Cultured Skin in the Modern Era and the Impact of Infrastructure Volatility on Learning Curves: A 33-Year Institutional Review.

Finding a perfect epidermal transplant remains a holy grail of burn surgery. The epidermis is a site of stem cells that allows for the epithelial regeneration. The use of CEA for the treatment of major burns was first reported in 1981. CEA requires specialized skills; thus, reports from different burn-centers have shown mixed results. Comparing our modern data with past data shows how this field has advanced while maintaining institutional control. We performed a retrospective analysis of all patients admitted between 01/01/1988-12/31/2021 for massive burns that were managed with CEA. Patients were divided into pre-defined groups: G1(early-era)=1988-1999, G2(pre-modern-era)=2000-2010, and G3(modern-era)=2011-2021. We compared demographics, %TBSA, presence of inhalation-injury, LOS, complications, and mortality. We treated 52 patients with CEA during the study period. In the modern-era, we found 11 patients; in the pre-modern-era, 10; and in the early-era, 31. Injury characteristics, including %TBSA and the presence of inhalation-injury, were not significantly different between the groups. We observed lower mortality rates in G1 and G3 (G1:20% vs. G2:42% vs. G3:27%, p<0.05), although the predicted mortality was not significantly different between the groups (G1:50% vs. G2:47% vs. G3:49%, NS). Patients in G1 also had a shorter hospital LOS, in days, (G1:90 vs. G2:127 vs. G3:205, p<0.05). Finally, the surface-area grafted per patient was the highest in G2 (G1:2,000cm2 vs. G2:4,187cm2 vs. G3:4,090cm2, p<0.01). CEA has not gained popularity despite proven positive outcomes. Our retrospective analysis showed that CEA should be considered as a treatment option for patients with large burns, given proper training and infrastructure.

Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome.

The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs). However, there is no consensus definition of detrimental dysbiosis. Based on metagenomics (MG) sequencing of 245 non-small cell lung cancer (NSCLC) patient feces, we constructed species-level co-abundance networks that were clustered into species-interacting groups (SIGs) correlating with overall survival. Thirty-seven and forty-five MG species (MGSs) were associated with resistance (SIG1) and response (SIG2) to ICIs, respectively. When combined with the quantification of Akkermansia species, this procedure allowed a person-based calculation of a topological score (TOPOSCORE) that was validated in an additional 254 NSCLC patients and in 216 genitourinary cancer patients. Finally, this TOPOSCORE was translated into a 21-bacterial probe set-based qPCR scoring that was validated in a prospective cohort of NSCLC patients as well as in colorectal and melanoma patients. This approach could represent a dynamic diagnosis tool for intestinal dysbiosis to guide personalized microbiota-centered interventions.

Validation of a bupropion, dextromethorphan, and omeprazole cocktail for simultaneous phenotyping of cytochrome P450 2B11, 2D15, and 3A12 activities in dogs.

OBJECTIVE: Develop a cytochrome P450 (CYP) phenotyping cocktail for dogs using specific substrates for hepatic P450 enzymes CYP2B11, CYP2D15, and CYP3A12 and determine whether alternative sampling methods (saliva and urine) or single time point samples could be used instead of multiple blood sampling. ANIMALS: 12 healthy client-owned dogs (8 females and 4 males) from February 2019 to May 2019. METHODS: In a randomized crossover study, dogs received oral administration of the probe drug bupropion (75 mg), dextromethorphan (30 mg), or omeprazole (40 mg) alone or as a 3-drug combination (Program in Individualized Medicine [PrIMe] cocktail) to evaluate simultaneous phenotyping of CYP2B11, CYP2D15, and CYP3A12. Pharmacokinetic profiles for the probe drugs and metabolites were determined using plasma, saliva, and urine. Dogs received probe drugs alone or combined. Pharmacokinetic profiles up to 6 hours postdose for the probe drugs and metabolites were determined using plasma, saliva, and urine. RESULTS: The PrIMe cocktail was well tolerated. There was no statistically significant interaction between the probe drugs when administered together. Single time point plasma metabolic ratios at 4 hours postdose for all probe drugs strongly correlated with the corresponding area under the plasma concentration-versus-time curve (AUC) ratios. Saliva AUC metabolic ratios for CYP3A12 and CYP2D15 and 6-hour urine for CYP2B11 and CYP2D15 were correlated with plasma AUC ratios. CONCLUSIONS: The PrIMe cocktail can be used for simultaneous CYP phenotyping using plasma 4-hour single time point sample metabolic ratios. Saliva and urine sampling are suitable for specific CYPs. CLINICAL RELEVANCE: The PrIMe cocktail has potential as a useful tool in dogs to detect clinically important CYP-mediated drug-drug interactions, identify novel pharmacogenes, determine the drug-metabolizing phenotype of individual dogs, aid in individualized dose selection, and evaluate the effects of various physiological states on drug metabolism.

Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer.

Aside from PD-L1 expression, biomarkers of response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are needed. In a previous retrospective analysis, we documented that fecal Akkermansia muciniphila (Akk) was associated with clinical benefit of ICI in patients with NSCLC or kidney cancer. In the current study, we performed shotgun-metagenomics-based microbiome profiling in a large cohort of patients with advanced NSCLC (n = 338) treated with first- or second-line ICIs to prospectively validate the predictive value of fecal Akk. Baseline stool Akk was associated with increased objective response rates and overall survival in multivariate analyses, independent of PD-L1 expression, antibiotics, and performance status. Intestinal Akk was accompanied by a richer commensalism, including Eubacterium hallii and Bifidobacterium adolescentis, and a more inflamed tumor microenvironment in a subset of patients. However, antibiotic use (20% of cases) coincided with a relative dominance of Akk above 4.8% accompanied with the genus Clostridium, both associated with resistance to ICI. Our study shows significant differences in relative abundance of Akk that may represent potential biomarkers to refine patient stratification in future studies.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune-related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer. METHODS: A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response. RESULTS: The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty-four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression-free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression-free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation. CONCLUSION: Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.

Personalized medicine: going to the dogs?

Interindividual variation in drug response occurs in canine patients just as it does in human patients. Although canine pharmacogenetics still lags behind human pharmacogenetics, significant life-saving discoveries in the field have been made over the last 20 years, but much remains to be done. This article summarizes the available published data about the presence and impact of genetic polymorphisms on canine drug transporters, drug-metabolizing enzymes, drug receptors/targets, and plasma protein binding while comparing them to their human counterparts when applicable. In addition, precision medicine in cancer treatment as an application of canine pharmacogenetics and pertinent considerations for canine pharmacogenetics testing is reviewed. The field is poised to transition from single pharmacogene-based studies, pharmacogenetics, to pharmacogenomic-based studies to enhance our understanding of interindividual variation of drug response in dogs. Advances made in the field of canine pharmacogenetics will not only improve the health and well-being of dogs and dog breeds, but may provide insight into individual drug efficacy and toxicity in human patients as well.

Effects of low-level laser therapy on bone healing and signs of pain in dogs following tibial plateau leveling osteotomy.

OBJECTIVE To assess the effect of low-level laser therapy (LLLT) on markers of synovial inflammation and signs of pain, function, bone healing, and osteoarthritis following tibial plateau leveling osteotomy (TPLO) in dogs with spontaneous cranial cruciate ligament rupture (CCLR). ANIMALS 12 client-owned dogs with unilateral CCLR. PROCEDURES All dogs were instrumented with an accelerometer for 2 weeks before and 8 weeks after TPLO. Dogs were randomly assigned to receive LLLT (radiant exposure, 1.5 to 2.25 J/cm2; n = 6) or a control (red light; 6) treatment immediately before and at predetermined times for 8 weeks after TPLO. Owners completed a Canine Brief Pain Inventory weekly for 8 weeks after surgery. Each dog underwent a recheck appointment, which included physical and orthopedic examinations, force plate analysis, radiography and synoviocentesis of the affected joint, and evaluation of lameness and signs of pain, at 2, 4, and 8 weeks after surgery. Select markers of inflammation were quantified in synovial fluid samples. Variables were compared between the 2 groups. RESULTS For the control group, mean ground reaction forces were greater at 2 and 4 weeks after TPLO and owner-assigned pain scores were lower during weeks 1 through 5 after TPLO, compared with corresponding values for the LLLT group. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the LLLT protocol used had no beneficial effects on signs of pain or pelvic limb function following TPLO. Further research is necessary to evaluate the effects of LLLT and to determine the optimum LLLT protocol for dogs with CCLR.

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids.

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC-MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism.

Pharmacokinetic Analysis of an Oral Multicomponent Joint Dietary Supplement (Phycox®) in Dogs.

Despite the lack of safety, efficacy and pharmacokinetic (PK) studies, multicomponent dietary supplements (nutraceuticals) have become increasingly popular as primary or adjunct therapies for clinical osteoarthritis in veterinary medicine. Phycox® is a line of multicomponent joint support supplements marketed for joint health in dogs and horses. Many of the active constituents are recognized anti-inflammatory and antioxidant agents. Due to a lack of PK studies in the literature for the product, a pilot PK study of select constituents in Phycox® was performed in healthy dogs. Two novel methods of analysis were developed and validated for quantification of glucosamine and select polyphenols using liquid chromatography-tandem mass spectrometry. After a single oral (PO) administrated dose of Phycox®, a series of blood samples from dogs were collected for 24 h post-dose and analyzed for concentrations of glucosamine HCl, hesperetin, resveratrol and naringenin. Non-compartmental PK analyses were carried out. Glucosamine was detected up to 8 h post-dose with a Tmax of 2 h and Cmax of 9.69 µg/mL. The polyphenols were not found at detectable concentrations in serum samples. Co-administration of glucosamine in the Phycox® formulation may enhance the absorption of glucosamine as determined by comparison of glucosamine PK data in the literature.

Pharmacological characterization of liquiritigenin, a chiral flavonoid in licorice.

Liquiritigenin is a chiral flavonoid present in plant based food, nutraceuticals, and traditional medicines. It is also an important ingredient present in licorice. The purpose of this study is to explore the pharmacological activity of racemic liquiritigenin utilizing several in vitro assays with relevant roles in colon cancer and diabetes. Where possible, the pure enantiomers were tested to identify the stereospecific contribution to the activity. In vitro antioxidant, anticancer, anti-inflammatory activities (cyclooxygenase inhibition), antidiabetic activities (alpha-amylase and alpha-glucosidase inhibition) as well as cytochrome P450 (CYP450) inhibitory activities were assessed. Racemic liquiritigenin demonstrated a dose-dependent inhibition of alpha-amylase enzyme whereas its pure enantiomers did not. Racemic liquiritigenin showed moderate antiproliferative activity on a HT-29 (human colorectal adenocarcinoma) cancer cell line that was dose-dependent and potent inhibitory effects on the cyclooxygenase-2 enzyme. The flavonoid did not inhibit the activity of cytochrome CYP2D6 over the concentration range studied but was a potent antioxidant. The current study demonstrated the importance of understanding the stereospecific pharmacological effects of liquiritigenin enantiomers in alpha-amylase inhibition.

Pre-Clinical Pharmacokinetic and Pharmacodynamic Characterization of Selected Chiral Flavonoids: Pinocembrin and Pinostrobin.

PURPOSE: Delineate the stereospecific pharmacokinetics and pharmacodynamics of the chiral flavonoids pinocembrin and pinostrobin. OBJECTIVE: Characterize for the first time the stereoselective pharmacokinetics of two flavonoids, pinocembrin and pinostrobin and their bioactivity in several in vitro assays with relevant roles in heart disease, colon cancer, and diabetes etiology and pathophysiology. METHODS: Chiral flavonoids were intravenously and orally administered to male Sprague-Dawley rats. Concentrations in serum and urine were characterized via stereospecific HPLC or LC/MS. Pure enantiomeric forms of each flavonoid were tested, where possible, to identify the stereospecific contribution to bioactivity in comparison to their racemates. RESULTS: Short half-lives (0.2-6 h) in serum were observed, while a better estimation of half-life (3-26 h) and other pharmacokinetic parameters were observed using urinary data. The flavonoids are predominantly excreted via non-renal routes (fe values of 0.3-4.6 %), and undergo rapid and extensive phase II metabolism. Chiral differences in the chemical structure of these compounds result in significant pharmacodynamic differences. CONCLUSION: The importance of understanding the stereospecific pharmacokinetics and pharmacodynamics of two chiral flavonoids were delineated.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Pharmacological effects of a C-phycocyanin-based multicomponent nutraceutical in an in-vitro canine chondrocyte model of osteoarthritis.

Multicomponent nutraceuticals are becoming increasingly popular treatments or adjunctive therapies for osteoarthritis in veterinary medicine despite lack of evidence of efficacy for many products. The objective of this study was to evaluate the anti-inflammatory and antioxidant activities of a commercially available C-phycocyanin-based nutraceutical and select constituent ingredients in an in-vitro model of canine osteoarthritis. Normal canine articular chondrocytes were used in an in-vitro model of osteoarthritis. Inflammatory conditions were induced using interleukin-1ß. The nutraceutical preparation as a whole, its individual constituents, as well as carprofen were evaluated at concentrations of 0 to 250 µg/mL for reduction of the following inflammatory mediators and indicators of catabolism of the extracellular matrix: prostaglandin E2 (PGE2), tumor necrosis factor-α (TFN-α), interleukin-6 (IL-6), metalloproteinase-3 (MMP-3), nitric oxide, and sulfated glycosaminoglycans (sGAGs). Validated, commercially available assay kits were used for quantitation of inflammatory mediators. The antioxidant capacities, as well as cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and lipoxygenase (LOX) inhibitory activities of the whole nutraceutical preparation and select constituents, were also assessed using validated commercially available assay kits. The antioxidant capacity of the nutraceutical and constituents was concentration-dependent. The nutraceutical and constituents appear to display anti-inflammatory activity primarily through the inhibition of COX-2. The nutraceutical displayed similar strength to carprofen in reducing TNF-α, IL-6, MMP-3, nitric oxide, and sGAGs at select concentration ranges. The C-phycocyanin (CPC)-based nutraceutical and constituents may be able to mediate 3 primary pathogenic mechanisms of osteoarthritis: inflammation, chondral degeneration, and oxidative stress in vitro. The nutraceutical may be clinically useful in veterinary medicine and its efficacy should be further investigated in vivo.

Les neutraceutiques à composés multiples deviennent de plus en plus populaires en médecine vétérinaire comme traitement ou thérapie alternative pour soigner l'ostéoarthrite, et ce malgré le manque d'évidence de l'efficacité de plusieurs produits. L'objectif de la présente étude était d'évaluer l'activité anti-inflammatoire et anti-oxydante d'un neutraceutique à base de C-phycocyanine disponible commercialement, et d'ingrédients constitutifs sélectionnés dans un modèle in vitro d'ostéoarthrite canine. Des chondrocytes articulaires canins normaux furent utilisés dans un modèle in vitro d'ostéoarthrite. Des conditions inflammatoires ont été induites en utilisant de l'interleukine-1ß. La préparation neutraceutique complète, ses constituants individuels, de même que du caprofène furent évalués à des concentrations de 0 à 250 µg/mL pour la réduction des médiateurs de l'inflammation suivants et des indicateurs du catabolisme de la matrice extracellulaire: prostaglandine E2 (PGE2), facteur-α nécrosant des tumeurs (TNF-α), interleukine-6 (IL-6), métalloprotéinase-3 (MMP-3), oxyde nitreux, et les glycosaminoglycans sulfatés (sGAGs). Des trousses commerciales validées furent utilisées pour la quantification des médiateurs de l'inflammation. Les capacités anti-oxydantes, de même que l'activité inhibitrice envers la cyclo-oxygénase 1 (COX-1), la cyclo-oxygénase-2 (COX-2), et la lipoxygénase (LOX) de la préparation neutraceutique complète et de constituants sélectionnés furent également évaluées au moyen de de trousses commerciales disponibles commercialement. La capacité anti-oxydante du neutraceutique et des constituants était dépendante de la concentration. Le neutraceutique et les constituants semblent manifester leur activité anti-inflammatoire principalement via l'inhibition de COX-2. Dans des écarts de concentrations sélectionnés, le neutraceutique a démontré une capacité similaire au carprofène en réduisant TNF-α, IL-6, MMP-3, oxyde nitreux, et sGAGs. Le neutraceutique à base de C-phycocyanine (CPC) et ses constituants peuvent être en mesure de médier trois mécanismes pathogéniques primaires de l'ostéo-arthrite: l'inflammation, la dégénération chondrale, et le stress oxydatif in vitro. Le neutraceutique pourrait être cliniquement utile en médecine vétérinaire et son efficacité devrait être investigué plus à fond in vivo.(Traduit par Docteur Serge Messier).

Preclinical Pharmacokinetics and Pharmacodynamics and Content Analysis of Gnetol in Foodstuffs.

Studies were undertaken to evaluate the bioavailability in rats and content analysis of gnetol in Gnetum gnemon products reported to contain gnetol and to examine the pharmacological properties of gnetol in in vitro models including anti-inflammatory/analgesic, antidiabetic, anti-adipogenesis, and anticancer activity. Male Sprague-Dawley rats were cannulated and dosed either intravenously with gnetol (10 mg/kg) or orally (100 mg/kg). Various methanolic extractions of G. gnemon products were quantified. Gnetol's effect on cell viability in selected cell lines with or without inflammatory stimulus was assessed. α-Amylase and α-glucosidase inhibition was evaluated. Cyclooxygenase (COX)-1, COX-2, and histone deacetylase inhibition and adipogenesis inhibition were examined. After oral and intravenous administration, gnetol was detected in both serum and urine as the parent compound and as a glucuronidated metabolite. The bioavailability of gnetol was determined to be 6%. Gnetol is rapidly glucuronidated and is excreted in urine and via nonrenal routes. Gnetol was found to exist as an aglycone and as a glycoside in G. gnemon products. Gnetol showed concentration-dependent reductions in cell viability in cancer cell lines with greatest activity in colorectal cancer and potent COX-1, histone deacetylase, and weak COX-2 activities along with limited reduction in inflammation. Gnetol also possessed concentration-dependent alpha-amylase, alpha-glucosidase, and adipogenesis activities. Pretreatment of mice with gnetol was able to increase the latency period to response in analgesia models.

Prevalence of abnormal systemic hemodynamics in veterans with and without spinal cord injury.

OBJECTIVE: Increased prevalence of heart rate and blood pressure abnormalities are evident in persons with spinal cord injury (SCI), but age, comorbid medical conditions, and prescription medication use may contribute. To determine differences in the prevalence of cardiac acceleration (heart rate ≥80 beats per minute), hypotension (blood pressure ≤110/70mmHg), orthostatic hypotension (OH) (-20/-10mmHg with upright positioning), and hypertension (HTN) (blood pressure ≥140/90mmHg) in veterans with and without SCI. DESIGN: Observational trial. SETTING: Medical center. PARTICIPANTS: Subjects included veterans with SCI (n=62; cervical: tetraplegia, C3-8; high thoracic, T1-5; low thoracic, T7-L2) and veterans without SCI (n=160). INTERVENTIONS: None. MAIN OUTCOME MEASURES: We assessed medical history, prescription medication use, and heart rate and blood pressure during a routine clinical visit. Prevalence rates of cardiac acceleration, hypotension, OH, and HTN were calculated using binary logistic regression analysis with 95% confidence intervals. The influence of SCI status, age, smoking status, cardiovascular diagnoses, and use of prescribed antihypertensive medications on the prevalence of abnormal heart rate and blood pressure recordings was determined. RESULTS: The diagnosis of HTN was reduced in the high thoracic and tetraplegia groups compared with the non-SCI and low thoracic groups. Use of antihypertensive medications was increased in the low thoracic group compared with the other 3 groups and was increased in the non-SCI group compared with the tetraplegia group. The prevalence of cardiac acceleration was reduced, and the prevalence of systolic hypotension was increased in the tetraplegia group. The prevalence of diastolic hypotension was increased in all SCI groups compared with the non-SCI group. For all analyses, increased prevalence of abnormal heart rate and blood pressure recordings was not further explained by the covariates, with the exception of age, cardiovascular diagnoses, and antihypertensive medications in the cardiac acceleration model; however, SCI status remained significant and was the dominant predictor variable. CONCLUSIONS: Our data suggest that SCI status contributes to the prevalence of cardiac acceleration and systolic and diastolic hypotension regardless of cardiovascular medical conditions or prescription antihypertensive medication use.

Tobacco smoke in infants with bronchopulmonary dysplasia.

UNLABELLED: Exposure to tobacco smoke has been not evaluated in children with bronchopulmonary dysplasia (BPD). We evaluate the association of in utero smoking (IUS) and environmental tobacco smoke (ETS) with the respiratory events of BPD and non-BPD children. Two hundred sixty-two children born before 35 weeks of gestational age (GA) and regularly followed up in our regional network for preterms were enrolled. They were paired according to their BPD status, their gestational age and birth weight (131 children with BPD and 131 without BPD, 28 mean weeks GA; mean weight 1000 g). Respiratory data were obtained prospectively during their first 2 years of life. A complementary questionnaire was completed by the parents about their child's respiratory health at the age of 2, their home environment, and tobacco status. IUS concerned 12.6 %; ETS, 48.8 % (67 % in BPD children treated with oxygen at home). No further influence on respiratory outcome could be found by exposure to intrauterine smoke or extrauterine tobacco smoke in this patient sample. CONCLUSION: IUS and ETS exposures are as high in preterm children as in a general pediatric population. The highest exposure occurs among BPD infants treated with oxygen at home. WHAT IS KNOWN: • Environmental tobacco smoke (ETS) and in utero smoking (IUS) are responsible for many morphological, functional, and clinical changes in children. • Children with bronchopulmonary dysplasia (BPD) have more respiratory events in their first years of life than preterm children without BPB, maybe triggered by ETS and IUS. What is New: • The exposition to ETS and IUS is high in preterm children with and without BDP, as high as in a general. • Pedaitric population, particularly in children with BPD and treated with oxygen at home. • No further influence on respiratory outcome could be found by exposure to ETS or IUS in our studied population.

Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases.

Acetylcholine (neuronal and non-neuronal origin) regulates bronchoconstriction, and mucus secretion. It has an inflammatory effect by inducing attraction, survival and cytokine release from inflammatory cells. Muscarinic receptors throughout the bronchial tree are mainly restricted to muscarinic M1, M2 and M3 receptors. Three long-acting muscarinic receptor antagonists (LAMAs) were approved for the treatment of chronic obstructive pulmonary disease (COPD) in Europe: once-daily tiotropium bromide; once-daily glycopyrronium bromide; and twice-daily aclidinium bromide. All have higher selectivity for M3 receptors than for M2 receptors, and dissociate more slowly from the M3 receptors than they do from the M2 receptors. Some LAMAs showed anti-inflammatory effects [inhibition of neutrophil chemotactic activity and migration of alveolar neutrophils, decrease of several cytokines in the bronchoalveolar lavage (BAL) including interleukin (IL)-6, tumor necrosis factor (TNF)-α and leukotriene (LT)B4] and antiremodeling effects (inhibition of mucus gland hypertrophy and decrease in MUC5AC-positive goblet cell number, decrease in MUC5AC overexpression). In the clinic, LAMAs showed a significant improvement of forced expiratory volume in 1 second (FEV1), quality of life, dyspnea and reduced the number of exacerbations in COPD and more recently in asthma. This review will focus on the three LAMAs approved in Europe in the treatment of chronic airway diseases.

Vorinostat with sustained exposure and high solubility in poly(ethylene glycol)-b-poly(DL-lactic acid) micelle nanocarriers: characterization and effects on pharmacokinetics in rat serum and urine.

The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anticancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat's pharmacokinetics in rats was investigated after intravenous (i.v.) (10 mg/kg) and oral (p.o.) (50 mg/kg) micellar administrations and compared with a conventional polyethylene glycol 400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 to 8.15 ± 0.60 and 10.24 ± 0.92 mg/mL at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19%, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the p.o. and i.v. pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.

Relationship between rate of change in acid exposure along the esophagus and length of Barrett's epithelium.

OBJECTIVE: Gastroesophageal reflux disease (GERD) plays a major role in the development of Barrett's esophagus. Recently, we demonstrated that duration of esophageal acid exposure in the distal esophagus correlates with the length of Barrett's mucosa. The aim of this study was to determine whether there is a relationship between the rate of the change in acid exposure along the esophagus and the length of Barrett's esophagus. METHODS: A total of 17 patients (16 men and one woman; mean age 66 +/- 15 yr, range 41-83 yr) with varying lengths of biopsy-proven Barrett's esophagus were recruited prospectively into the study. Ambulatory 24-h esophageal pH monitoring was performed using a commercially available pH probe with four sensors located 5 cm apart. For each patient, a least squares regression line of the fraction of the study that the pH was <4 against the height of the sensor above the lower esophageal sphincter was fit. The slope of the regression line was used to represent the rate of change in acid exposure. Linear regression analysis was conducted to analyze the relationship between the rate of change in acid exposure and the length of Barrett's mucosa. RESULTS: The mean Barrett's length was 5 +/- 3 cm (range 1-11 cm). Linear regression demonstrated a statistically significant relationship between the rate of change in acid exposure and the length of Barrett's esophagus for the 24-h duration of the study, as well as for the fraction of the study that patients were in the upright position (p = 0.0096 and 0.0076, respectively). For the supine position, the relationship did not reach statistical significance (p = 0.095). CONCLUSIONS: We demonstrated a significant relationship between the rate of change in acid exposure and the length of Barrett's mucosa. Thus, as the rate at which recorded acid exposure values increases from the proximal to distal esophagus, the length of Barrett's esophagus significantly increases (for percent total time and upright position).