Front Microbiol. 2022 Aug 17;13:953964. doi: 10.3389/fmicb.2022.953964. eCollection 2022.

ABSTRACT

Pseudomonas aeruginosa, a ubiquitous opportunistic pathogen, is a leading cause of chronic infection of airways in cystic fibrosis (CF) patients. Chronic infections typically arise from colonization by environmental strains, followed by adaptation of P. aeruginosa to the conditions within the CF airway. It has been suggested that oxygen availability can be an important source of selection causing trait changes associated with the transition to chronic infection, but little data exist on the response of P. aeruginosa to varying levels of oxygen. Here, we use a diverse collection of P. aeruginosa strains recovered from both CF patients and environmental sources to evaluate the role of oxygen availability in driving adaptation to the CF lung while also accounting for phylogenetic relatedness. While we can detect a signal of phylogeny in trait responses to oxygen availability, niche of origin is a far stronger predictor. Specifically, strains isolated from the lungs of CF patients are more sensitive to external oxidative stress but more resistant to antibiotics under anoxic conditions. Additionally, many, though not all, patho-adaptive traits we assayed are insensitive to oxygen availability. Our results suggest that inferences about trait expression, especially those associated with the transition to chronic infection, depend on both the available oxygen and niche of origin of the strains being studied.

PMID:36060748 | PMC:PMC9428489 | DOI:10.3389/fmicb.2022.953964

Front Physiol. 2022 Aug 19;13:904203. doi: 10.3389/fphys.2022.904203. eCollection 2022.

ABSTRACT

Mechanosensation is essential for normal gastrointestinal (GI) function, and abnormalities in mechanosensation are associated with GI disorders. There are several mechanosensitive ion channels in the GI tract, namely transient receptor potential (TRP) channels, Piezo channels, two-pore domain potassium (K2p) channels, voltage-gated ion channels, large-conductance Ca2+-activated K+ (BKCa) channels, and the cystic fibrosis transmembrane conductance regulator (CFTR). These channels are located in many mechanosensitive intestinal cell types, namely enterochromaffin (EC) cells, interstitial cells of Cajal (ICCs), smooth muscle cells (SMCs), and intrinsic and extrinsic enteric neurons. In these cells, mechanosensitive ion channels can alter transmembrane ion currents in response to mechanical forces, through a process known as mechanoelectrical coupling. Furthermore, mechanosensitive ion channels are often associated with a variety of GI tract disorders, including irritable bowel syndrome (IBS) and GI tumors. Mechanosensitive ion channels could therefore provide a new perspective for the treatment of GI diseases. This review aims to highlight recent research advances regarding the function of mechanosensitive ion channels in the GI tract. Moreover, it outlines the potential role of mechanosensitive ion channels in related diseases, while describing the current understanding of interactions between the GI tract and mechanosensitive ion channels.

PMID:36060694 | PMC:PMC9437298 | DOI:10.3389/fphys.2022.904203

Pediatr Pulmonol. 2022 Sep 5. doi: 10.1002/ppul.26136. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary Exacerbations (PEx), pathogens colonizing the respiratory tract, and patients' age are associated with progressive worsening of lung function among patients with Cystic Fibrosis (CF). However, the effect of these factors on longitudinal changes of LCI remains unclear.

AIM: To assess the role of age, different types of bronchial infection, and PEx on LCI deterioration.

METHODS: We conducted a retrospective study assessing MBW and spirometry changes among CF patients evaluated at quarterly outpatient clinic visits over eight years. MBW and spirometry were performed at each visit, sputum samples and/or cough swabs were obtained for culture, whereas respiratory symptoms and clinical examination findings were recorded. Patients who had ≥5 serial MBW measurements, one of which coincided with a pulmonary exacerbation, were reviewed.

RESULTS: 76 patients were included in the study: mean age 10.61 years (range 1.75 to 23.75). A total of 1152 MBW tests and 1047 spirometry tests were performed. LCI was significantly higher among CF patients aged 11 to 15, 16 to 20, and over 20 years than those under five years of age; ΔLCI: 1.16 (CI 0.43 to 1.90) and 3. 25 (CI 2.33 to 4.17), respectively. Furthermore, LCI was significantly elevated in CF patients with positive cultures for PsA (0.52 LCI (CI -0.12 to 0.71) and Stenotrophomonas Maltophilia (1.41 LCI (CI 0.61 to 2.21). Moreover, increased values of LCI in CF patients were significantly associated with increased risk of PEx (OR 1.19, CI [1.14 to 1.25], p <0.001).

CONCLUSION: LCI demonstrates a progression of lung disease and corresponds to changes in bacterial infections and PEx among patients with CF. LCI may be a valuable marker for tracking disease deterioration and may have a role in the routine clinical care of patients with CF. This article is protected by copyright. All rights reserved.

PMID:36059241 | DOI:10.1002/ppul.26136

Zhonghua Shao Shang Za Zhi. 2022 Aug 20;38(8):794-798. doi: 10.3760/cma.j.cn501120-20210517-00191.

ABSTRACT

Sweat glands are widely distributed in human skin, among which eccrine sweat glands play major roles in heat dissipation and sweat secretion. Sweat secretion is mainly regulated by nervous system and includes two processes of secretion of secretory coil and reabsorption of sweat duct, involving various ion channels and proteins such as calcium ion channel, potassium ion channel, sodium-potassium-chloride co-transporter 1, Best2 protein, aquaporin 5, cystic fibrosis transmembrane conductance regulator, and epithelial sodium ion channel. This paper reviews the nerve conduction system and various ion channels involved in sweat secretion of exocrine sweat glands in order to provide a theoretical basis for the study of regeneration, repair, and transformation of stem cells.

PMID:36058703 | DOI:10.3760/cma.j.cn501120-20210517-00191

Respir Med. 2022 Aug 28;202:106970. doi: 10.1016/j.rmed.2022.106970. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of this study was to assess the long-term clinical impact of the application of e-health as part of a virtual model of care in patients with Cystic Fibrosis (CF).

METHODS: Digital care group (DCG) were deemed suitable for using the NuvoAir Home platform to monitor their disease at home as part of a virtual model of care project. The usual care group (UCG) remained on usual care. NuvoAir Home platform consists of a smartphone application, Bluetooth spirometer and a clinician portal. Data on pulmonary function, Cystic Fibrosis Questionnaire-Revised (CFQR) and pulmonary exacerbations were collected at baseline and after twelve months. A survey for the digital care group was emailed to evaluate their experience using the technology.

RESULTS: Between February 2020 and May 2020 a cohort of 43 CF patients were recruited for the DCG (26 females; mean age 31.6 ± 6.8; 16 homozygous for delta F508; FEV1 48.4 ± 16.3% predicted) and 36 CF patients for UCG (18 females; mean age 29.1 ± 9.4; 6 homozygous for delta F508; FEV1 77.0 ± 25.0% predicted). CFQ-R score improved significantly through 12 months in the DCG with a mean change of 13.8 points, p < 0.0001, and no changes for the UCG (p = 0.73). When we analyzed the subgroup of CF patients on digital and usual care who did not receive CFTR modulator therapy, we found a change in CFQ-R score which was significantly associated with the use of digital technology while adjusting for baseline differences (p = 0.020). There was no significant difference in the change in lung function and number of exacerbations. 90% of patients reported they understood their CF better using the NuvoAir Home platform. No changes in medical treatment were reported during that time.

CONCLUSIONS: The application of digital technologies in the management of adults with CF showed an improvement in patients' quality of life. Using a virtual model of care was well accepted by CF patients and improved their understanding of their medical condition.

PMID:36058164 | DOI:10.1016/j.rmed.2022.106970

BMJ Paediatr Open. 2022 Apr;6(1):e001422. doi: 10.1136/bmjpo-2022-001422.

ABSTRACT

OBJECTIVE: To analyse the association of faecal calprotectin with the genetic and clinical characteristics of paediatric patients with cystic fibrosis (PwCF). In a subset of these patients, we aimed to associate histological inflammatory features of rectal mucosa to faecal calprotectin levels.

METHODS: In a prospective study, faecal calprotectin levels were collected in all 23 PwCF attending our paediatric centre, together with demographic and clinical data. Associations between faecal calprotectin and clinical features were determined. In 11 of these patients, endoscopic rectal biopsies were obtained and the association between faecal calprotectin and histological inflammatory markers was analysed. Statistical analyses included Spearman's correlation coefficient, Mann-Whitney U test and Fisher's exact test. Sensitivity and specificity was calculated.

RESULTS: Median age of PwCF was 12 years, 19 had pancreatic insufficiency (PI) (19/23). Seventeen (17/23) had elevated faecal calprotectin, and the median value was 88 µg/g (IQR=178 µg/g). Higher faecal calprotectin levels were observed in the PI group (101 vs 30 µg/g, p=0.027). No significant correlation between elevated faecal calprotectin level and body mass index z-score was found. Five patients (22%) reported abdominal pain, three (13%) complained of diarrhoea and three (13%) had constipation, but these symptoms were not associated with elevated faecal calprotectin.Unspecific focal rectal inflammation was found in four patients (4/11). An association between rectal mucosa inflammation and elevated faecal calprotectin was found (p=0.015). Sensitivity was 100% and specificity was 86%.

CONCLUSIONS: In our PwCF, elevated faecal calprotectin was frequent, particularly if PI, and it was not related to gastrointestinal symptoms or malnutrition. Elevated faecal calprotectin was present in patients with histological evidence of rectal inflammation. Faecal calprotectin may be an indicator of asymptomatic rectal inflammation in PwCF.

PMID:36053631 | DOI:10.1136/bmjpo-2022-001422

Cochrane Database Syst Rev. 2022 Sep 2;9:CD002204. doi: 10.1002/14651858.CD002204.pub5.

ABSTRACT

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is an allergic reaction to colonisation of the lungs with the fungus Aspergillus fumigatus, and affects around 10% of people with cystic fibrosis. ABPA is associated with an accelerated decline in lung function. High doses of corticosteroids are the main treatment for ABPA; although the long-term benefits are not clear, and their many side effects are well-documented. A group of compounds, the azoles, have activity against A fumigatus, and have been proposed as an alternative treatment for ABPA. Of this group, itraconazole is the most active. A separate antifungal compound, amphotericin B, has been used in aerosolised form to treat invasive infection with A fumigatus, and may have potential for the treatment of ABPA. Antifungal therapy for ABPA in cystic fibrosis needs to be evaluated. This is an update of a previously published review.

OBJECTIVES: The review aimed to test the hypotheses that antifungal interventions for the treatment of ABPA in cystic fibrosis: 1. improve clinical status compared to placebo or standard therapy (no placebo); and 2. do not have unacceptable adverse effects. If benefit was demonstrated, we planned to assess the optimal type, duration, and dose of antifungal therapy.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, and abstract books of conference proceedings. Date of the most recent search of the Group's Trials Register was 28 September 2021. We searched ongoing trials registries, most recently on 11 March 2022. Earlier, we also approached pharmaceutical companies regarding possible unpublished trials.

SELECTION CRITERIA: Published or unpublished randomised controlled trials, in which antifungal treatments were compared to either placebo or no treatment, or where different doses of the same treatment were used in the treatment of ABPA in people with cystic fibrosis.

DATA COLLECTION AND ANALYSIS: The searches identified six trials; none of which met the inclusion criteria for the review.

MAIN RESULTS: We included no completed randomised controlled trials. There is currently one ongoing trial, which we may find eligible for a future update.

AUTHORS' CONCLUSIONS: At present, there are no randomised controlled trials that evaluate the use of antifungal therapies for the treatment of ABPA in people with cystic fibrosis, although one trial is currently ongoing. Trials with clear outcome measures are needed to properly evaluate the use of corticosteroids in people with ABPA and cystic fibrosis.

PMID:36053129 | DOI:10.1002/14651858.CD002204.pub5

Am J Clin Exp Urol. 2022 Aug 15;10(4):246-251. eCollection 2022.

ABSTRACT

BACKGROUND: Given the association between chronic sodium losses and growth parameters and establishment of normal weight gain and linear growth in patients with cystic fibrosis (CF), in this study, we aimed to evaluate the sodium status in Iranian CF patients and its association with their growth parameters.

METHODS: In this prospective cross-sectional study, 44 children with CF were included. Serum and urinary sodium and creatinine levels were measured in patients, and the fractional excretion of sodium was calculated. The patients categorized in groups with FENa <0.5%, between 0.5% and 1.5% and >1.5%. Growth parameters were compared in the group, and its association with FENa level was evaluated.

RESULTS: In this study, 44 (27 boys and 17 girls) children with CF were included. Mean age of the studied population was 55.63 (33.2) months. In the studied patients with CF, 90.9% had a z score of -2_+2 (normal range) for BMI, 72.7% for weight, and 70% for height. From children with CF, 18 (40.9%) had FENa less than 0.5, 17 (38.6%) had FENA between 0.5-1.5, and 9 had FENa >1.5. From studied patients with CF, 16 (88.9%) had normal serum Na levels, but the FENa was ≤0.5. Based on the Spearman correlation test, there was not any significant correlation between FENa classification and the Z score of weight (P=0.92), height (P=0.83), and BMI (P=0.99).

CONCLUSION: Our findings indicated that most patients with a low level of FENa had normal serum sodium levels. We did not find a significant association between FENa and growth parameters. The association had a trend to be significant for BMI. It is suggested that it may be due to appropriate follow-up of the studied population. However, it is recommended to plan more studies by including healthy subjects to obtain results that are more accurate.

PMID:36051617 | PMC:PMC9428568

J Allergy Clin Immunol. 2022 Aug 29:S0091-6749(22)01022-3. doi: 10.1016/j.jaci.2022.07.012. Online ahead of print.

NO ABSTRACT

PMID:36050126 | DOI:10.1016/j.jaci.2022.07.012

Microb Pathog. 2022 Aug 29:105742. doi: 10.1016/j.micpath.2022.105742. Online ahead of print.

ABSTRACT

Inquilinus limosus is an emerging multi-resistant opportunistic pathogen documented mainly in cystic fibrosis patients. Infection with I. limosus is accompanied by either an acute respiratory exacerbation or a progressive loss of pulmonary function. This study examined the interaction of Inquilinus limosus with the bronquial human epithelial cell line 16HBE14o-. Almost 100% of the bacteria that attached to the bronquial cells were found internalized and located in acidic LAMP2 positive compartments. According to confocal studies combined with antibiotic protection assays, I. limosus is able to survive and eventually replicate in these compartments. I. limosus was found nontoxic to cells and did not induce neither IL-6 nor IL-8 cytokine production, a characteristic that may help the bacteria to evade host immune response. Overall, this study indicates that I. limosus displays pathogenic properties based on its ability to survive intracellularly in epithelial cells eventually leading to antibiotic failure and chronic infection.

PMID:36049652 | DOI:10.1016/j.micpath.2022.105742

Respir Med. 2022 Aug 22;202:106953. doi: 10.1016/j.rmed.2022.106953. Online ahead of print.

NO ABSTRACT

PMID:36049345 | DOI:10.1016/j.rmed.2022.106953

Hum Mol Genet. 2022 Sep 1:ddac221. doi: 10.1093/hmg/ddac221. Online ahead of print.

ABSTRACT

INTRODUCTION AND AIM OF STUDY: The signal transducer and activator of transcription 3 (STAT3) has been identified as one of the cystic fibrosis (CF) modifying genes. In this study, we aimed to assess the association between STAT3 genotype and CF patient survival over several decades and to investigate the effect of STAT3 inhibition on epithelial CFTR expression.

METHODS: We analyzed the informative genetic marker STAT3Sat for its association with survival in 174 p.Phe508del-CFTR homozygous CF patients treated at the CF center in Hannover spanning birth cohorts from > 3 decades (1959 to 1994). Furthermore, we treated two epithelial cell lines with STAT3 inhibitors and monitored changes of CFTR protein expression by western blot.

RESULTS: Only for p.Phe508del-CFTR homozygous patients born prior to 1975, survival was significantly influenced by STAT3sat genotype (p = 0.023). The expression levels of STAT3 and CFTR positively correlated in epithelial cell lines (p = 0.01).

CONCLUSIONS: Our results in different birth cohorts identified a time-dependent impact of STAT3 genotype on CF patients' survival and found that improved symptomatic treatment of later-born CF patients obviates STAT3's modifying influence. Consistent with our previous results, STAT3-specific inhibition resulted in increased CFTR expression in the epithelial cell line 16HBE14o-. Thus, care should be taken when CF modifying genes are studied in cross-sectional cohorts as the impact of modifying genes might not be invariant in the light of changing therapeutic regimens.

PMID:36048831 | DOI:10.1093/hmg/ddac221

ACS Infect Dis. 2022 Sep 1. doi: 10.1021/acsinfecdis.2c00196. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is a highly antibiotic-resistant opportunistic pathogenic bacteria that is responsible for thousands of deaths each year. Infections with P. aeruginosa disproportionately impact individuals with compromised immune systems as well as cystic fibrosis patients, where P. aeruginosa lung infection is a leading cause of morbidity and mortality. In previous work, we showed that a combination of gallium (Ga) nitrate and Ga protoporphyrin worked well in several bacterial infection models but its mechanism of action (MOA) is unknown. In the current work, we have investigated the MOA of Ga combination therapy in P. aeruginosa and its analysis in the in vivo model. In P. aeruginosa treated with Ga combination therapy, we saw a decrease in catalase and superoxide dismutase (SOD) activity, key antioxidant enzymes, which could correlate with a higher potential for oxidative stress. Consistent with this hypothesis, we found that, following combination therapy, P. aeruginosa demonstrated higher levels of reactive oxygen species, as measured using the redox-sensitive fluorescent probe, H2DCFDA. We also saw that the Ga combination therapy killed phagocytosed bacteria inside macrophages in vitro. The therapy with low dose was able to fully prevent mortality in a murine model of P. aeruginosa lung infection and also significantly reduced lung damage. These results support our previous data that Ga combination therapy acts synergistically to kill P. aeruginosa, and we now show that this may occur through increasing the organism's susceptibility to oxidative stress. Ga combination therapy also showed itself to be effective at treating infection in a murine pulmonary-infection model.

PMID:36049087 | DOI:10.1021/acsinfecdis.2c00196

Cochrane Database Syst Rev. 2022 Sep 1;9:CD002202. doi: 10.1002/14651858.CD002202.pub3.

ABSTRACT

BACKGROUND: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review.

OBJECTIVES: The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022.

SELECTION CRITERIA: Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD.

DATA COLLECTION AND ANALYSIS: Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE.

MAIN RESULTS: We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence).

AUTHORS' CONCLUSIONS: There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.

PMID:36047926 | DOI:10.1002/14651858.CD002202.pub3

J Clin Res Pediatr Endocrinol. 2022 Sep 1. doi: 10.4274/jcrpe.galenos.2022.2022-5-20. Online ahead of print.

ABSTRACT

Gastroparesis is a long-term complication of diabetes related to autonomic neuropathy. It is clinically characterized by delayed gastric emptying and upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Gastric emptying scintigraphy is the gold standard for the diagnosis as it reveals delayed gastric emptying. Therapeutic strategies include dietary modifications, improvement of glycemic control, and prokinetic drugs. Case descriptions of diabetic gastroparesis in pediatric age are very scarce. We hereby report the case of a 16-year-old adolescent with severe presentation of diabetic gastroparesis. She presented with recurrent episodes of nausea, vomiting and abdominal pain which led progressively to reduced oral intake and weight loss. Her past glycemic control had been quite brittle as demonstrated by several hospitalizations due to diabetic ketoacidosis and recurrent episodes of severe hypoglycemia. After the exclusion of infectious, mechanical, metabolic, and neurological causes of vomiting, a gastric emptying scintigraphy was performed, leading to the diagnosis of gastroparesis. Treatment with metoclopramide was started with progressive relief of symptoms. To improve glycemic control, insulin therapy with advanced hybrid closed loop system was successfully practiced. Pediatricians should seriously consider diabetic gastroparesis in children and adolescents with long-standing, poorly controlled diabetes.

PMID:36047486 | DOI:10.4274/jcrpe.galenos.2022.2022-5-20

Front Pediatr. 2022 Aug 15;10:941852. doi: 10.3389/fped.2022.941852. eCollection 2022.

ABSTRACT

Traditional approaches to understanding the origins of chronic pancreatitis (CP) and find treatments led to abysmal failure. Thus, no drugs now exists to meet this need. Outdated concepts of the etiopathogenesis of CP have been replaced with new insights and disease models that provide the framework for early detection of the pathogenic pancreatitis process. Application of these principals require a new paradigm in disease definition and management, i.e. personalized / precision medicine. The key is acute pancreatitis (AP) starting with the first (sentinel) acute pancreatitis (AP) event (SAPE). This event sensitizes the pancreas to recurrent acute pancreatitis (RAP) as ongoing stressors drive various inflammatory responses to cause CP. The problem is the complex etiologies of AP and the additional genetic and environmental factors that promote progression to RAP and CP. This paper provides a background on the key conceptual changes that facilitate new approaches and the rationale for using mechanism-specific therapies to prevent RAP and CP.

PMID:36046477 | PMC:PMC9421067 | DOI:10.3389/fped.2022.941852

Cell Mol Life Sci. 2022 Sep;79(9):503. doi: 10.1007/s00018-022-04528-3. Epub 2022 Sep 1.

ABSTRACT

Early recognition and enhanced degradation of misfolded proteins by the endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) cause defective protein secretion and membrane targeting, as exemplified for Z-alpha-1-antitrypsin (Z-A1AT), responsible for alpha-1-antitrypsin deficiency (A1ATD) and F508del-CFTR (cystic fibrosis transmembrane conductance regulator) responsible for cystic fibrosis (CF). Prompted by our previous observation that decreasing Keratin 8 (K8) expression increased trafficking of F508del-CFTR to the plasma membrane, we investigated whether K8 impacts trafficking of soluble misfolded Z-A1AT protein. The subsequent goal of this study was to elucidate the mechanism underlying the K8-dependent regulation of protein trafficking, focusing on the ERAD pathway. The results show that diminishing K8 concentration in HeLa cells enhances secretion of both Z-A1AT and wild-type (WT) A1AT with a 13-fold and fourfold increase, respectively. K8 down-regulation triggers ER failure and cellular apoptosis when ER stress is jointly elicited by conditional expression of the µs heavy chains, as previously shown for Hrd1 knock-out. Simultaneous K8 silencing and Hrd1 knock-out did not show any synergistic effect, consistent with K8 acting in the Hrd1-governed ERAD step. Fractionation and co-immunoprecipitation experiments reveal that K8 is recruited to ERAD complexes containing Derlin2, Sel1 and Hrd1 proteins upon expression of Z/WT-A1AT and F508del-CFTR. Treatment of the cells with c407, a small molecule inhibiting K8 interaction, decreases K8 and Derlin2 recruitment to high-order ERAD complexes. This was associated with increased Z-A1AT secretion in both HeLa and Z-homozygous A1ATD patients' respiratory cells. Overall, we provide evidence that K8 acts as an ERAD modulator. It may play a scaffolding protein role for early-stage ERAD complexes, regulating Hrd1-governed retrotranslocation initiation/ubiquitination processes. Targeting K8-containing ERAD complexes is an attractive strategy for the pharmacotherapy of A1ATD.

PMID:36045259 | DOI:10.1007/s00018-022-04528-3

J Cyst Fibros. 2022 Aug 28:S1569-1993(22)00647-6. doi: 10.1016/j.jcf.2022.08.010. Online ahead of print.

ABSTRACT

BACKGROUND: Long-term treatment with inhaled antibiotics is recommended for people with cystic fibrosis (pwCF) chronically infected with Pseudomonas aeruginosa (PA). However, pwCF without chronic PA infection are also commonly treated with inhaled antibiotics. Using data from the European Cystic Fibrosis Patient Registry (ECFSPR) we aimed to determine the prevalence and factors associated with inhaled antibiotic treatment in pwCF without chronic PA infection, and long-term outcomes with inhaled antibiotics use.

METHODS: The ECFSPR was searched for pwCF 6 years of age and older who were not chronically infected with PA at baseline. Factors associated with inhaled antibiotic use were first assessed through a logistic regression. From this model a propensity score was computed for each individual, providing the likelihood of being treated with inhaled antibiotics. Long-term outcomes with and without inhaled antibiotics were assessed separately for propensity scores tertiles.

RESULTS: 7210 pwCF without chronic PA infection at baseline were included, with 2722 (37.75%) receiving long-term treatment with inhaled antibiotics. Treatment with inhaled antibiotics was more prevalent with severe genotype, diabetes, pancreatic insufficiency, and past infection with chronic PA (OR 3.8, 95% CI, 2.88-5.04). Treatment with inhaled antibiotics was not associated with a reduced risk for acquisition of PA or other resistant pathogens, or with improved lung function decline, mortality, or transplantation.

CONCLUSIONS: Many pwCF without chronic PA infection are receiving long-term treatment with inhaled antibiotics despite lack of support from clinical trials or practice guidelines. We did not observe improve outcomes with inhaled antibiotics. Our findings suggest controlled studies evaluating specific inhaled antibiotic regimens targeting specific pathogens or indications be performed to determine their effect.

PMID:36045028 | DOI:10.1016/j.jcf.2022.08.010

Ann Am Thorac Soc. 2022 Aug 31. doi: 10.1513/AnnalsATS.202203-201OC. Online ahead of print.

ABSTRACT

RATIONALE: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment.

OBJECTIVES: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx is associated with improved clinical outcomes compared to treatment without systemic corticosteroids.

METHODS: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006-2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighing was used.

RESULTS: 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36, 95% CI: -1.14, 0.42; p=0.4) or a higher odds of returning to lung function baseline (odds ratio (OR), 0.97, 95% CI: 0.84-1.12; p=0.7), but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio (HR), 0.91 (95% CI: 0.85-0.96; p=0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (HR 0.96 (95% CI: 0.86, 1.07; p=0.42).

CONCLUSIONS: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

PMID:36044723 | DOI:10.1513/AnnalsATS.202203-201OC

IEEE Pulse. 2022 Jul-Aug;13(4):14-19. doi: 10.1109/MPULS.2022.3191445.

ABSTRACT

Ions can say a lot about a baby's health. High levels of chloride in sweat can indicate cystic fibrosis (CF), a disorder that causes respiratory and digestive problems; abnormal sodium levels are signs of increased risk for seizure or muscle problems; and too-high or too-low potassium concentrations can cause heart arrhythmias or other muscle issues. These ions-commonly called electrolytes- are also important throughout life. For instance, too much or too little sodium can lead to confusion, seizures, and muscle weakness or cramping.

PMID:36044473 | DOI:10.1109/MPULS.2022.3191445