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Synthesis and Biological Activities of Ethyl 2-(2-pyridylacetate) Derivatives Containing Thiourea, 1,2,4-triazole, Thiadiazole and Oxadiazole Moieties.

Molecules. 2017 Mar 06;22(3):

Authors: Szulczyk D, Tomaszewski P, Jóźwiak M, Kozioł AE, Lis T, Collu D, Iuliano F, Struga M

Abstract
Thirty six novel heterocyclic derivatives of ethyl 2-(2-pyridylacetate) were efficiently synthesized. The new compounds involve the linkage of a 2-pyridyl ring with thiosemicarbazide (compounds 1-7), 1,2,4-triazole (compounds 1a-7a), 1,3,4-thiadiazole (compounds 1b-7b), and 1,3,4-oxadiazole (compounds 1f-7f) moieties. The last group of compounds 1e-7e involves the connection of a 2-pyridyl ring with 1,2,4-triazole and thiourea. ¹H-NMR, (13)C-NMR and MS methods were used to confirm the structures of the obtained derivatives. The molecular structures of 3, 3b, 7a and 7f were further confirmed by X-ray crystallography. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram-negative rods and Candida albicans. In addition, the obtained compounds were tested for cytotoxicity and antiviral activity against HIV-1.

PMID: 28272311 [PubMed - in process]

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Complement effectors, C5a and C3a, in cystic fibrosis lung fluid correlate with disease severity.

PLoS One. 2017;12(3):e0173257

Authors: Hair PS, Sass LA, Vazifedan T, Shah TA, Krishna NK, Cunnion KM

Abstract
In cystic fibrosis (CF), lung damage is mediated by a cycle of obstruction, infection, inflammation and tissue destruction. The complement system is a major mediator of inflammation for many diseases with the effectors C5a and C3a often playing important roles. We have previously shown in a small pilot study that CF sputum soluble fraction concentrations of C5a and C3a were associated with clinical measures of CF disease. Here we report a much larger study of 34 CF subjects providing 169 testable sputum samples allowing longitudinal evaluation comparing C5a and C3a with clinical markers. Levels of the strongly pro-inflammatory C5a correlated negatively with FEV1% predicted (P < 0.001), whereas the often anti-inflammatory C3a correlated positively with FEV1% predicted (P = 0.01). C5a concentrations correlated negatively with BMI percentile (P = 0.017), positively with worsening of an acute pulmonary exacerbation score (P = 0.007) and positively with P. aeruginosa growth in sputum (P = 0.002). C5a levels also correlated positively with concentrations of other sputum markers associated with worse CF lung disease including neutrophil elastase (P < 0.001), myeloperoxidase activity (P = 0.006) and DNA concentration (P < 0.001). In contrast to C5a, C3a levels correlated negatively with worse acute pulmonary exacerbation score and correlated negatively with sputum concentrations of neutrophil elastase, myeloperoxidase activity and DNA concentration. In summary, these data suggest that in CF sputum, increased C5a is associated with increased inflammation and poorer clinical measures, whereas increased C3a appears to be associated with less inflammation and improved clinical measures.

PMID: 28278205 [PubMed - in process]

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Nasal polyposis in cystic fibrosis: follow-up of children and adolescents for a 3-year period.

Braz J Otorhinolaryngol. 2016 Oct 17;:

Authors: Weber SA, Iyomasa RM, Corrêa CC, Florentino WN, Ferrari GF

Abstract
INTRODUCTION: Nasal polyposis is often found in patients with cystic fibrosis.
OBJECTIVE: To assess the incidence of nasal polyposis, the response to medical treatment, recurrence and the need for surgical intervention in children and adolescents with cystic fibrosis during a three-year follow-up.
METHODS: Clinical symptoms (pulmonary, pancreatic insufficiency, malnutrition, nasal obstruction), two positive sweat chloride tests, and genotype findings in 23 patients with cystic fibrosis were analyzed. All patients underwent nasal endoscopy every 12 months from January 2005 to December 2007, to assess the presence and grade of Nasal Polyps. Nasal polyposis, when present, were treated with topical corticosteroids for 6-12 months, with progress being evaluated within the 3 years of follow-up.
RESULTS: In the first evaluation, nasal polyposis was diagnosed in 30.43% of patients (3 bilateral and 4 unilateral), recurrent pneumonia in 82.6%, pancreatic insufficiency in 87%, and malnutrition in 74%. The presence of nasal polyposis was not associated with chloride values in the sweat, genotype, clinical signs of severity of cystic fibrosis, or nasal symptoms. In the three-year period of follow up, 13 patients (56.52%) had at least one event of polyposis, with the youngest being diagnosed at 32 months of age. Only one patient underwent surgery (polypectomy), and there was one diagnosis of nasopharyngeal carcinoma.
CONCLUSION: The study showed a high incidence of nasal polyposis. Monitoring through routine endoscopy in patients with cystic fibrosis, even in the absence of nasal symptoms, is highly recommended. The therapy with topical corticosteroids achieved good results. Thus, an interaction between pediatricians and otolaryngologists is necessary.

PMID: 28277226 [PubMed - as supplied by publisher]

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Red blood cell distribution width is not a reliable biomarker for low iron stores in children with cystic fibrosis.

Pediatr Hematol Oncol. 2017 Feb 10;:1-7

Authors: Akkermans MD, Uijterschout L, Nuijsink M, Hendriks DM, van Goudoever JB, Brus F

Abstract
Low iron stores in children, absolute iron deficiency (AID), can lead to impaired neurodevelopment and requires iron therapy. In the presence of infection/inflammation, like in cystic fibrosis (CF), serum ferritin (SF) is not a reliable biomarker for AID. Red blood cell distribution width (RDW) is a promising alternative reported not to be influenced by infection in healthy children. Currently, there are no data on the diagnostic capacity of RDW to detect AID in pediatric CF patients. This was a prospective observational study that investigated iron status biomarkers in 53 Dutch pediatric CF patients. AID was defined using World Health Organization criteria for SF in stable patients (no recent pulmonary exacerbation) and C-reactive protein (CRP) ≤10 mg/l. Patients with AID had higher RDW levels than patients without AID (p = 0.019). An RDW ≥13.2% showed the following test statistics: sensitivity 100%; specificity 39.4%; positive predictive value 20%; and negative predictive value 100%. Furthermore, we found a correlation between RDW and CRP in the total group that originated from the stable patients (r = 0.308; p = 0.042). In conclusion, the diagnostic capacity of RDW for detecting AID in pediatric CF patients seems limited because RDW levels might also be influenced by chronic infection/inflammation in these patients.

PMID: 28276750 [PubMed - as supplied by publisher]

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Immunity status of invasive pulmonary aspergillosis patients with structural lung diseases in Chinese adults.

J Thorac Dis. 2017 Feb;9(2):247-253

Authors: Liang S, Jiang R, Lu HW, Mao B, Li MH, Li CW, Gu SY, Bai JW, Xu JF

Abstract
BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a fungal infection frequently observed in patients with immune dysfunction, such as those suffering from structural lung diseases. Nevertheless, studies assessing IPA combined with other common respiratory diseases remain scarce, particularly those regarding the immune status of its patients. Different structural lung diseases are known to differently affect patient immune status; however, the mechanisms by which this is conferred have yet to be determined. Thus, our study aims to compare the immune status of IPA patients with the structural lung diseases chronic obstructive pulmonary diseases (COPD), interstitial lung disease (ILD) and non-cystic fibrosis bronchiectasis (NCFB).
METHODS: This study was performed retrospectively with data collected over the years 2004 to 2013 at Shanghai Pulmonary Hospital, Tongji University, and included 77 patients whose lower respiratory tract (LRT) samples tested positive for. Our analysis considered blood examinations of CD3+, CD4+, CD8+, CD4+/CD8+, IgG, IgA and IgM levels.
RESULTS: CD4+/CD8+ double positive cells, representing cell-mediated immunity, were less abundant in IPA patients with COPD than those with ILD and NCFB (0.81±0.09 vs. 1.39±0.25 and 0.81±0.09 vs. 1.57±0.06, respectively, P<0.001). In agreement with this result, corticosteroid and broad-spectrum antibiotic use were most common in individuals with COPD (57%). IgA levels, which indicate humoral immunity, were lower in IPA patients with NCFB than those with COPD or ILD (0.95±0.28 vs. 1.64±0.40 g/L and 0.95±0.28 vs. 3.16±0.83 g/L, respectively, P<0.001).
CONCLUSIONS: Immunity status differs between IPA patients with different structural lung diseases. Among IPA patients with COPD, ILD and NCFB, those with COPD have the lowest cell-mediated immunity, while those with NCFB have the lowest humoral immunity.

PMID: 28275471 [PubMed - in process]

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Low flow veno-venous extracorporeal CO2 removal for acute hypercapnic respiratory failure.

Minerva Anestesiol. 2017 Mar 08;:

Authors: Hilty MP, Riva T, Cottini SR, Kleinert EM, Maggiorini A, Maggiorini M

Abstract
BACKGROUND: Ventilation with low tidal volume and airway pressure results in a survival benefit in ARDS patients. Previous research suggests that avoiding mechanical ventilation altogether may be beneficial in some cases of respiratory failure. Our hypothesis was that low flow veno-venous extracorporeal CO2 removal (ECCO2R) enables maintenance of a lung protective ventilation strategy or awake spontaneous ventilation despite severe hypercapnic respiratory failure (HRF).
METHODS: Twenty patients with HRF were investigated while mechanically ventilated (n=14) or breathing spontaneously close to respiratory exhaustion (n=6). Low flow ECCO2R was performed using a hemoperfusion device with a polypropylene gas-exchanger.
RESULTS: Causes of HRF were severe ARDS (n=11), COPD (n=4), chronic lung transplant rejection (n=3) and cystic fibrosis (n=2). During the first 8h of ECCO2R, PaCO2 decreased from 10.6(9.3-12.9) to 7.9(7.3-9.3)kPa (p<0.001) and pH increased from 7.23(7.09-7.40) to 7.36(7.27-7.41) (p<0.05). Thereafter, steady state was achieved while maintaining lung protective tidal volume (4.7(3.8- 6.5)ml/kg) and peak ventilator pressure (28(27-30)mbar at 24h). During the first 48h, thrombocyte count decreased by 52%(p<0.01), Fibrinogen by 38%(p<0.05). Intubation could be avoided in all spontaneously breathing patients. In 4/6 high blood flow extracorporeal circulation was required due to increased oxygen demand. 6/14 mechanically ventilated patients recovered from respiratory support.
CONCLUSIONS: Our results suggest that in mechanically ventilated patients with HRF, low flow ECCO2R supports the maintenance of lung protective tidal volume and peak ventilator pressure. In selected awake patients with acute HRF, it may be a novel treatment approach to avoid mechanical ventilation, hence preventing ventilator- and sedation-associated morbidity and mortality.

PMID: 28275225 [PubMed - as supplied by publisher]

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Variation in lung function as a marker of adherence to oral and inhaled medication in cystic fibrosis.

Eur Respir J. 2017 Mar;49(3):

Authors: White H, Shaw N, Denman S, Pollard K, Wynne S, Peckham DG

Abstract
The aim of this study was to characterise adherence in an adult population with cystic fibrosis (CF) and to investigate if variation in lung function was a predictor of adherence to treatment.The adherence of patients aged ≥16 years from an adult CF centre was measured by medication possession ratio (MPR) and self-report. Patients were assigned to one of three adherence categories (<50%, 50 to <80%, ≥80%) by their composite score (MPR). Ordinal regression was used to identify predictors of adherence, including coefficient variation measures for forced expiratory volume in 1 s (FEV1), weight and C-reactive protein concentration, measured from 6 months and 12 months before baseline.MPR data for 106 of 249 patients (mean age 29.8±9.2 years) was retrieved, indicating a mean adherence of 63%. The coefficient of variation for FEV1 was inversely related to adherence and was a univariate predictor of adherence (6 months: OR 0.92, 95% CI 0.87-0.98, p=0.005; 12 months: OR 0.94, 95% CI 0.93-0.99, p=0.03) and remained significant in the final models. The coefficient of variation of weight and C-reactive protein were not predictive of adherence.The coefficient of variation of FEV1 was identified as an objective predictor of adherence. Further evaluation of this potential marker of adherence is now required.

PMID: 28275171 [PubMed - in process]

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CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.

Sci Rep. 2017 Dec;7(1):90

Authors: Edlund A, Pedersen MG, Lindqvist A, Wierup N, Flodström-Tullberg M, Eliasson L

Abstract
Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl(-) channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.

PMID: 28273890 [PubMed - in process]

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When is too little care, too much harm in cystic fibrosis? Psychological and ethical approaches to the problem.

J Cyst Fibros. 2017 Mar;16(2):299-303

Authors: Massie J, Morgan A, Gillam L

Abstract
Some parents of children with cystic fibrosis (CF) do not adhere to treatments recommended by the CF team. This can be a challenging issue for CF clinicians and can create conflict between the parents and treating team. Both parents and treating team believe they are acting in the best interests of the child, but do not share a common opinion as to what that entails. In this paper we present an understanding of the psychological framework of parents' illness representation that may foster a better understanding by CF clinicians of how to approach parents who hold a conflicting opinion regarding optimal care. Continuing to work with families towards optimal care is a moral obligation, but the key ethical decision is when to intervene to protect the child. In this paper we introduce the concept of the zone of parental discretion as an ethical tool to help decide the best way forward when parents do not accept medical advice on the optimal care of their child with CF.

PMID: 28267483 [PubMed - in process]

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Hyponatremia in children with acute respiratory infections: A reappraisal.

Pediatr Pulmonol. 2017 Mar 07;:

Authors: Lavagno C, Milani GP, Uestuener P, Simonetti GD, Casaulta C, Bianchetti MG, Fare PB, Lava SA

Abstract
Hyponatremia (<135 mmol/L), typically associated with an elevated anti-diuretic hormone level, is common among children admitted with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. The main consequences of acute hyponatremia include cerebral edema and Ayus-Arieff pulmonary edema. A widespread belief is that, in children with pneumonia or bronchiolitis, hyponatremia results from inappropriate anti-diuresis. By contrast, the pathogenic role of extracellular fluid volume depletion or decreased effective circulating blood volume is underscored. Considering the prevalence of hyponatremia, sodium determination is advised on admission in children diagnosed with bronchiolitis, pneumonia, or pulmonary exacerbation of cystic fibrosis. There is no necessity to do anything beyond reassessing the appropriateness of fluid therapy in cases with mild (130-134 mmol/L) hyponatremia. In children with sodium <130 mmol/L, the underlying etiology is sometimes evident from history and physical findings. Given that clinical assessment of fluid volume status is difficult in hyponatremia, further laboratory evaluation is often required in these patients. An increase in sodium level ≤6 mmol/L per day is currently considered the therapeutic goal in all cases. Emergency correction with a 2 mL/kg body weight bolus of 3.0% saline over 10-15 min intravenously is advised in cases with severe symptoms due to hyponatremia and in cases with symptoms, even if mild, due to a rapid-onset (<48 h) of hyponatremia (two additional doses are administered if the patient's condition does not improve).

PMID: 28267276 [PubMed - as supplied by publisher]

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Propranolol treatment for infantile hemangioma does not increase risk of childhood wheezing.

Pediatr Pulmonol. 2017 Mar 07;:

Authors: Mei-Zahav M, Blau H, Hoshen M, Zvulunov A, Mussaffi H, Prais D, Stafler P, Steuer G, Lapidoth M, Amitai DB

Abstract
OBJECTIVE: Propranolol is the treatment of choice for infantile hemangiomas requiring medical intervention. Although contraindicated in asthma, its bronchoconstrictive effect in infants and children has not been extensively studied. We aimed to assess the incidence of wheezing episodes in infants and children treated with propranolol for infantile hemangiomas.
STUDY DESIGN: A retrospective case-control study.
SETTING: a tertiary pediatric hospital.
PATIENTS: All Children followed for infantile hemangioma between 2009 and 2014. Children followed conservatively served as control group and were matched 1:1 for gender and month of birth by random matching to children treated with propranolol.
INTERVENTIONS: All respiratory episodes (asthma, wheezing, stridor, and pneumonia) and respiratory associated hospitalizations were recorded from hospital records, from the primary care physician visits records and pharmacy prescriptions. The main outcome measure was the incidence of respiratory episodes in the treatment and the control groups.
RESULTS: A total of 1828 clinic visits were reviewed for 683 children. In addition, primary care physician visits records were available in 80% of them. Two hundred and sixteen children were treated with propranolol. Incidence of respiratory episodes and recurrent respiratory episodes was similar in the propranolol and control groups (8.3% vs 12%, P = 0.265; 3.7% vs 6.5%, P = 0.274, respectively). Time to first episode was similar in the treatment and control groups (5.03 ± 3.32 vs 4.45 ± 3.21 months, respectively, P = 0.09). Respiratory hospital admission rate was similar in both groups.
CONCLUSIONS: Propranolol treatment does not exacerbate wheezing episodes in infants and children.

PMID: 28267266 [PubMed - as supplied by publisher]

Funding Opportunity PAR-17-216 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites cooperative agreement applications for investigator-initiated clinical trials of natural products to treat clinical symptoms such as those associated with sleep disturbance, pain conditions, or some mental health conditions (e.g., mild to moderate depression, anxiety, and post-traumatic stress), or examine the effects of probiotics and other natural products on gut-microbiome interactions with the brain and/or immune system. All applications submitted under this FOA must be supported by sufficient preliminary data of bioavailability and documentation that the natural product produces a replicable and measurable biological signature (i.e., measure of the mechanism of action), whenever it is possible or practical to measure and used by the patient population of interest.

Funding Opportunity PAR-17-174 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages cooperative agreement applications for investigator-initiated multi-site clinical trials (Phase III and beyond) to study the effects of natural products in NCCIH designated areas of high research priority. Applicants should describe plans for a Clinical Coordinating Center to develop and implement the proposed multi-site clinical trial. The objective of the Clinical Coordinating Center is to provide the design scientific rationale and a comprehensive scientific and operational plan for the clinical trial. The Clinical Coordinating Center is expected to be responsible for project management, participant recruitment and retention strategies, performance milestones, scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism.

Funding Opportunity PAR-17-172 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA), utilizing the U24 grant funding mechanism, encourages applications for a collaborating Data Coordinating Center (DCC) application that accompanies an investigator-initiated multi-site clinical trial (Phase III and beyond) application submitted under PAR-17-174. The DCC application must be specific to the collaborating Clinical Coordinating Center (CCC) application. The objective of the DCC application is to propose a comprehensive plan that provides overall project coordination, and administrative, data management, and biostatistical support for the proposed clinical trial. Both a DCC application and a corresponding CCC application need to be submitted simultaneously for consideration by NCCIH.

Funding Opportunity PAR-17-173 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA), utilizing the U24 grant funding mechanism, encourages applications for a collaborating Data Coordinating Center (DCC) application that accompanies an investigator-initiated multi-site clinical trial (Phase III and beyond) application submitted under PAR-17-175. The DCC application must be specific to the collaborating Clinical Coordinating Center (CCC) application. The objective of the DCC application is to propose a comprehensive plan that provides overall project coordination, and administrative, data management, and biostatistical support for the proposed clinical trial. Both a DCC application and a corresponding CCC application need to be submitted simultaneously for consideration by NCCIH.

Funding Opportunity PAR-17-175 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) encourages applications for investigator-initiated multi-site clinical trials (e.g. efficacy, effectiveness or pragmatic trials) to study the effects of mind and body interventions in NCCIH designated areas of high research priority. Clinical Coordinating Centers should develop and implement the proposed multi-site clinical trial. The objective of a Clinical Coordinating Center application is to present the scientific rationale and a comprehensive scientific and operational plan for the clinical trial. Clinical Coordinating Center applications are expected to describe plans for project management, participant recruitment and retention strategies, performance milestones, scientific conduct, and dissemination of results. Clinical Coordinating Center applications submitted under this FOA will utilize a two-phase, milestone-driven cooperative agreement (UG3/UH3) funding mechanism.

Funding Opportunity PAR-17-215 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites cooperative agreement applications for investigator-initiated clinical trials of mind and body interventions in NCCIH-designated areas of high research priority. Applications submitted under this FOA are expected to propose a clinical trial to develop and test adaptive interventions; optimize the intervention by evaluating which element of a complex intervention are critical for changes in outcome; assessing whether the intervention can be delivered with fidelity across sites in preparation for a future multi-site trial; or collect additional preliminary data such as determining the duration or frequency of the intervention to be used in a future multi-site trial. It is important, therefore, to already have sufficient preliminary data that includes: demonstration of feasibility of recruitment and accrual of participants; demonstration of participant adherence to the intervention as well as retention of participants throughout the study; completion of final data collection from any related studies; and evidence that the intervention has promise of clinical benefit. This FOA is not intended to support multi-site efficacy or effectiveness trials, nor will it support trials to test mind and body interventions for the treatment or prevention of cancer.

Notice NOT-AI-17-018 from the NIH Guide for Grants and Contracts

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Drugs in clinical development for the treatment of amyotrophic lateral sclerosis.

Expert Opin Investig Drugs. 2017 Mar 06;:

Authors: Martinez A, Palomo Ruiz MD, Perez DI, Gil C

Abstract
INTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clin ical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert Opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.

PMID: 28277881 [PubMed - as supplied by publisher]