, covering all the current classes: amlodipine, atenolol, clonidine, chlortalidone, doxazosin, hydrochlorothiazide, nifedipine, olmesartan, ramipril and telmisartan. Both standards and quality controls were prepared in urine matrix. Only 100μL of each sample were added with 40μL of internal standard and 860μL of water:acetonitrile 90:10, acidified with 0.05% formic acid. Chromatographic separation was performed on an Acquity(®) UPLC HSS T3 1.8μm 2.1×150mm column, with a gradient of water and acetonitrile, both added with 0.05% formic acid. Accuracy, intra-day and inter-day precision fitted FDA guidelines for all analytes, while matrix effects resulted reproducible among different urine lots. Method performances were tested on urine samples from hypertensive patients with good results. This simple analytical method could represent a useful tool for the management of antihypertensive therapy.

PMID: 28538203 [PubMed - as supplied by publisher]

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Spectrum of genomic alterations in FGFR3: current appraisal of the potential role of FGFR3 in advanced urothelial carcinoma.

BJU Int. 2016 Nov;118(5):681-691

Authors: Sethakorn N, O'Donnell PH

Abstract
Molecular analysis has identified subsets of urothelial carcinoma (UC) expressing distinct genetic signatures. Genomic alterations in the oncogenic fibroblast growth factor receptor 3 (FGFR3) pathway are among the most well described in UC and have led to extensive and ongoing investigation of FGFR3-targeted therapies in this disease, although no new drugs have yet been approved. Given the unmet need for effective treatments in advanced and metastatic UC, a better understanding of the known molecular alterations of FGFR3 and of the previous and ongoing clinical investigations of this promising target in UC deserves attention. The objective of the present review is to describe the landscape of alterations and biology of FGFR3 in UC, comprehensively summarize the current state of UC clinical trials of FGFR3 inhibitors, and discuss future therapeutic applications. Using the Pubmed and Clinicaltrials.gov databases, articles describing the spectrum and biological activity of FGFR3 genomic alterations and trials of FGFR3 inhibitors in UC were identified. Search terms included 'FGFR3 genomic alterations' and 'urothelial cancer' or 'bladder cancer'. Genomic alterations, including translocations and activating mutations, are increasingly described in advanced and metastatic UC. The majority of clinical trials have been performed in unselected populations; however, recent studies have reported encouraging preliminary data. We argue that routine use of molecular genomic tumour analysis in UC may inform selection of patients for appropriate trials and we further investigate the potential of FGFR3 as a meaningful clinical target for this difficult disease.

PMID: 27271022 [PubMed - indexed for MEDLINE]

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Pharmacokinetic Pharmacogenetic Prescribing Guidelines for Antidepressants: A Template for Psychiatric Precision Medicine.

Mayo Clin Proc. 2016 Jul;91(7):897-907

Authors: Nassan M, Nicholson WT, Elliott MA, Rohrer Vitek CR, Black JL, Frye MA

Abstract
Antidepressants are commonly prescribed medications in the United States, and there is increasing interest in individualizing treatment selection for more than 20 US Food and Drug Administration-approved treatments for major depressive disorder. Providing greater precision to pharmacotherapeutic recommendations for individual patients beyond the large-scale clinical trials evidence base can potentially reduce adverse effect toxicity profiles and increase response rates and overall effectiveness. It is increasingly recognized that genetic variation may contribute to this differential risk to benefit ratio and thus provides a unique opportunity to develop pharmacogenetic guidelines for psychiatry. Key studies and concepts that review the rationale for cytochrome P450 2D6 (CYP2D6) and cytochrome P450 2C19 (CYP2C19) genetic testing can be delineated by serum levels, adverse events, and clinical outcome measures (eg, antidepressant response). In this article, we report the evidence that contributed to the implementation of pharmacokinetic pharmacogenetic guidelines for antidepressants primarily metabolized by CYP2D6 and CYP2C19.

PMID: 27289413 [PubMed - indexed for MEDLINE]

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TRPC6 G757D Loss-of-Function Mutation Associates with FSGS.

J Am Soc Nephrol. 2016 Sep;27(9):2771-83

Authors: Riehle M, Büscher AK, Gohlke BO, Kaßmann M, Kolatsi-Joannou M, Bräsen JH, Nagel M, Becker JU, Winyard P, Hoyer PF, Preissner R, Krautwurst D, Gollasch M, Weber S, Harteneck C

Abstract
FSGS is a CKD with heavy proteinuria that eventually progresses to ESRD. Hereditary forms of FSGS have been linked to mutations in the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene encoding a nonselective cation channel. Most of these TRPC6 mutations cause a gain-of-function phenotype, leading to calcium-triggered podocyte cell death, but the underlying molecular mechanisms are unclear. We studied the molecular effect of disease-related mutations using tridimensional in silico modeling of tetrameric TRPC6. Our results indicated that G757 is localized in a domain forming a TRPC6-TRPC6 interface and predicted that the amino acid exchange G757D causes local steric hindrance and disruption of the channel complex. Notably, functional characterization of model interface domain mutants suggested a loss-of-function phenotype. We then characterized 19 human FSGS-related TRPC6 mutations, the majority of which caused gain-of-function mutations. However, five mutations (N125S, L395A, G757D, L780P, and R895L) caused a loss-of-function phenotype. Coexpression of wild-type TRPC6 and TRPC6 G757D, mimicking heterozygosity observed in patients, revealed a dominant negative effect of TRPC6 G757D. Our comprehensive analysis of human disease-causing TRPC6 mutations reveals loss of TRPC6 function as an additional concept of hereditary FSGS and provides molecular insights into the mechanism responsible for the loss-of-function phenotype of TRPC6 G757D in humans.

PMID: 26892346 [PubMed - indexed for MEDLINE]

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Hepatic complications induced by immunosuppressants and biologics in inflammatory bowel disease.

World J Hepatol. 2017 May 08;9(13):613-626

Authors: Tran-Minh ML, Sousa P, Maillet M, Allez M, Gornet JM

Abstract
The incidence of inflammatory bowel diseases (IBD) is rising worldwide. The therapeutic options for IBD are expanding, and the number of drugs with new targets will rapidly increase in coming years. A rapid step-up approach with close monitoring of intestinal inflammation is extensively used. The fear of side effects represents one the most limiting factor of their use. Despite a widespread use for years, drug induced liver injury (DILI) management remains a challenging situation with Azathioprine and Methotrexate. DILI seems less frequent with anti-tumor necrosis factor agents and new biologic therapies. The aim of this review is to report incidence, physiopathology and practical guidelines in case of DILI occurrence with the armamentarium of old and new drugs in the field of IBD.

PMID: 28539989 [PubMed - in process]

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Chemoembolization Adopting Polyethylene Glycol Drug-Eluting Embolics Loaded With Doxorubicin for the Treatment of Hepatocellular Carcinoma.

AJR Am J Roentgenol. 2017 May 24;:1-5

Authors: Aliberti C, Carandina R, Sarti D, Mulazzani L, Pizzirani E, Guadagni S, Fiorentini G

Abstract
OBJECTIVE: The purpose of this study is to determine the efficacy and tolerability of transarterial chemoembolization (TACE) using polyethylene glycol (PEG) drug-elutable microspheres loaded with doxorubicin for treatment of hepatocellular carcinoma (HCC).
SUBJECTS AND METHODS: Forty-two patients with unresectable HCC, as determined by a tumor board, were assigned to undergo TACE and were treated with PEG drug-elutable embolics loaded with doxorubicin. Patients were prospectively enrolled and included 32 (76%) men and 10 (24%) women. Their median age was 65 years (range, 42-83 years). Patients were treated with 50 mg of doxorubicin loaded in 2 mL of PEG embolics (mean [± SD] diameter, 100 ± 25 µm) that were infused via a chemoembolization method. Data collected included previous cancer therapy, tumor size, number of lesions, history of TACE, tumor response (at 1, 3, and 6 months), type and intensity of adverse events, and quality of life (QOL) analysis.
RESULTS: One month after TACE, the overall tumor response rate was 79% (50% complete response, 29% partial response, 17% stable disease, and 5% progressive disease). At 3 months, the rates were 48% for complete response, 24% for partial response, 24% for stable disease, and 3% for progressive disease. At 6 months, the rates were 43% for complete response, 19% for partial response, 29% for stable disease, and 10% for progressive disease. TACE was well tolerated by all patients, with no evidence of procedure-related complications or systemic drug-related adverse events. Fever (33%), increase in transaminase level (17%), and pain (33%) were the most frequent adverse events, and their intensity was mostly mild (grades 1 and 2). The QOL scores were 80 at 1 month, 81 at 3 months, and 82 at 6 months after TACE.
CONCLUSION: These data suggest that PEG embolics are efficacious and safe for the treatment of HCC, as indicated by their good tolerability, QOL scores, and high tumor response.

PMID: 28537756 [PubMed - as supplied by publisher]

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Low rates of pregnancy screening in adolescents before teratogenic exposures in a national sample of children's hospitals.

Cancer. 2016 Nov 15;122(21):3394-3400

Authors: Rao P, Li Y, Getz KD, Miller TP, Huang YS, Wilkes JJ, Seif AE, Bagatell R, Fisher BT, Gracia C, Aplenc R

Abstract
BACKGROUND: Adolescents with cancer engage in sexual behaviors and are exposed to teratogenic chemotherapy. There are no data regarding pregnancy screening patterns for adolescents before chemotherapy exposure.
METHODS: A cross-sectional study of leukemia and emergency room (ER) admissions in the Pediatric Health Information System from 1999 to 2011 was conducted. Females who were 10 to 18 years old and 1) had newly diagnosed acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) or 2) had ER visits with computed tomography (CT) of the abdomen/pelvis were included. The exposure was a hospital visit with either chemotherapy or an abdominal/pelvic CT scan. The main outcome was a pregnancy test billed on the same day or before the teratogenic exposure within the same index admission. Log-binomial regressions were used to compute prevalence ratios and 95% confidence intervals comparing pregnancy screening in the leukemia and ER cohorts.
RESULTS: A total of 35,650 admissions were identified. The proportion of visits with an appropriately timed pregnancy test was 35%, 64%, and 58% in the ALL (n = 889), AML (n = 127), and ER cohorts (n = 34,634), respectively. Patients with ALL were significantly less likely to have a pregnancy test than the ER cohort (adjusted prevalence ratio, 0.71; 95% confidence interval, 0.65-0.78), but there was no significant difference between the AML and ER cohorts (adjusted prevalence ratio, 1.12; 95% confidence interval, 0.99-1.27). There was substantial hospital-level variation in pregnancy screening patterns.
CONCLUSIONS: Adolescents with acute leukemia and ER visits have low rates of pregnancy screening before teratogenic exposures. Standardized practice guidelines for pregnancy screening among adolescents may improve screening rates. Cancer 2016;122:3394-3400. © 2016 American Cancer Society.

PMID: 27618636 [PubMed - indexed for MEDLINE]

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Role of oral pentosan polysulphate in the reduction of local side effects of BCG therapy in patients with non-muscle-invasive bladder cancer: a pilot study.

BJU Int. 2016 Nov;118(5):758-762

Authors: Yadav S, Tomar V, Yadav SS, Priyadarshi S, Banerjee I

Abstract
OBJECTIVE: To assess the role of oral pentosan polysulphate (PPS) in the reduction of bacille Calmette-Guérin (BCG)-related local side effects in patients with high grade Ta/T1 non-muscle-invasive bladder cancer (NMIBC).
PATIENTS AND METHODS: A total of 32 symptomatic patients receiving BCG instillation were randomized into three groups: group A received placebo (vitamin B complex tablet) thrice daily; group B received PPS 100 mg thrice daily; and group C received PPS 100 mg once daily and placebo (vitamin B complex tablet) twice daily for 6 weeks. A visual analogue scale (VAS) score for bladder pain, Overactive Bladder-Validated 8 Question Screener (OAB-V8) scores and dysuria were evaluated in the three groups before and during each weekly visit for BCG instillation.
RESULTS: The mean ± sd post-treatment VAS scores were significantly lower in groups B (4.4 ± 1.2) and C (5.8 ± 0.8) than in group A (8 ± 0.4). In addition, the post-treatment VAS score was significantly lower in group B than in group C (P<0.01). The mean post-treatment OAB-V8 score was significantly lower only in group B (decreased from 15.5 to 9.7). Dysuria decreased in groups B and C but persisted in group A.
CONCLUSION: The present study shows that oral PPS (100 mg) thrice daily is effective in relieving BCG-related local side effects.

PMID: 27010115 [PubMed - indexed for MEDLINE]

Related Articles

Frequency of Adverse Events Before, During, and After Hospital Admission.

South Med J. 2016 Oct;109(10):631-635

Authors: Croft LD, Liquori ME, Ladd J, Day HR, Pineles L, Lamos EM, Mehrotra P, Perencevich EN, Harris AD, Morgan DJ

Abstract
OBJECTIVES: Adverse events (AEs) are unintended physical injuries resulting from or contributed to by medical or surgical care. We determined the frequency and type of AEs before, during, and after hospital admission.
METHODS: We conducted a cohort study of 296 adult hospital patients. We used the standardized Institute for Healthcare Improvement Global Trigger Tool for Measuring Adverse Events to review the medical records of the hospital patients for occurrence, timing relative to hospital admission, severity, and preventability of AEs. We also identified the primary physiologic system affected by the AE.
RESULTS: Among 296 patients, we identified 338 AEs. AEs occurred with similar frequency before (n = 148; 43.8%) and during hospital admission (n = 162; 47.9%). Fewer AEs occurred after discharge (n = 28; 8.3%). Half of all AEs (n = 169; 50.0%) were severe, whereas 47.9% (n = 162) were preventable.
CONCLUSIONS: AEs occur with similar frequency before and during hospitalization and may contribute more to hospital admissions than previously recognized. These findings suggest that efforts to improve patient safety should include outpatient settings in addition to the more commonly targeted acute care settings.

PMID: 27706501 [PubMed - indexed for MEDLINE]

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[Drug therapy of otorhinolaryngological diseases in pregnancy : An update].

HNO. 2016 Nov;64(11):843-854

Authors: Riepl R, Friebe-Hoffmann U

Abstract
The majority of women take at least one form of medication during pregnancy. Due to often discrepant information about the risk assessment of pharmaceuticals during pregnancy, physicians are often beset by uncertainty with respect to prescription and the fear of medicolegal consequences is high. As prospective clinical trials on drug safety during pregnancy are prohibited due to ethical reasons and animal studies are of limited applicability to humans, drug recommendations often only rely on observational data. An objective examination of the topic not only contributes to effective treatment of illnesses in pregnancy but also prevents impairment of fetal outcome by omission of necessary maternal treatment. The aim of this article is to give a structured presentation of medications that can be used during pregnancy for treating medical conditions of the ear, nose and throat, in the sense of practical guidelines.

PMID: 27680545 [PubMed - indexed for MEDLINE]

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Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension: A Meta-analysis of Randomized Controlled Trials.

Chest. 2016 Aug;150(2):353-66

Authors: Liu HL, Chen XY, Li JR, Su SW, Ding T, Shi CX, Jiang YF, Zhu ZN

Abstract
BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH)-specific therapy for PAH pooled PAH-specific combination therapy and monotherapy. This flaw may threaten the authenticity of their findings.
METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials that evaluated any PAH-specific medications in the treatment of PAH. We calculated ORs with 95% CIs for dichotomous data and standardized mean differences for continuous data.
RESULTS: In total, 35 randomized controlled trials involving 6,702 patients were included. In monotherapy vs placebo/conventional therapy, significance was obtained in mortality reduction (OR, 0.50 [95% CI, 0.33 to 0.76]; P = .001), 6-min walk test (mean difference, 31.10 m [95% CI, 25.40 to 36.80]; P < .00001), New York Heart Association/World Health Organization functional class (OR, 2.48 [95% CI, 1.51 to 4.07]; P = .0003), and hemodynamic status based on mean pulmonary artery pressure, pulmonary vascular resistance, cardiac index, and incidence of withdrawal due to adverse effects. In combination therapy vs monotherapy, significance was reached for the 6-min walk test (mean difference, 19.96 m [95% CI, 15.35 to 24.57]; P < .00001), functional class (OR, 1.65 [95% CI, 1.20 to 2.28]; P = .002), hemodynamic status, and incidence of withdrawal due to adverse effects (OR, 2.01 [95% CI, 1.54 to 2.61]; P < .00001) but not for mortality reduction (OR, 0.98 [95% CI, 0.57 to 1.68]; P = .94).
CONCLUSIONS: Our meta-analysis revealed that PAH-specific monotherapy could improve mortality, exercise capacity, functional class, and hemodynamic status compared with placebo or conventional therapy. However, combination therapy could further improve exercise capacity, functional class, and hemodynamic status compared with monotherapy, but it had no proven effect on mortality. Combination therapy had a much higher incidence of withdrawal due to adverse effects than monotherapy.

PMID: 27048870 [PubMed - indexed for MEDLINE]

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The Impact of Aging and Medical Status on Dysgeusia.

Am J Med. 2016 Jul;129(7):753.e1-6

Authors: Syed Q, Hendler KT, Koncilja K

Abstract
Disorders of taste and smell can cause an aversion to food in a sick patient and therefore affect his/her ability to maintain optimal nutrition. This can lead to a reduced level of strength, muscle mass, function, and quality of life. Additionally, reduced ability to differentiate between various intensities or concentrations of a tastant can result in increased intake of salt and sugar and exacerbation of chronic diseases such as heart failure and diabetes. These implications can be heightened in the elderly, who are particularly frail and are challenged by polypharmacy and multiple comorbid conditions. In this article, we will review the prevalence, etiology, and management of taste disorders. Additionally, we will review the association between taste and smell disorders and how disorders of smell can affect perception of taste.

PMID: 26899755 [PubMed - indexed for MEDLINE]

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The extent of medication errors and adverse drug reactions throughout the patient journey in acute care in Australia.

Int J Evid Based Healthc. 2016 Sep;14(3):113-22

Authors: Roughead EE, Semple SJ, Rosenfeld E

Abstract
AIM: To provide an estimate of the numbers of medication errors and adverse drug reactions that occur along a person's journey through their hospital stay in Australia.
METHODS: A search of databases and online resources was undertaken to identify published literature on medication safety in the acute care setting in Australia from 2008 to 2013. Data on the rates of adverse drug reactions and medication errors associated with hospitalization was extracted from the published studies. This evidence was synthesized with evidence from previous reviews of medication safety in the acute care setting in Australia conducted in 2002 and 2008.
RESULTS: Findings from the Australian literature across the two previous reviews of medication safety and the present review indicate the proportion of all hospital admissions that are medication-related is between 2 and 3%. Studies assessing medication errors on admission to hospital suggest there may be an overall rate of two errors for every three patients at the time of admission to hospital. Large studies examining the rates of prescribing errors in major Australian teaching hospitals give insight into the rates of prescription error and suggest that prescription error rates of up to one error per patient occur in the hospital system. The best available evidence from more recent research suggests that errors (excluding errors of timing) occur in around 9% of medication administrations in hospital. At hospital discharge, errors in medication documentation in discharge summaries may occur at a rate of up to two errors per patient.
CONCLUSIONS: Medication safety in the various stages of the patient journey through acute care in Australia continues to be a significant problem. However, the extent of medication-related problems in acute care needs to be interpreted within the context of increasingly complex health care. There are an estimated 230 000 medication-related hospital admissions occurring per year. This suggests an annual cost of medication-related admissions of AU$1.2 billion.

PMID: 26886682 [PubMed - indexed for MEDLINE]

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Notice NOT-HD-17-013 from the NIH Guide for Grants and Contracts

Funding Opportunity PA-17-297 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages Research Project Grant (R01) applications to study molecular and cellular mechanisms of tissue injury and repair associated with alcohol use in humans. Excessive alcohol consumption has the potential to adversely affect multiple organ systems including the liver, brain, heart, pancreas, lung, kidney, endocrine and immune systems, as well as bone and skeletal muscle. In addition, there is accumulating evidence that long term alcohol consumption is associated with reduced host capacity for recovery and repair following trauma. The mechanisms for these alcohol-induced effects on tissue injury and repair are currently not fully understood. NIAAA is especially interested in integrative research that elucidates alcohols effects on complex mechanisms of injury and repair that are either common or specific to each organ system. This FOA also encourages the study of alcohols effect on stem cells, embryonic development, and regeneration. Also encourages are studies on molecular and cellular actions of moderate alcohol consumption. A better understanding of these underlying mechanisms may provide new avenues for developing more effective and novel approaches for prognosis, diagnosis, intervention, and treatment of alcohol-induced organ damage.