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Frontiers in Pediatrics 2024In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary... (Review)
Review
In contrast to significant declines in deaths due to lung cancer and cardiac disease in Westernised countries, the mortality due to 'chronic obstructive pulmonary disease' (COPD) has minimally changed in recent decades while 'the incidence of bronchiectasis' is on the rise. The current focus on producing guidelines for these two airway 'diseases' has hindered progress in both treatment and prevention. The elephant in the room is that neither COPD nor bronchiectasis is a disease but rather a consequence of progressive untreated airway inflammation. To make this case, it is important to review the evolution of our understanding of airway disease and how a pathological appearance (bronchiectasis) and an arbitrary physiological marker of impaired airways (COPD) came to be labelled as 'diseases'. Valuable insights into the natural history of airway disease can be obtained from the pre-antibiotic era. The dramatic impacts of antibiotics on the prevalence of significant airway disease, especially in childhood and early adult life, have largely been forgotten and will be revisited as will the misinterpretation of trials undertaken in those with chronic (bacterial) bronchitis. In the past decades, paediatricians have observed a progressive increase in what is termed 'persistent bacterial bronchitis' (PBB). This condition shares all the same characteristics as 'chronic bronchitis', which is prevalent in young children during the pre-antibiotic era. Additionally, the radiological appearance of bronchiectasis is once again becoming more common in children and, more recently, in adults. Adult physicians remain sceptical about the existence of PBB; however, in one study aimed at assessing the efficacy of antibiotics in adults with persistent symptoms, researchers discovered that the majority of patients exhibiting symptoms of PBB were already on long-term macrolides. In recent decades, there has been a growing recognition of the importance of the respiratory microbiome and an understanding of the ability of bacteria to persist in potentially hostile environments through strategies such as biofilms, intracellular communities, and persister bacteria. This is a challenging field that will likely require new approaches to diagnosis and treatment; however, it needs to be embraced if real progress is to be made.
PubMed: 38910961
DOI: 10.3389/fped.2024.1391290 -
Journal of Nanobiotechnology Jun 2024Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our...
Recently, environmental temperature has been shown to regulate bone homeostasis. However, the mechanisms by which cold exposure affects bone mass remain unclear. In our present study, we observed that exposure to cold temperature (CT) decreased bone mass and quality in mice. Furthermore, a transplant of exosomes derived from the plasma of mice exposed to cold temperature (CT-EXO) can also impair the osteogenic differentiation of BMSCs and decrease bone mass by inhibiting autophagic activity. Rapamycin, a potent inducer of autophagy, can reverse cold exposure or CT-EXO-induced bone loss. Microarray sequencing revealed that cold exposure increases the miR-25-3p level in CT-EXO. Mechanistic studies showed that miR-25-3p can inhibit the osteogenic differentiation and autophagic activity of BMSCs. It is shown that inhibition of exosomes release or downregulation of miR-25-3p level can suppress CT-induced bone loss. This study identifies that CT-EXO mediates CT-induced osteoporotic effects through miR-25-3p by inhibiting autophagy via targeting SATB2, presenting a novel mechanism underlying the effect of cold temperature on bone mass.
Topics: Animals; Autophagy; Mice; Exosomes; MicroRNAs; Cold Temperature; Osteogenesis; Mice, Inbred C57BL; Mesenchymal Stem Cells; Osteoporosis; Cell Differentiation; Bone and Bones; Female; Bone Density; Sirolimus
PubMed: 38910236
DOI: 10.1186/s12951-024-02640-z -
Environmental Pollution (Barking, Essex... Jun 2024Domestic wastewater is a significant reservoir of antibiotic resistance genes, which pose environmental and public health risks. We aimed to define an antibiotic...
Domestic wastewater is a significant reservoir of antibiotic resistance genes, which pose environmental and public health risks. We aimed to define an antibiotic resistome signature, represented by core genes, i.e., shared by ≥90% of the metagenomes of each of three conceptual environmental compartments - wastewater (influent, sludge, effluent), freshwater, and agricultural soil. The definition of resistome signatures would support the proposal of a framework for monitoring treatment efficacy and assessing the impact of treated wastewater discharge into the environment, such as freshwater and agricultural soil. Metagenomic data from 163 samples originating from wastewater (n=81), freshwater (n=58), and agricultural soils (n=24) across different regions (29 countries, 5 continents), were analysed regarding antibiotic resistance diversity, based on annotation against a database that merged CARD and ResFinder databases. The relative abundance of the total antibiotic resistance genes (corresponding to the ratio between the antibiotic resistance genes and total reads number) was not statistically different between raw and treated wastewater, being significantly higher than in freshwater or agricultural soils. The latter had the significantly lowest relative abundance of antibiotic resistance genes. Genes conferring resistance to aminoglycosides, beta-lactams, and tetracyclines were among the most abundant in wastewater environments, while multidrug resistance was equally distributed across all environments. The wastewater resistome signature included 27 antibiotic resistance genes that were detected in at least 90% of the wastewater resistomes, and that were not frequent in freshwater or agricultural soil resistomes. Among these were genes responsible for resistance to tetracyclines (n=8), macrolide-lincosamide-streptogramin B (n=7), aminoglycosides (n=4), beta-lactams (n=3), multidrug (n=2), sulphonamides (n=2), and polypeptides (n=1). This comprehensive assessment provides valuable insights into the dynamics of antibiotic resistance in urban wastewater systems and their potential ecological implications in diverse environmental settings. Furthermore, provides guidance for the implementation of One Health monitoring approaches.
PubMed: 38909773
DOI: 10.1016/j.envpol.2024.124424 -
PloS One 2024Syphilis, caused by Treponema pallidum, is resurging globally. Molecular typing allows for the investigation of its epidemiology. In Pakistan and other nations, T....
Syphilis, caused by Treponema pallidum, is resurging globally. Molecular typing allows for the investigation of its epidemiology. In Pakistan and other nations, T. pallidum subsp. pallidum has developed widespread macrolide resistance in the past decade. A study at the Peshawar Regional Blood Centre from June 2020-June 2021 analyzed serum samples from 32,812 blood donors in Khyber Pakhtunkhwa, Pakistan, to assess circulating T. pallidum strains and antibiotic resistance. Blood samples were initially screened for T. pallidum antibodies using a chemiluminescent microparticle immunoassay (CMIA). CMIA-reactive samples underwent polymerase chain reaction (PCR) targeted the polA, tpp47, bmp, and tp0319 genes. PCR-positive samples were further analyzed for molecular subtyping using a CDC-developed procedure and tp0548 gene examination. All PCR-positive samples were analyzed for the presence of point mutations A2058G and A2059G in 23S rRNA, as well as the G1058C mutation in 16S rRNA. These mutations are known to impart antimicrobial resistance to macrolides and doxycycline, respectively. Out of 32,812 serum samples, 272 (0.83%) were CMIA-reactive, with 46 being PCR-positive. Nine T. pallidum subtypes were identified, predominantly 14d/f. The A2058G mutation in 23S rRNA was found in 78% of cases, while G1058C in 16S rRNA and A2059G in 23S rRNA were absent. The research found donor blood useful for assessing T. pallidum molecular subtypes and antibiotic resistance, especially when chancres are not present. The prevalent subtype was 14d/f (51.85%), and the high macrolide resistance of 36 (78%) indicates caution in using macrolides for syphilis treatment in Khyber Pakhtunkhwa, Pakistan.
Topics: Treponema pallidum; Humans; Pakistan; Syphilis; Blood Donors; Anti-Bacterial Agents; Drug Resistance, Bacterial; Male; Female; Adult; Macrolides; RNA, Ribosomal, 23S; RNA, Ribosomal, 16S; Middle Aged; Doxycycline; Young Adult
PubMed: 38905249
DOI: 10.1371/journal.pone.0305720 -
Microbiology Spectrum Jun 2024To analyze the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. Thirteen clinical strains...
To analyze the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. Thirteen clinical strains isolated from 2003 to 2019 were selected, 10 of which were resistant to erythromycin (MIC >64 µg/mL), including 8 P1-type I and 2 P1-type II. Three were sensitive (<1 µg/mL) and P1-type II. One resistant strain had an A→G point mutation at position 2064 in region V of the 23S rRNA, the others had it at position 2063, while the three sensitive strains had no mutation here. Genome assembly and comparative genome analysis revealed a high level of genome consistency within the P1 type, and the primary differences in genome sequences concentrated in the region encoding the P1 protein. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. Clinical information showed seven cases were diagnosed with severe pneumonia, all of which were infected with drug-resistant strains. Notably, BS610A4 and CYM219A1 exhibited a gene multi-copy phenomenon and shared a conserved functional domain with the DUF31 protein family. Clinically, the patients had severe refractory pneumonia, with pleural effusion, necessitating treatment with glucocorticoids and bronchoalveolar lavage. The primary variations between strains occur among different P1-types, while there is a high level of genomic consistency within P1-types. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.IMPORTANCE is an important pathogen of community-acquired pneumonia, and macrolide resistance brings difficulties to clinical treatment. We analyzed the characteristics of as well as macrolide antibiotic resistance through whole-genome sequencing and comparative genomics. The work addressed primary variations between strains that occur among different P1-types, while there is a high level of genomic consistency within P1-types. In P1-type II strains, three specific gene mutations were identified: C162A and A430G in L4 gene and T1112G mutation in the CARDS gene. All the strains isolated from severe pneumonia cases were drug-resistant, two of which exhibited a gene multi-copy phenomenon, sharing a conserved functional domain with the DUF31 protein family. Three mutation loci associated with specific types were identified, and no specific genetic alterations directly related to clinical presentation were observed.
PubMed: 38904371
DOI: 10.1128/spectrum.03615-23 -
PLoS Neglected Tropical Diseases Jun 2024In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.
BACKGROUND
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
TRIAL REGISTRATION
CTRI/2017/04/008421.
Topics: Humans; Amphotericin B; Phosphorylcholine; Bangladesh; Male; Antiprotozoal Agents; Adult; Adolescent; Female; Middle Aged; Young Adult; Child; India; Leishmaniasis, Visceral; Treatment Outcome; Leishmaniasis, Cutaneous; Drug Therapy, Combination
PubMed: 38900786
DOI: 10.1371/journal.pntd.0012242 -
Microbiology (Reading, England) Jun 2024Long-term administration of certain macrolides is efficacious in patients with persistent pulmonary infection, despite how limited the clinically achievable...
Long-term administration of certain macrolides is efficacious in patients with persistent pulmonary infection, despite how limited the clinically achievable concentrations are, being far below their MICs. An increase in the sub-MIC of macrolide exposure-dependent sensitivity to nitrosative stress is a typical characteristic of . However, a few clinical isolates do not respond to sub-MIC of macrolide treatment. Therefore, we examined the effects of sub-MIC of erythromycin (EM) on the sensitivity to nitrosative stress together with an efflux pump inhibitor (EPI) phenylalanine arginyl β-naphthylamide (PAβN). The sensitivity to nitrosative stress increased, suggesting that the efflux pump was involved in inhibiting the sub-MIC of macrolide effect. Analysis using efflux pump-mutant revealed that MexAB-OprM, MexXY-OprM, and MexCD-OprJ are factors in reducing the sub-MIC of macrolide effect. Since macrolides interfere with quorum sensing (QS), we demonstrated that the QS-interfering agent furanone C-30 (C-30) producing greater sensitivity to nitric oxide (NO) stress than EM. The effect of C-30 was decreased by overproduction of MexAB-OprM. To investigate whether the increase in the QS-interfering agent exposure-dependent sensitivity to nitrosative stress is characteristic of clinical isolates, we examined the viability of treated with NO. Although treatment with EM could reduce cell viability, a high variability in EM effects was observed. Conversely, C-30 was highly effective at reducing cell viability. Treatment with both C-30 and PAβN was sufficiently effective against the remaining isolates. Therefore, the combination of a QS-interfering agent and an EPI could be effective in treating infections.
Topics: Pseudomonas aeruginosa; Quorum Sensing; Microbial Sensitivity Tests; Anti-Bacterial Agents; Nitrosative Stress; Erythromycin; Membrane Transport Proteins; Furans; Dipeptides; Macrolides; Pseudomonas Infections; Humans; Bacterial Outer Membrane Proteins; Bacterial Proteins
PubMed: 38900549
DOI: 10.1099/mic.0.001464 -
Indian Journal of Dermatology,... May 2024Background Increasing rates of macrolide and fluroquinolone resistance in Mycoplasma genitalium (MG) are being reported worldwide with resultant treatment failure. Aims...
Background Increasing rates of macrolide and fluroquinolone resistance in Mycoplasma genitalium (MG) are being reported worldwide with resultant treatment failure. Aims and objectives We aimed to determine the level of antibiotic resistance of MG in men who have sex with men (MSM) attending a sexually transmitted infections (STIs) clinic in New Delhi, India. Methods Real-time polymerase chain reaction (PCR) assays targeting MgPa and pdhD genes were performed to detect MG rectal, urogenital or oropharyngeal infections in 180 MSM between January 2022 and June 2023. Macrolide resistance-associated mutations (MRM) and quinolone resistance-associated mutations (QRM) were detected by specific amplification of domain V of 23SrRNA gene and appropriate regions of parC and gyrA genes respectively followed by sequencing. PCR-based screening for Chlamydia trachomatis (CT) infection was also performed. Results A total of 13 (7.2%) MSM were positive for MG infection. The most common site of infection was anorectum (8/13; 61.5%) followed by the urethra (5/13; 38.5%). None of the patients had infection at both the sites, and no oropharyngeal MG infection was detected. CT infection was detected in 37 (20.6%) MSM. Of the 13 MG-infected MSM, 6 (46.2%) were co-infected with CT. MRM and QRM were found in five (46.2%) and two (15.4%) strains, respectively. Both Quinolone resistance mutation (QRM)-harbouring strains also harboured MRM. All the five MG isolates carried the MRM A2071G. Both the QRM isolates co-harboured the parC and gyrA single-nucleotide polymorphisms. There was no correlation between the presence of antibiotic resistance and co-infection with CT (P = 0.52). Limitation Because all patients in the study were MSM, the high rate of resistance to macrolides and fluoroquinolones could not be extrapolated for non-MSM patients. Conclusion This is a report of an initial survey of antibiotic resistance to MG in a country where its diagnosis and treatment are not routinely available. We found a high prevalence of MG-carrying MRM, QRM and dual-class resistance in MSM in the absence of antibiotic exposure. This study mandates the need for both screening and detection of antimicrobial resistance against MG.
PubMed: 38899414
DOI: 10.25259/IJDVL_933_2023 -
Veterinaria Italiana Mar 2024The aim of this study was to determine the concentration of TNF-alpha (TNF-α) in dogs naturally infected with Dirofilaria immitis (D. immitis) and to assess whether...
The aim of this study was to determine the concentration of TNF-alpha (TNF-α) in dogs naturally infected with Dirofilaria immitis (D. immitis) and to assess whether there are any changes in TNF-α concentration and their dependence during therapy for heartworm disease (HWD). For this study, 14 client-owned dogs with HWD were selected. Clinical and parasitological examinations (modified Knott test for circulating microfilariae and SNAP Test IDEXX for circulating D. immitis antigen) had been used for diagnosing D. immitis and HWD. All dogs were treated with an alternative therapy for HWD (oral doxycycline 10 mg/kg b.w., once daily for 6 weeks, then alternately 4 weeks without and 2 weeks with the medication, and oral ivermectin 6-14 µg/kg b.w., every 2 weeks). The dogs blood sera at the moment of HWD diagnosis, during and at the end of therapy were frozen for further quantifying of TNF-α (Canine TNF-alpha ELISA kit, Thermo scientific). At the moment of HWD diagnosis TNF-α was detected in 9 dogs (7.21±12.44 pg/ml). Concentration of TNF-α was not significantly change during the therapy, neither related to the level of D. immitis antigen nor to antigen level changes. The alternative therapy for HWD has no influence on TNF-α concentration dynamics.
Topics: Animals; Dogs; Dirofilariasis; Dog Diseases; Tumor Necrosis Factor-alpha; Dirofilaria immitis; Male; Female; Doxycycline; Ivermectin
PubMed: 38898794
DOI: 10.12834/VetIt.2662.22847.2 -
Current Microbiology Jun 2024Delftia has been separated from freshwater, sludge, and soil and has emerged as a novel opportunistic pathogen in the female vagina. However, the genomic...
Delftia has been separated from freshwater, sludge, and soil and has emerged as a novel opportunistic pathogen in the female vagina. However, the genomic characteristics, pathogenicity, and biotechnological properties still need to be comprehensively investigated. In this study, a Delftia strain was isolated from the vaginal discharge of a 43-year-old female with histologically confirmed cervical intraepithelial neoplasm (CIN III), followed by whole-genome sequencing. Phylogenetic analysis and average nucleotide identity (ANI) analysis demonstrated that it belongs to Delftia lacustris, named D. lacustris strain LzhVag01. LzhVag01 was sensitive to β-lactams, macrolides, and tetracyclines but exhibited resistance to lincoamines, nitroimidazoles, aminoglycosides, and fluoroquinolones. Its genome is a single, circular chromosome of 6,740,460 bp with an average GC content of 66.59%. Whole-genome analysis identified 16 antibiotic resistance-related genes, which match the antimicrobial susceptibility profile of this strain, and 11 potential virulence genes. These pathogenic factors may contribute to its colonization in the vaginal environment and its adaptation and accelerate the progression of cervical cancer. This study sequenced and characterized the whole-genome of Delftia lacustris isolated from vaginal discharge, which provides investigators and clinicians with valuable insights into this uncommon species.
Topics: Delftia; Genome, Bacterial; Vaginal Discharge; Humans; Female; Adult; Phylogeny; Anti-Bacterial Agents; Drug Resistance, Bacterial; Virulence Factors; Species Specificity
PubMed: 38898312
DOI: 10.1007/s00284-024-03758-x