Factors affecting the growth of infants diagnosed with cystic fibrosis by newborn screening.

BMC Pediatr. 2019 Oct 15;19(1):356

Authors: Patterson KD, Kyriacou T, Desai M, Carroll WD, Gilchrist FJ

Abstract
BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) improves nutritional outcomes. Despite early dietetic intervention some children fail to grow optimally. We report growth from birth to 2 years in a cohort of children diagnosed with CF by NBS and identify the variables that influence future growth.
METHODS: One hundred forty-four children were diagnosed with CF by the West Midlands Regional NBS laboratory between November 2007 and October 2014. All anthropometric measurements and microbiology results from the first 2 years were collated as was demographic and CF screening data. Classification modelling was used to identify the key variables in determining future growth.
RESULTS: Complete data were available on 129 children. 113 (88%) were pancreatic insufficient (PI) and 16 (12%) pancreatic sufficient (PS). Mean birth weight (z score) was 3.17 kg (- 0.32). There was no significant difference in birth weight (z score) between PI and PS babies: 3.15 kg (- 0.36) vs 3.28 kg (- 0.05); p = 0.33. By the first clinic visit the difference was significant: 3.42 kg (- 1.39) vs 4.60 kg (- 0.48); p < 0.0001. Weight and height remained lower in PI infants in the first year of life. In the first 2 years of life, 18 (14%) infants failed to regain their birth weight z score. The median time to achieve a weight z score of - 2, - 1 and 0 was 18, 33 and 65 weeks respectively. The median times to reach the same z scores for height were 30, 51 and 90 weeks. Birth weight z score, change in weight z score from birth to first clinic, faecal elastase, isolation of Pseudomonas aeruginosa, isolation of Staphylococcus aureus and sweat chloride were the variables identified by the classification models to predict weight and height in the first and second year of life.
CONCLUSIONS: Babies with CF have a lower birth weight than the healthy population. For those diagnosed with CF by NBS, the weight difference between PI and PS babies was not significantly different at birth but became so by the first clinic visit. The presence of certain factors, most already identifiable at the first clinic visit can be used to identify infant at increased risk of poor growth.

PMID: 31615474 [PubMed - in process]

StatPearls

Book. 2019 01

Authors:

Abstract
Cystic fibrosis (CF), a rare genetic disorder, characterized by multisystem involvement including progressive, potentially fatal pulmonary disease, has been described as being the most prevalent inherited fatal disorder in the White population of Northern European origin. However, this autosomal recessive disorder also presents in other populations, including African-Americans, Hispanics, and Asians. In patients with CF,  Researchers first noted sweat chloride abnormality in CF patients in 1953; this spawned the development of the sweat test in 1959. Since the discovery of the CF gene in 1989, which codes for the protein cystic fibrosis transmembrane regulator (CFTR), there are reports of more than 2000 mutations.  The cystic fibrosis transmembrane regulator is at the apical surface of the epithelial cells in the airways, gastrointestinal tract, pancreas, genitourinary system, and the sweat glands in the skin. The defective, deficient or absent CFTR function results in abnormal chloride transport across the chloride channels and abnormal sodium transport along with the secondary effect on water movement across the cell membrane. Decreased chloride secretion along with increased sodium reabsorption (along with water as a secondary effect) across the apical surface of the epithelial cells results in increased viscosity of secretions in the organs involved and in the case of skin, elevated levels of chloride in the sweat. Detection of elevated values of sweat chloride, in a suspected patient, by quantitative pilocarpine iontophoresis test (QPIT) is considered to be the gold standard for the diagnosis of cystic fibrosis.[1]

PMID: 31613508

StatPearls

Book. 2019 01

Authors:

Abstract
The pancreas is an abdominal organ possessing both endocrine and exocrine functions. It produces a variety of hormones that mostly pertain to regulating blood sugar levels. As an exocrine gland, it secretes pancreatic fluid that contains bicarbonate and digestive enzymes. Commonly, there are a few broad categories of diseases that affect the pancreas: pancreatitis, pancreatic insufficiency, cystic lesions of the pancreas, and pancreatic tumors. Pancreatitis is a generalized inflammation of the pancreas due to activation of digestive enzymes produced by the pancreas while still inside the organ. Acutely, this can result from gallstones, alcohol-misuse, or hypertriglyceridemia. Gallstones are the etiology of the majority of acute pancreatitis cases, 40 to 70%,[1] while alcohol misuse accounts for 25 to 35%.[2] Pancreatitis typically presents as an acute onset of epigastric pain that may radiate through to the back. Nausea and vomiting frequently accompany abdominal pain. The revised Atlanta classification separates acute pancreatitis into two subtypes: interstitial edematous pancreatitis and necrotizing pancreatitis. The severity further classifies acute pancreatitis into mild, moderately severe, or severe, based on the absence of organ failure, the presence of transient organ failure, or persistent organ failure, respectively.[3] The mortality rate from acute pancreatitis is approximately 5%, while those with necrotizing pancreatitis see a higher rate at 17%.[4] Chronic pancreatitis can occur in alcoholics, in which scarring of the gland prevents it from functioning properly.  Pancreatic insufficiency is the result when the pancreas is unable to produce enough digestive enzymes to break down food in the digestive tract. This condition is typically a deficiency in the exocrine function of the gland that can be caused by a variety of disease processes; most commonly cystic fibrosis in children and chronic pancreatitis in adults. Pancreatic exocrine cancer is one of the leading causes of cancer-related deaths in the United States, trailing only behind lung, colorectal, and breast. It also ranks among the most lethal cancers, with a one-year survival rate of 20% and a five-year survival rate of only 5%.[5] The lethality is mostly due to the insidious onset of the malignancy, with symptoms (e.g., jaundice, weight loss, and vague subacute epigastric pain) not presenting until late in the course of illness. Frequently, at the time of diagnosis, the lesion is inoperable due to extension into nearby structures. Over one-third of the tumors are Stage IV upon identification, and less than 20% of these cancers are candidates for surgical resection.[6][7] The most common malignancy is a ductal adenocarcinoma involving the exocrine glands; the majority of these tumors get discovered in the head of the pancreas.  Pancreatic neuroendocrine tumors (NETs) are malignancies that form in the endocrine tissue of the pancreas. Also known as islet cell tumors, these are rare tumors occurring in approximately 1 in every 100000 people, and only 1% of all pancreatic tumors are NETs.[8] NETs can result in the overproduction and secretion of pancreatic hormones, including insulin, gastrin, glucagon, and vasoactive intestinal peptide (VIP), resulting in specific clinical syndromes on presentation. Cystic lesions of the pancreas are a relatively common incidental finding on body imaging, with prevalence in the general population ranging from 2.4 to 24%. Classification of these cysts is important as they can either be true cysts, pseudocysts (usually related to pancreatitis), or related to benign or malignant neoplasms. Radiological imaging has historically helped distinguish the etiology of the cystic lesions in 75 to 90% of presentations.[9] True epithelial cysts are rare in the general population and are classically only associated with cystic fibrosis, von Hippel-Lindau disease, an autosomal dominant polycystic kidney disease. Pseudocysts, related to pancreatitis or trauma, are the most common cystic lesion identified in the pancreas. Approximately 20 to 40% of patients with chronic pancreatitis develop pseudocysts, while only 2-3% of those with acute pancreatitis will develop them.[9] Cysts associated with malignancy may rarely occur with exocrine tumors, occasionally with endocrine tumors, or in isolation. Cystic neoplasms include intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cystadenomas.

PMID: 31613505

StatPearls

Book. 2019 01

Authors:

Abstract
There are two main modes of transport of molecules across any biological membrane. These are passive and active transport. Passive transport, most commonly by diffusion, occurs along a concentration gradient from high to low concentration. No energy is necessary for this mode of transport. Examples will include diffusion of gases across alveolar membranes and diffusion of neurotransmitters such as acetylcholine across the synapse or neuromuscular junction. Osmosis is a form of passive transport when water molecules move from low solute concentration(high water concentration) to high solute or low water concentration across a membrane that is not permeable to the solute. There is a form of passive transport called facilitated diffusion. It occurs when molecules such as glucose or amino acids move from high concentration to low concentration facilitated by carrier proteins or pores in the membrane. Active transport requires energy for the process by transporting molecules against a concentration or electrochemical gradient. Active transport is an energy-driven process where membrane proteins transport molecules across cells, mainly classified as either primary or secondary, based on how energy is coupled to fuel these mechanisms. The former constitutes means by which a chemical reaction, e.g., ATP hydrolysis, powers the direct transport of molecules to establish specific concentration gradients, as seen with sodium/potassium-ATPase and hydrogen-ATPase pumps. The latter employs those established gradients to transport other molecules.[1][2] These gradients support the roles of other membrane proteins and other workings of the cell and are crucial to the maintenance of cellular and bodily homeostasis. As such, the importance of active transport is apparent when considering the various defects throughout the body that can manifest in a wide variety of diseases, including cystic fibrosis and cholera, all because of an impairment in some aspect of active transport.[3]

PMID: 31613498

Losartan Rescues Inflammation-Related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis.

Am J Respir Crit Care Med. 2019 Oct 15;:

Authors: Kim MD, Baumlin N, Yoshida M, Polineni D, Salathe SF, David JK, Peloquin CA, Wanner A, Dennis JS, Sailland J, Whitney P, Horrigan FT, Sabater JR, Abraham WM, Salathe M

Abstract
RATIONALE: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large conductance, Ca2+-activated and voltage-dependent K+ channels (BK), critical for mucociliary function in the absence of CFTR.
OBJECTIVES AND METHODS: Losartan's anti-inflammatory effectiveness to rescue BK activity and thereby mucociliary function was tested in vitro using primary, fully re-differentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacological sheep model of CF- and inflammation-associated mucociliary dysfunction.
MEASUREMENTS AND MAIN RESULTS: Nasal scrapings from CF patients showed that neutrophilic inflammation correlated with reduced expression of LRRC26, the γ subunit mandatory for BK function in the airways. TGF-β1, downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression); ciliary beat frequency and airway surface liquid (ASL) volume improved; and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic sheep model of CF, ewes inhaled CFTRinh172 and neutrophil elastase for three days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1.
CONCLUSIONS: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.

PMID: 31613648 [PubMed - as supplied by publisher]

Structure of Pseudomonas aeruginosa ribosomes from an aminoglycoside-resistant clinical isolate.

Proc Natl Acad Sci U S A. 2019 Oct 14;:

Authors: Halfon Y, Jimenez-Fernandez A, La Rosa R, Espinosa Portero R, Krogh Johansen H, Matzov D, Eyal Z, Bashan A, Zimmerman E, Belousoff M, Molin S, Yonath A

Abstract
Resistance to antibiotics has become a major threat to modern medicine. The ribosome plays a fundamental role in cell vitality by the translation of the genetic code into proteins; hence, it is a major target for clinically useful antibiotics. We report here the cryo-electron microscopy structures of the ribosome of a pathogenic aminoglycoside (AG)-resistant Pseudomonas aeruginosa strain, as well as of a nonresistance strain isolated from a cystic fibrosis patient. The structural studies disclosed defective ribosome complex formation due to a conformational change of rRNA helix H69, an essential intersubunit bridge, and a secondary binding site of the AGs. In addition, a stable conformation of nucleotides A1486 and A1487, pointing into helix h44, is created compared to a non-AG-bound ribosome. We suggest that altering the conformations of ribosomal protein uL6 and rRNA helix H69, which interact with initiation-factor IF2, interferes with proper protein synthesis initiation.

PMID: 31611393 [PubMed - as supplied by publisher]

In vitro Activities of β-Lactam-β-Lactamase Inhibitor Antimicrobial Agents Against Cystic Fibrosis Respiratory Pathogens.

Antimicrob Agents Chemother. 2019 Oct 14;:

Authors: Caverly LJ, Spilker T, Kalikin LM, Stillwell T, Young C, Huang DB, LiPuma JJ

Abstract
We tested the in vitro activities of ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, piperacillin-tazobactam, and 11 other antimicrobial agents against 420 Burkholderia, Achromobacter, Stenotrophomonas, and Pandoraea strains, 89% of which were cultured from respiratory specimens from persons with cystic fibrosis. Among the β-lactam-β-lactamase inhibitor agents, meropenem-vaborbactam had the greatest activity against Burkholderia and Achromobacter; including multi-drug-resistant and extensively-drug-resistant strains. None of the newer β-lactam-β-lactamase combination drugs showed increased activity compared to older agents against Stenotrophomonas maltophilia or Pandoraea spp.

PMID: 31611364 [PubMed - as supplied by publisher]

Improved culture detection of Staphylococcus aureus from sputum of patients with cystic fibrosis (CF).

J Clin Pathol. 2019 Oct 13;:

Authors: Wen H, Stirling J, McCaughan J, Schock B, Downey DG, Ennis M, Moore JE

PMID: 31611286 [PubMed - as supplied by publisher]

Cystic fibrosis transmembrane conductance regulator modulators reduce the risk of recurrent acute pancreatitis among adult patients with pancreas sufficient cystic fibrosis.

Pancreatology. 2019 Sep 28;:

Authors: Akshintala VS, Kamal A, Faghih M, Cutting GR, Cebotaru L, West NE, Jennings MT, Dezube R, Whitcomb DC, Lechtzin N, Merlo CA, Singh VK

Abstract
BACKGROUND: Approximately 1 in 5 patients with pancreas sufficient cystic fibrosis (PS-CF) will develop acute pancreatitis (AP). It is not known whether ivacaftor alone or in combination with other CFTR (cystic transmembrane regulator) modulators (tezacaftor or lumacaftor) can reduce the risk of AP in patients with PS-CF and AP history.
METHODS: We retrospectively queried the CF registry at our institution for adult patients with PS-CF, a documented history of AP and initiation of CFTR modulators for pulmonary indications. Patient characteristics including demographics, CFTR genotype, pancreatitis risk factors, pancreatic exocrine function and other relevant laboratory, imaging parameters were obtained from the time of the sentinel AP episode through the follow-up period.
RESULTS: A total of 15 adult CF patients were identified with mean age of 44.1 years (SD ± 13.8). In the 24 months preceding CFTR modulator initiation, six of these patients had at least 1 episode of AP with median of 2 episodes [1.75, 2.5]. None of the patients had evidence of pancreatic calcifications or exocrine pancreas insufficiency at the time of CFTR modulator initiation. The mean duration of follow-up after CFTR modulator initiation was 36.7 months (SD ± 21.5). None of the patients who remained on CFTR modulators developed an episode of AP or required hospitalization for AP related abdominal pain during follow-up.
CONCLUSIONS: CFTR modulators, alone or in combination, substantially reduce the risk of recurrent AP over a mean follow-up period of 3 years in adult patients with PS-CF and a history of prior AP. These data suggest that any augmentation of CFTR function can reduce the risk of pancreatitis.

PMID: 31611131 [PubMed - as supplied by publisher]

Inflammatory Myofibroblastic Tumor After Lung Transplant-A Rare and Aggressive Complication: A Case Report.

Transplant Proc. 2019 Oct 11;:

Authors: Poggi C, Pecoraro Y, Carillo C, Anile M, Amore D, Mantovani S, Naldi G, Pagini A, Bassi M, Cagnetti S, Mottola E, D'Agostino F, Vannucci J, Pernazza A, Cimino G, Savi D, Gomellini S, Pugliese F, De Giacomo T, Rendina EA, Venuta F, Diso D

Abstract
INTRODUCTION: Malignant diseases are well-known complications after lung transplantation (LT). Among these, inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with a not well-known and often aggressive biological behavior.
MATERIAL AND METHODS: We hereby describe 2 cases of cystic fibrosis patients who underwent bilateral sequential LT (BSLT) complicated by IMT.
RESULTS: A 26-year-old man presented a right endobronchial lesion 6 months after BSLT. Two consecutive fiber bronchoscopic biopsies showed granulation tissue. For the persistent lesion growth, the patient underwent a transthoracic biopsy showing histologic diagnosis of IMT. Therefore, he underwent to right pneumonectomy that was unfortunately complicated after 6 months with a late bronchopleural fistula and empyema with exitus 6 months later. A 31-year-old woman 1 year after BSLT presented with a left voluminous pleural-parenchymal lesion; the histologic examination after biopsy revealed an IMT. She underwent a removal of the lesion with a macroscopic R0 resection. Histologic, immunophenotypic, and cytogenetic examinations showed a strong overexpression of anaplastic lymphoma kinase requiring biological adjuvant therapies; however, the patient refused it. Four years later, she presented a recurrence treated with debulking procedure and adjuvant radiotherapy. At last follow-up, the patient was alive with stable disease and optimal graft function.
CONCLUSIONS: Although IMT is a rare complication after lung transplant, to obtain a careful diagnosis, an early and aggressive treatment is mandatory.

PMID: 31611127 [PubMed - as supplied by publisher]

Impact of Cold Ischemic Time on Airway Complications After Lung Transplantation: A Single-center Cohort Study.

Transplant Proc. 2019 Oct 10;:

Authors: Mendogni P, Pieropan S, Rosso L, Tosi D, Carrinola R, Righi I, Damarco F, Musso V, Bonitta G, Morlacchi LC, Rossetti V, Nosotti M

Abstract
BACKGROUND: Despite significant improvements in lung transplantation procedures, the incidence of airway complications (ACs) remains high (2%-18%); these complications are associated with high costs, great morbidities, and a decreased quality of life. There is general disagreement over potential risk factors determining ACs, including graft cold ischemic time (CIT). The aim of this study was to evaluate the association between CIT and ACs.
METHODS: All patients undergoing lung transplantation between January 2011 and December 2017 were evaluated. We excluded retransplantations and patients with 90-day mortality. Demographic and clinical data regarding donors, recipients, and surgical procedures were analyzed using propensity score weighted marginal Cox regression model.
RESULTS: Out of the 161 lung transplantations performed in the study timeframe, 147 fulfilled the inclusion criteria and supplied complete data to be analyzed. Median follow-up was 25.5 months (interquartile range = 35.2). Ten patients (6.8%) had late ACs; out of the 260 anastomoses considered, 14 proved to be complicated (5.4%). Median time to event was 5.5 months (range, 3-15). ACs were classified as bronchial stenosis (12) and malacia (2). Mean CIT was 446.6 minutes (range, 117-1200). Without considering time-to-event data, CIT was significantly higher in complicated anastomoses (P = .002). The unweighted marginal univariate Cox model showed a significant association between ACs and CIT (P < .001). The propensity score weighted marginal univariable Cox model confirmed this significant association (P < .001).
CONCLUSIONS: The prolonged CIT time seems to be a risk factor for the development of late ACs; we endorse any measure that could limit CIT within 600 minutes.

PMID: 31611126 [PubMed - as supplied by publisher]

Frequency of Cystic Fibrosis Transmembrane Conductance Regulator Variants in Individuals Evaluated for Primary Ciliary Dyskinesia.

J Pediatr. 2019 Oct 11;:

Authors: Hannah WB, Truty R, Gonzales V, Kithcart GP, Ouyang K, Zeman MK, Li C, Drumm M, Nykamp K, Gaston BM

Abstract
OBJECTIVE: To evaluate whether cystic fibrosis transmembrane conductance regulator (CFTR) variants are more common among individuals tested for primary ciliary dyskinesia (PCD) compared with controls.
STUDY DESIGN: Data were studied from 1021 individuals with commercial genetic testing for suspected PCD and 91 777 controls with genetic testing at the same company (Invitae) for symptoms/diseases unrelated to PCD or CFTR testing. The prevalence of CFTR variants was compared between controls and each of 3 groups of individuals tested for PCD (PCD-positive, -uncertain, and -negative molecular diagnosis).
RESULTS: The prevalence of 1 pathogenic CFTR variant was similar among the individual groups. When combining the PCD-uncertain and PCR-negative molecular diagnosis groups, there was a higher prevalence of single pathogenic CFTR variants compared with controls (P = .03). Importantly, >1% of individuals who had negative genetic testing results for PCD had 2 pathogenic CFTR variants (8 of 723), and the incidence of cystic fibrosis (CF) (2 pathogenic variants) is roughly 1 in 3000 individuals of Caucasian ethnicity (∼0.03%). This incidence was also greater than that of 2 pathogenic CFTR variants in the control population (0.09% [84 of 91 777]; P = 9.60 × 10-16). These variants correlate with mild CFTR-related disease.
CONCLUSIONS: Our results suggest that a single pathogenic CFTR variant is not likely to be a PCD-mimetic, but ongoing studies are needed in individuals in whom PCD is suspected and genetic testing results are uncertain or negative. Furthermore, CF may be misdiagnosed as PCD, reflecting phenotypic overlap. Among individuals evaluated for PCD, CF should be considered in the differential even in the CF newborn screening era.

PMID: 31610925 [PubMed - as supplied by publisher]

Improving the phenotype risk score as a scalable approach to identifying patients with Mendelian disease.

J Am Med Inform Assoc. 2019 Oct 14;:

Authors: Bastarache L, Hughey JJ, Goldstein JA, Bastraache JA, Das S, Zaki NC, Zeng C, Tang LA, Roden DM, Denny JC

Abstract
OBJECTIVE: The Phenotype Risk Score (PheRS) is a method to detect Mendelian disease patterns using phenotypes from the electronic health record (EHR). We compared the performance of different approaches mapping EHR phenotypes to Mendelian disease features.
MATERIALS AND METHODS: PheRS utilizes Mendelian diseases descriptions annotated with Human Phenotype Ontology (HPO) terms. In previous work, we presented a map linking phecodes (based on International Classification of Diseases [ICD]-Ninth Revision) to HPO terms. For this study, we integrated ICD-Tenth Revision codes and lab data. We also created a new map between HPO terms using customized groupings of ICD codes. We compared the performance with cases and controls for 16 Mendelian diseases using 2.5 million de-identified medical records.
RESULTS: PheRS effectively distinguished cases from controls for all 15 positive controls and all approaches tested (P < 4 × 1016). Adding lab data led to a statistically significant improvement for 4 of 14 diseases. The custom ICD groupings improved specificity, leading to an average 8% increase for precision at 100 (-2% to 22%). Eight of 10 adults with cystic fibrosis tested had PheRS in the 95th percentile prio to diagnosis.
DISCUSSION: Both phecodes and custom ICD groupings were able to detect differences between affected cases and controls at the population level. The ICD map showed better precision for the highest scoring individuals. Adding lab data improved performance at detecting population-level differences.
CONCLUSIONS: PheRS is a scalable method to study Mendelian disease at the population level using electronic health record data and can potentially be used to find patients with undiagnosed Mendelian disease.

PMID: 31609419 [PubMed - as supplied by publisher]

State of the art in cystic fibrosis pharmacology-Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: I. Anti-methicillin-resistant Staphylococcus aureus (MRSA) antibiotics.

Pediatr Pulmonol. 2019 Oct 14;:

Authors: Epps QJ, Epps KL, Young DC, Zobell JT

Abstract
Acute pulmonary exacerbations (APE) are a complication of cystic fibrosis (CF) and are associated with morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) is one of many organisms that has been detected in the airways of patients with CF. This review provides an evidence-based summary of pharmacokinetic/pharmacodynamic (PK/PD), tolerability, and efficacy studies utilizing anti-MRSA antibiotics (ie, ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim (SMZ/TMP), and tetracycline derivatives (doxycycline, minocycline, tigecycline) in the treatment of APE and identifies areas where further study is warranted. A recent utilization study of antimicrobials for anti-MRSA has shown some CF Foundation accredited care centers and affiliate programs are using doses higher than the FDA-approved doses. Further studies are needed to determine the PK/PD properties in CF patients with clindamycin, minocycline, rifampin, SMZ/TMP, telavancin, and tigecycline; as well as, efficacy and tolerability studies with ciprofloxacin, clindamycin, doxycycline, levofloxacin, minocycline, rifampin, SMZ/TMP, in CF patients with MRSA.

PMID: 31609097 [PubMed - as supplied by publisher]

Oral administration of Lactobacillus acidophilus alleviates exacerbations in Pseudomonas aeruginosa and Staphylococcus aureus pulmonary infections.

Pak J Pharm Sci. 2019 Jul;32(4):1621-1630

Authors: Shoaib A, Xin L, Xin Y

Abstract
Staphylococcus aureus and Pseudomonas aeruginosa are largely the cause of morbidity and mortality in both hospital and community settings. These pathogens remain the important cause of pulmonary infections in patients with cystic fibrosis with a worldwide prevalence. Although, antibiotics are efficient measures of treating bacterial lung infections, the occurrence of antibiotic resistant bacteria has been encouraging the researchers to explore novel therapeutic approaches. It has been discovered that certain lactic acid bacteria possess protective effects against bacterial and viral respiratory infections. The aim of present study was to investigate the capability of orally administered L. acidophilus to ameliorate S. aureus and P. aeruginosa pulmonary infections. Animals were exposed to aerosol of pathogenic suspension. After 24 hours of infection, L. acidophilus treatment was administered orally for 7 consecutive days. Evaluation of tissue bacteriology, histopathology and serum cytokinomics were performed. In parallel, human alveolar A549 cells were utilized to determine possible role of probiotic on pulmonary infections. Oral administration of L. acidophilus significantly (P<0.05) alleviate lung bacterial load and severity of infection as depicted by our histopathological studies. Results obtained from cytokinomics revealed that pro-inflammatory cytokines induced due to lung infection were suppressed in oral probiotic treatment groups. In addition, treatment with L. acidophilus induced murine lung anti inflammatory, IL-10 cytokine level. Current work suggests that orally administered L. acidophilus in mice is able to attenuate S. aureus and P. aeruginosa induced lung cytotoxicity by modulation of host immune response.

PMID: 31608882 [PubMed - in process]

Ovarian Metabolic activity in Dehydroepiandrosterone-Induced Polycystic Ovary in Wistar rats Treated with Aspirin.

JBRA Assist Reprod. 2019 Oct 14;:

Authors: Olaniyan OT, Bamidele O, Uche S, Femi A, Ayobami D, Ayoola O, Builders M, Mali PC

Abstract
OBJECTIVES: Polycystic ovary syndrome (PCOS) represents 75% of the cases of anovulatory infertility. The aim of this study was to investigate the role of aspirin on dehydroepiandrosterone (DHEA) - induced polycystic ovary syndrome in Wistar rats.
METHODS: Twenty eight (28) pre-pubertal female Wistar rats of 21 days old weighing 16 - 21 g were divided into 4 groups (7 rats/group) and treated as follows; group I received distilled water and served as Control; Group II received 6 mg/100 g body weight DHEA in 0.2 ml of oil subcutaneously to induce PCOS. Group III received 7.5 mg/kg of aspirin orally; Group IV received 6 mg/100kg of body weight of DHEA in 0.2ml of oil subcutaneously and 7.5 mg/kg of aspirin orally. After 15 days of administration, the rats were slaughtered by cervical dislocation. Blood samples and ovaries were collected for reproductive hormonal analysis, biochemical and histopathological analysis. The expressions of mRNA androgen receptor (AR) gene in the ovary were determined by real time reverse transcriptase polymerase chain reaction (qPCR). All the data was analyzed using one way ANOVA with the Graph pad prism software version 6. A p<0.05 was considered significant.
RESULTS: The results obtained showed that dehydroepiandrosterone treatment caused significant decrease (p<0.05) in total protein, superoxide Dismutase (SOD), glutathione-s- transferase (GST), Ca2+ ATPase, and significant increase (p<0.05) in malondialdehyde, vascular endothelial growth factor, tumor necrosis factor and estrogen as compared to Controls. The group co-administered with DHEA and aspirin showed significant increases in SOD, GST, CAT, GSH, Progesterone, Ca2+ ATPase, Na+ ATPase, H+ ATPase and significant reduction (p<0.05) in malondialdehyde, VEGF, TNF-α and estrogen as compared with the DHEA group. The histopathological analysis showed reductions in cystic fibrosis, atretic ovaries, increased expression of Bcl-2 and E- Cadherin and reduced Bax expression in the group that received Aspirin and DHEA.
CONCLUSION: This study clearly demonstrates that Aspirin has ameliorating effects against polycystic ovary syndrome via anti-inflammatory and hormonal modulatory pathways.

PMID: 31608617 [PubMed - as supplied by publisher]

Physiology of sweat gland function: The roles of sweating and sweat composition in human health.

Temperature (Austin). 2019;6(3):211-259

Authors: Baker LB

Abstract
The purpose of this comprehensive review is to: 1) review the physiology of sweat gland function and mechanisms determining the amount and composition of sweat excreted onto the skin surface; 2) provide an overview of the well-established thermoregulatory functions and adaptive responses of the sweat gland; and 3) discuss the state of evidence for potential non-thermoregulatory roles of sweat in the maintenance and/or perturbation of human health. The role of sweating to eliminate waste products and toxicants seems to be minor compared with other avenues of excretion via the kidneys and gastrointestinal tract; as eccrine glands do not adapt to increase excretion rates either via concentrating sweat or increasing overall sweating rate. Studies suggesting a larger role of sweat glands in clearing waste products or toxicants from the body may be an artifact of methodological issues rather than evidence for selective transport. Furthermore, unlike the renal system, it seems that sweat glands do not conserve water loss or concentrate sweat fluid through vasopressin-mediated water reabsorption. Individuals with high NaCl concentrations in sweat (e.g. cystic fibrosis) have an increased risk of NaCl imbalances during prolonged periods of heavy sweating; however, sweat-induced deficiencies appear to be of minimal risk for trace minerals and vitamins. Additional research is needed to elucidate the potential role of eccrine sweating in skin hydration and microbial defense. Finally, the utility of sweat composition as a biomarker for human physiology is currently limited; as more research is needed to determine potential relations between sweat and blood solute concentrations.

PMID: 31608304 [PubMed]

Infection with Prevotella nigrescens induces TLR2 signalling and low levels of p65 mediated inflammation in Cystic Fibrosis bronchial epithelial cells.

J Cyst Fibros. 2019 Oct 10;:

Authors: Bertelsen A, Elborn JS, Schock BC

Abstract
Prevotella spp. are frequently identified in Cystic Fibrosis sputum. This study examined whether infection with Prevotella nigrescens, a frequently identified member of this species, contributes to inflammation in CF bronchial epithelial cells through activation of TLR- and NF-κB signalling pathways. CFBE41o- cells were infected with either P.nigrescens or Pseudomonas aeruginosa and incubated under anaerobic conditions for 4h. P.nigrescens activated TLR2 signalling but not TLR4 signalling while P.aeruginosa activated TLR4 signalling with a lesser effect on TLR2. P.aeruginosa induced significant IκBα phosphorylation 10min post infection with a return to control levels by 30min post infection. A significant induction in nuclear p65 DNA binding was observed at 2h post infection. In contrast, infection with P.nigrescens induced phosphorylation of IκBα 120min post infection, with significant induction in nuclear p65 DNA binding at 4h post infection only. Cytokine gene and protein responses were lower for P.nigrescens compared to P.aeruginosa. This study demonstrates the ability of a clinical P.nigrescens isolate to provoke a delayed NF-κB(p65) driven response through induction in TLR2 signalling and activation of sustained levels of IKKα.

PMID: 31607634 [PubMed - as supplied by publisher]

A negative screening of rare genetic variants in the ADIPOQ and STATH genes in cystic fibrosis.

Pulmonology. 2019 Oct 09;:

Authors: Coutinho CAAC, Marson FAL, Ribeiro JD, Bertuzzo CS

Abstract
BACKGROUND: The phenotypic variability in cystic fibrosis (CF) is widely recognized and modulated by environmental and genetic factors, including CFTR pathogenic variants and modifier genes genetic variants. In this context, determining the presence of variants in genes involved in immune response may allow a better understanding of CF variability, mainly in lung disease. Thus, ADIPOQ and STATH genes were selected and the analysis of exons and exon/intron junctions was performed for the determination of variations in its sequence, to determine the possible genetic modulation.
METHODS: A total of 49 patients with CF, diagnosed for showing abnormal [chloride] levels in the sweat test, and identification of two pathogenic variants in CFTR categorized as class I and II were included. Genetic sequencing was performed for the identification of variants in the modifier genes.
RESULTS: In our analysis, there was absence of rare genetic variants in STATH and ADIPOQ genes associated with the clinical variability. Thus, we are not able to establish an association between the disease severity and rare genetic variants in STATH and ADIPOQ genes, considering exons and exon/intron junctions.
CONCLUSIONS: Considering the negative screening for rare genetic variants in ADIPOQ and STATH genes, it may be concluded that these genes are not associated with phenotypic modulation of CF in our population. To understand the modifier genes and its action at CF variability it is essential to promote a better overview of the disease. Also, negative reports can help to direct new studies without the use of unnecessary financial support.

PMID: 31606405 [PubMed - as supplied by publisher]

Non-invasive ventilation versus oxygen therapy in cystic fibrosis: Long-term effects.

Respirology. 2019 Oct 11;:

Authors: Sarc I, Ziherl K, Esquinas AM

PMID: 31605448 [PubMed - as supplied by publisher]