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Pharmaceutics Jun 2024Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug...
Dry-powder inhalers (DPIs) are valued for their stability but formulating them is challenging due to powder aggregation and limited flowability, which affects drug delivery and uniformity. In this study, the incorporation of L-leucine (LEU) into hot-melt extrusion (HME) was proposed to enhance dispersibility while simultaneously maintaining the high aerodynamic performance of inhalable microparticles. This study explored using LEU in HME to improve dispersibility and maintain the high aerodynamic performance of inhalable microparticles. Formulations with crystalline itraconazole (ITZ) and LEU were made via co-jet milling and HME followed by jet milling. The LEU ratio varied, comparing solubility, homogenization, and aerodynamic performance enhancements. In HME, ITZ solubility increased, and crystallinity decreased. Higher LEU ratios in HME formulations reduced the contact angle, enhancing mass median aerodynamic diameter (MMAD) size and aerodynamic performance synergistically. Achieving a maximum extra fine particle fraction of 33.68 ± 1.31% enabled stable deep lung delivery. This study shows that HME combined with LEU effectively produces inhalable particles, which is promising for improved drug dispersion and delivery.
PubMed: 38931905
DOI: 10.3390/pharmaceutics16060784 -
Nutrients Jun 2024: Modulator therapies improve weight and body mass index (BMI) in cystic fibrosis (CF) patients. We aimed to compare the nutritional risk index (NRI) in adult CF...
: Modulator therapies improve weight and body mass index (BMI) in cystic fibrosis (CF) patients. We aimed to compare the nutritional risk index (NRI) in adult CF patients receiving modulator (MT) or only non-modulator (conventional) therapies (non-MT). : A single-center prospective cohort study was conducted between June and December 2023. The NRI based on weight gain and albumin was calculated at beginning and end of a 12-week period in both groups. This design was pragmatic, since it was based on individual patient access to MT for 12 weeks. : In total, 107 patients were included [mean (SD) age: 23.85 (4.98) years, 54.7% male, 46.7% MT]. In the MT group, mean (SD) weight (kg) and albumin (g/dL) increased significantly [changes: +3.09 (2.74) and +0.17 (0.37); < 0.001]. In the non-MT group, weight and albumin decreased significantly [changes: -0.99 (1.73) and -0.12 (0.30); < 0.001]. Compared to the MT group, baseline mean (SD) NRI in the non-MT group was significantly higher [100.65 (11.80) vs. 104.10 (10.10); = 0.044]. At the end of the 12 weeks, mean (SD) NRI in the MT group was higher than in the non-MT group [104.18 (10.40) vs. 102.58 (12.39); = 0.145]. In the MT group, the NRI category improved in 22 (44%), and worsened in 3 (6%) patients ( < 0.001). In the non-MT group, the NRI category improved in 2 (3.5%), and worsened in 10 (17.5%) patients ( < 0.001). : This is the first study reporting on a positive effect of MT on NRIs, based on weight gain and albumin. Personalized nutrition and routine follow-up of adults with CF based on NRI is recommended prior to MT initiation.
Topics: Humans; Cystic Fibrosis; Male; Prospective Studies; Female; Adult; Nutritional Status; Young Adult; Body Mass Index; Weight Gain; Nutrition Assessment; Cohort Studies; Serum Albumin; Adolescent; Risk Factors
PubMed: 38931166
DOI: 10.3390/nu16121811 -
Nutrients Jun 2024The metabolic-status-related mechanisms underlying the deterioration of the lung function in obese asthma have not been completely elucidated.
BACKGROUND
The metabolic-status-related mechanisms underlying the deterioration of the lung function in obese asthma have not been completely elucidated.
OBJECTIVE
This study aimed to investigate the basal metabolic rate (BMR) in patients with obese asthma, its association with the lung function, and its mediating role in the impact of obesity on the lung function.
METHODS
A 12-month prospective cohort study (n = 598) was conducted in a real-world setting, comparing clinical, body composition, BMR, and lung function data between patients with obese (n = 282) and non-obese (n = 316) asthma. Path model mediation analyses for the BMR and skeletal muscle mass (SMM) were conducted. We also explored the effects of the BMR on the long-term lung function in patients with asthma.
RESULTS
Patients with obese asthma exhibited greater airway obstruction, with lower FEV (1.99 vs. 2.29 L), FVC (3.02 vs. 3.33 L), and FEV/FVC (65.5 vs. 68.2%) values compared to patients with non-obese asthma. The patients with obese asthma also had higher BMRs (1284.27 vs. 1210.08 kcal/d) and SMM (23.53 vs. 22.10 kg). Both the BMR and SMM mediated the relationship between obesity and the lung function spirometers (FEV, %FEV, FVC, %FVC, and FEV/FVC). A higher BMR or SMM was associated with better long-term lung function.
CONCLUSIONS
Our study highlights the significance of the BMR and SMM in mediating the relationship between obesity and spirometry in patients with asthma, and in determining the long-term lung function. Interventions for obese asthma should focus not only on reducing adiposity but also on maintaining a high BMR.
Topics: Humans; Asthma; Obesity; Prospective Studies; Male; Female; Basal Metabolism; Middle Aged; Lung; Adult; Muscle, Skeletal; Respiratory Function Tests; Body Composition; Cohort Studies
PubMed: 38931162
DOI: 10.3390/nu16121809 -
Molecules (Basel, Switzerland) Jun 2024An untargeted metabolomic study identified four potential lung cancer diagnostic biomarkers in human urine. One of the potential biomarkers was an unidentified feature...
An untargeted metabolomic study identified four potential lung cancer diagnostic biomarkers in human urine. One of the potential biomarkers was an unidentified feature possessing a / value of 561+. "561+" was isolated from human urine and tentatively identified as 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol glucuronide with unknown C24,25 stereochemistry using H NMR and mass spectrometry. In a prior report, the C24,25 stereochemistry of the aglycone, 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol, was found to be 24,25 through GC analysis of the acetonide-TMS derivative. An authentic sample was prepared and found not to have the same stereochemistry as "561+". To identify the C24,25 stereochemistry, four C24,C25 diastereoisomeric alcohols of 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol were prepared from chiral amino acids. Using an LCMS method, the C24,C25 stereochemistry of the "561+" aglycone was determined to be 24,25. With the correct aglycone in hand, it was coupled with glucuronic acid to complete the first reported synthesis of 27-nor-5β-cholestane-3α,7α,12α,24,25S pentol glucuronide. Deuterium labeled 27-nor-5β-cholestane-3α,7α,12α,24,25 pentol was also synthesized for use as an internal standard for MS quantitation.
Topics: Humans; Lung Neoplasms; Biomarkers, Tumor; Glucuronides; Deuterium; Male; Female
PubMed: 38930845
DOI: 10.3390/molecules29122781 -
Journal of Clinical Medicine Jun 2024The incidence of obesity and asthma continues to enhance, significantly impacting global public health. Adipose tissue is an organ that secretes hormones and cytokines,... (Review)
Review
The incidence of obesity and asthma continues to enhance, significantly impacting global public health. Adipose tissue is an organ that secretes hormones and cytokines, causes meta-inflammation, and contributes to the intensification of bronchial hyperreactivity, oxidative stress, and consequently affects the different phenotypes of asthma in obese people. As body weight increases, the risk of severe asthma increases, as well as more frequent exacerbations requiring the use of glucocorticoids and hospitalization, which consequently leads to a deterioration of the quality of life. This review discusses the relationship between obesity and severe asthma, the underlying molecular mechanisms, changes in respiratory function tests in obese people, its impact on the occurrence of comorbidities, and consequently, a different response to conventional asthma treatment. The article also reviews research on possible future therapies for severe asthma. The manuscript is a narrative review of clinical trials in severe asthma and comorbid obesity. The articles were found in the PubMed database using the keywords asthma and obesity. Studies on severe asthma were then selected for inclusion in the article. The sections: 'The classification connected with asthma and obesity', 'Obesity-related changes in pulmonary functional tests', and 'Obesity and inflammation', include studies on subjects without asthma or non-severe asthma, which, according to the authors, familiarize the reader with the pathophysiology of obesity-related asthma.
PubMed: 38930006
DOI: 10.3390/jcm13123474 -
Journal of Clinical Medicine Jun 2024The association of obesity with right ventricular function and the interplay between right heart and pulmonary circulation is incompletely understood. We evaluate the...
The association of obesity with right ventricular function and the interplay between right heart and pulmonary circulation is incompletely understood. We evaluate the role of obesity as a determinant of right ventricular-pulmonary artery coupling (RVAC). We retrospectively studied consecutive subjects without overt cardiovascular or pulmonary disease. Subjects were stratified according to body mass index (BMI) as normal weight, overweight, or obese. A transthoracic echocardiographic study was used to assess left and right heart functional and structural parameters. RVAC was assessed using the ratio of peak systolic velocity of the tricuspid annulus to pulmonary artery systolic pressure (PASP). A total of 145 subjects were enrolled with diabetes mellitus incidence higher in obese. There was no difference in left ventricular global longitudinal strain and in PASP or markers of right ventricular systolic function based on BMI. RVAC was significantly lower in the presence of obesity (normal weight: 0.52 (0.19) cm·(sec·mmHg) vs. overweight: 0.47 (0.16) cm·(sec·mmHg) vs. obese: 0.43 (0.14) cm·(sec·mmHg), = 0.03), even after adjustment for confounders (β: -0.085, 95% confidence interval: -0.163, -0.009, = 0.029). Our findings highlight the relationship between metabolic impairment and RVAC, suggesting additional mechanisms for heart failure development observed in obese subjects.
PubMed: 38929919
DOI: 10.3390/jcm13123389 -
Journal of Clinical Medicine Jun 2024Disorders of mucociliary clearance, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and bronchiectasis of unknown origin, are characterised by periods... (Review)
Review
Disorders of mucociliary clearance, such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and bronchiectasis of unknown origin, are characterised by periods with increased respiratory symptoms, referred to as pulmonary exacerbations. These exacerbations are hard to predict and associated with lung function decline and the loss of quality of life. To optimise treatment and preserve lung function, there is a need for non-invasive and reliable methods of detection. Breath analysis might be such a method. We systematically reviewed the existing literature on breath analysis to detect pulmonary exacerbations in mucociliary clearance disorders. Extracted data included the study design, technique of measurement, definition of an exacerbation, identified compounds and diagnostic accuracy. Out of 244 identified articles, 18 were included in the review. All studies included patients with CF and two also with PCD. Age and the definition of exacerbation differed between the studies. There were five that measured volatile organic compounds (VOCs) in exhaled breath using gas chromatography with mass spectrometry, two using an electronic nose and eleven measured organic compounds in exhaled breath condensate. Most studies showed a significant correlation between pulmonary exacerbations and one or multiple compounds, mainly hydrocarbons and cytokines, but the validation of these results in other studies was lacking. The detection of pulmonary exacerbations by the analysis of compounds in exhaled breath seems possible but is not near clinical application due to major differences in results, study design and the definition of an exacerbation. There is a need for larger studies, with a longitudinal design, international accepted definition of an exacerbation and validation of the results in independent cohorts.
PubMed: 38929901
DOI: 10.3390/jcm13123372 -
Medicina (Kaunas, Lithuania) May 2024: Renal haemangioma is a benign tumour, and due to its characteristics, it must be distinguished from malignant diseases. We present a clinical case of primary renal...
: Renal haemangioma is a benign tumour, and due to its characteristics, it must be distinguished from malignant diseases. We present a clinical case of primary renal angiosarcoma initially mistaken for haemangioma due to their similarity. : A 58-year-old man was admitted to the hospital with suspicion of pulmonary embolism. The patient complained of pain on the left side. An ultrasound and CT scan of the abdomen showed a tumour mass ~20.5 × 17.2 × 15.4 cm in size in the projection of the left kidney. On CT images, there were data for clear cell renal clear cell carcinoma (ccRCC). A left nephrectomy was performed. However, histological examination revealed renal haemangioma. Three months later, the patient presented to the hospital with abdominal and lumbar pain. A CT scan showed multiple small hypoechoic foci up to 2 cm in size in the liver, lungs, and intra-abdominally, with the most data for carcinosis. Histological re-verification of the left kidney showed a renal vascular tumour with pronounced signs of infarction and necrosis with the majority of the evidence supporting angiosarcoma. Despite treatment, the patient's outcome was fatal. : Based on the clinical presentation, radiological images and histological examination data, the tumour was initially misdiagnosed as kidney haemangioma. Due to the rarity of this tumour, there are no established treatment protocols or clinical guidelines for managing primary kidney angiosarcoma.
Topics: Humans; Male; Middle Aged; Hemangiosarcoma; Kidney Neoplasms; Fatal Outcome; Tomography, X-Ray Computed; Nephrectomy
PubMed: 38929502
DOI: 10.3390/medicina60060885 -
International Journal of Molecular... Jun 2024The gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result...
The gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all exocrine glands and, therefore, the multi-organ disease cystic fibrosis (CF). In recent years, several studies have reported on CFTR expression in immune cells as demonstrated by immunofluorescence, flow cytometry, and immunoblotting. However, these data are mainly restricted to single-cell populations and show significant variation depending on the methodology used. Here, we investigated transcription and protein expression using standardized protocols in a comprehensive panel of immune cells. Methods: We applied a high-resolution Western blot protocol using a combination of highly specific monoclonal CFTR antibodies that have been optimized for the detection of CFTR in epithelial cells and healthy primary immune cell subpopulations sorted by flow cytometry and used immortalized cell lines as controls. The specificity of CFTR protein detection was controlled by peptide competition and enzymatic Peptide-N-Glycosidase-F (PNGase) digest. transcripts were analyzed using quantitative real-time PCR and normalized to the level of epithelial T84 cells as a reference. Results: mRNA expression could be shown for primary CD4 T cells, NK cells, as well as differentiated THP-1 and Jurkat T cells. In contrast, we failed to detect transcripts for CD14 monocytes and undifferentiated THP-1 cells, as well as for B cells and CD8 T cells. Prominent immunoreactive bands were detectable by immunoblotting with the combination of four CFTR antibodies targeting different epitopes of the CFTR protein. However, in biosamples of non-epithelial origin, these CFTR-like protein bands could be unmasked as false positives through peptide competition or PNGase digest, meaning that the observed mRNA transcripts were not necessarily translated into CFTR proteins, which could be detected via immunoblotting. Our results confirm that mRNA expression in immune cells is many times lower than in that cells of epithelial origin. The immunoreactive signals in immune cells turned out to be false positives, and may be provoked by the presence of a high-affinity protein with a similar epitope. Non-specific binding (e.g., Fab-interaction with glycosyl branches) might also contribute to false positive signals. Our findings highlight the necessity of accurate controls, such as CFTR-negative cells, as well as peptide competition and glycolytic digest in order to identify genuine CFTR protein by immunoblotting. Our data suggest, furthermore, that CFTR protein expression data from techniques such as histology, for which the absence of a molecular weight or other independent control prevents the unmasking of false positive immunoreactive signals, must be interpreted carefully as well.
Topics: Cystic Fibrosis Transmembrane Conductance Regulator; Humans; RNA, Messenger; Leukocytes, Mononuclear; Blotting, Western; Real-Time Polymerase Chain Reaction; Cystic Fibrosis; Killer Cells, Natural; Flow Cytometry; CD4-Positive T-Lymphocytes
PubMed: 38928073
DOI: 10.3390/ijms25126367 -
BMC Medicine Jun 2024Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current...
BACKGROUND
Evidence from observational studies indicates that lung cancer screening (LCS) guidelines with high rates of lung cancer (LC) underdiagnosis, and although current screening guidelines have been updated and eligibility criteria for screening have been expanded, there are no studies comparing the efficiency of LCS guidelines in Chinese population.
METHODS
Between 2005 and 2022, 31,394 asymptomatic individuals were screened using low-dose computed tomography (LDCT) at our institution. Demographic data and relevant LC risk factors were collected. The efficiency of the LCS for each guideline criteria was expressed as the efficiency ratio (ER). The inclusion rates, eligibility rates, LC detection rates, and ER based on the different eligibility criteria of the four guidelines were comparatively analyzed. The four guidelines were as follows: China guideline for the screening and early detection of lung cancer (CGSL), the National Comprehensive Cancer Network (NCCN), the United States Preventive Services Task Force (USPSTF), and International Early Lung Cancer Action Program (I-ELCAP).
RESULTS
Of 31,394 participants, 298 (155 women, 143 men) were diagnosed with LC. For CGSL, NCCN, USPSTF, and I-ELCAP guidelines, the eligibility rates for guidelines were 13.92%, 6.97%, 6.81%, and 53.46%; ERe for eligibility criteria were 1.46%, 1.64%, 1.51%, and 1.13%, respectively; and for the inclusion rates, they were 19.0%, 9.5%, 9.3%, and 73.0%, respectively. LCs which met the screening criteria of CGSL, NCCN, USPSTF, and I-ELCAP guidelines were 29.2%, 16.4%, 14.8%, and 86.6%, respectively. The age and smoking criteria for CGSL were stricter, hence resulting in lower rates of LC meeting the screening criteria. The CGSL, NCCN, and USPSTF guidelines showed the highest underdiagnosis in the 45-49 age group (17.4%), while the I-ELCAP guideline displayed the highest missed diagnosis rate (3.0%) in the 35-39 age group. Males and females significantly differed in eligibility based on the criteria of the four guidelines (P < 0.001).
CONCLUSIONS
The I-ELCAP guideline has the highest eligibility rate for both males and females. But its actual efficiency ratio for those deemed eligible by the guideline was the lowest. Whereas the NCCN guideline has the highest ERe value for those deemed eligible by the guideline.
Topics: Humans; Lung Neoplasms; Male; China; Female; Tomography, X-Ray Computed; Middle Aged; Early Detection of Cancer; Aged; Practice Guidelines as Topic; Mass Screening; Adult
PubMed: 38926820
DOI: 10.1186/s12916-024-03445-5