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We report the case of a 42-year-old man with bronchiectasis who had a history of infertility treatment for obstructive azoospermia. Young's syndrome was suspected based on the triad of obstructive azoospermia, sinusitis, and bronchiectasis. He had normal electron microscopy findings, normal nasal nitric oxide levels (116 nL/min), and no situs inversus. However, we found compound heterozygous variants in CFAP221. This led to a diagnosis of primary ciliary dyskinesia (PCD). Distinguishing PCD from Young's syndrome in patients with the triad of obstructive azoospermia, sinusitis, and bronchiectasis is challenging. Young's syndrome may be a phenotype of PCD.
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BACKGROUND: Clofazimine (CFZ) has shown promising effects against Mycobacterium avium-intracellulare complex pulmonary disease (MAC-PD) and Mycobacterium abscessus species pulmonary disease (MABS-PD). However, the optimal CFZ dose remains unknown. We aimed to explore the relationship between steady-state CFZ concentration and its safety and efficacy in MAC-PD and MABS-PD. METHODS: This prospective observational study focused on patients with MAC-PD and MABS-PD treated with CFZ (UMIN 000041053). To understand the safety and efficacy profile of CFZ and elucidate its optimal concentration, we analyzed CFZ-induced pigmentation grade, QTc interval, and culture conversion outcomes in relation to serum CFZ concentration using Student's t-test, a concentration-QTc model, and multivariable logistic regression analysis, respectively. In total, 64 patients (34 with MAC-PD; 30 with MABS-PD) were included. RESULTS: The steady-state concentration of CFZ was higher in the moderate-to-severe pigmentation group than in the none-to-light pigmentation group (P < 0.001). At a CFZ concentration of 1 mg/L, the QTc interval was prolonged by 17.3 ms (95 % confidence interval [CI], 3.9-25.4) from baseline. Culture conversion was achieved in 33 (51.6 %) patients. The only significant predictor of culture conversion was surgery (adjusted odds ratio, 5.4; 95 % CI, 1.3-38.0). CFZ concentration and MIC of CFZ less than 0.25 mg/L were not associated with culture conversion in this study. CONCLUSION: CFZ-induced pigmentation and QT interval prolongation are associated with serum CFZ concentrations. CFZ dosage may be optimized by monitoring serum CFZ concentration.
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Clofazimina , Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Humanos , Clofazimina/administración & dosificación , Clofazimina/uso terapéutico , Femenino , Masculino , Estudios Prospectivos , Anciano , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Persona de Mediana Edad , Mycobacterium abscessus/efectos de los fármacos , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Complejo Mycobacterium avium/efectos de los fármacos , Resultado del Tratamiento , Enfermedades Pulmonares/tratamiento farmacológico , Enfermedades Pulmonares/microbiología , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinéticaRESUMEN
Allergic reactions can profoundly influence the quality of life. To address the health risks posed by allergens and overcome the permeability limitations of the current filter materials, this work introduces a novel microhoneycomb (MH) material for practical filter applications such as masks. Through a synthesis process integrating ice-templating and a gas-phase post-treatment with silane, MH achieves unprecedented levels of moisture resistance and mechanical stability while preserving the highly permeable microchannels. Notably, MH is extremely elastic, with a 92% recovery rate after being compressed to 80% deformation. The filtration efficiency surpasses 98.1% against pollutant particles that simulate airborne pollens, outperforming commercial counterparts with fifth-fold greater air permeability while ensuring unparalleled user comfort. Moreover, MH offers a sustainable solution, being easily regenerated through back-flow blowing, distinguishing it from conventional nonwoven fabrics. Finally, a prototype mask incorporating MH is presented, demonstrating its immense potential as a high-performance filtration material, effectively addressing health risks posed by allergens and other harmful particles.
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BACKGROUND: Although international nontuberculous mycobacterial pulmonary disease (NTM-PD) guidelines highlight symptom presence at diagnosis, the clinical characteristics of asymptomatic Mycobacterium avium complex pulmonary infection (MAC-PI) patients remain understudied. We clarified the clinical characteristics and course of asymptomatic MAC-PI patients. METHODS: We retrospectively analyzed 200 consecutive patients with MAC-PIs and adequate available data who newly met the microbiological and radiological criteria for NTM-PD at Fukujuji Hospital from January 2018 to June 2020. We compared the clinical characteristics and course of asymptomatic patients with symptomatic patients and evaluated factors influencing treatment initiation through multivariate analysis. RESULTS: 111 patients were symptomatic and 89 were asymptomatic at diagnosis. While the proportion was significantly lower than that in the symptomatic group (28.8 %), 15.7 % of asymptomatic group patients had cavitary lesions (P = 0.042). In the asymptomatic group, treatments were initiated in 38 (42.7 %) patients, and cavitary lesions, a positive acid-fast bacilli smear, and younger age were independent risk factors for treatment initiation. Among 22 (57.9 %) patients who experienced disease progression necessitating treatment during follow-up, 13 (34.2 %) displayed radiological progression without any worsening of symptoms. Agents used for treatment were consistent across the groups, with no significant differences in culture conversion, microbiological recurrence rates, or spontaneous culture conversion rates. CONCLUSION: Routine health checkups and radiological examinations can detect clinically important MAC-PIs even in the absence of symptoms. Considering that the clinical course of asymptomatic MAC-PI patients is largely similar to that of symptomatic patients, timely and appropriate management and intervention are essential for all MAC-PI patients.
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Complejo Mycobacterium avium , Infección por Mycobacterium avium-intracellulare , Humanos , Masculino , Femenino , Infección por Mycobacterium avium-intracellulare/diagnóstico por imagen , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Infección por Mycobacterium avium-intracellulare/microbiología , Infección por Mycobacterium avium-intracellulare/diagnóstico , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Complejo Mycobacterium avium/aislamiento & purificación , Progresión de la Enfermedad , Infecciones Asintomáticas , Tomografía Computarizada por Rayos X/métodos , Anciano de 80 o más Años , Factores de Riesgo , Factores de EdadRESUMEN
BACKGROUND: von Hippel-Lindau disease-associated hemangioblastomas (HBs) account for 20%-30% of all HB cases, with the appearance of new lesions often observed in the natural course of the disease. By comparison, the development of new lesions is rare in patients with sporadic HB. OBSERVATIONS: A 65-year-old man underwent clipping for an unruptured aneurysm of the anterior communicating artery. Fourteen years later, follow-up magnetic resonance imaging (MRI) revealed a strongly enhanced mass in the right cerebellar hemisphere, diagnosed as a sporadic HB. A retrospective review of MRI studies obtained over the follow-up period revealed the gradual development of peritumoral edema and vascularization before mass formation. LESSONS: Newly appearing high-intensity T2 lesions in the cerebellum may represent a preliminary stage of tumorigenesis. Careful monitoring of these patients would be indicated, which could provide options for early treatment to improve patient outcomes.
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We present the case of a 58-year-old female patient with primary ciliary dyskinesia (PCD). She was born to parents with a consanguineous marriage. Chest computed tomography conducted at age 41 years indicated no situs inversus, and findings of bronchiectasis were limited to the middle and lingular lobes. Despite long-term macrolide therapy, bronchiectasis exacerbations frequently occurred. PCD was suspected because of the low nasal nitric oxide level (20.7 nL/min). Electron microscopy revealed outer and inner dynein arm defects, and a genetic analysis identified a homozygous single-nucleotide deletion in the DNAAF1 gene. Based on these results, the patient was diagnosed with PCD due to a biallelic DNAAF1 mutation.
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BACKGROUND: A clinically applicable mortality risk prediction system for pulmonary TB may improve treatment outcomes, but no easy-to-calculate and accurate score has yet been reported. The aim of this study was to construct a simple and objective disease severity score for patients with pulmonary TB. RESEARCH QUESTION: Does a clinical score consisting of simple objective factors predict the mortality risk of patients with pulmonary TB? STUDY DESIGN AND METHODS: The data set from our previous prospective study that recruited patients newly diagnosed with pulmonary TB was used for the development cohort. Patients for the validation cohort were prospectively recruited between March 2021 and September 2022. The primary end point was all-cause in-hospital mortality. Using Cox proportional hazards regression, a mortality risk prediction model was optimized in the development cohort. The disease severity score was developed by assigning integral points to each variate. RESULTS: The data from 252 patients in the development cohort and 165 patients in the validation cohort were analyzed, of whom 39 (15.5%) and 17 (10.3%), respectively, died in the hospital. The disease severity score (named the AHL score) included three clinical parameters: activities of daily living (semi-dependent, 1 point; totally dependent, 2 points); hypoxemia (1 point), and lymphocytes (< 720/µL, 1 point). This score showed good discrimination with a C statistic of 0.902 in the development cohort and 0.842 in the validation cohort. We stratified the score into three groups (scores of 0, 1-2, and 3-4), which clearly corresponded to low (0% and 1.3%), intermediate (13.5% and 8.9%), and high (55.8% and 39.3%) mortality risk in the development and validation cohorts. INTERPRETATION: The easy-to-calculate AHL disease severity score for patients with pulmonary TB was able to categorize patients into three mortality risk groups with great accuracy. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Center; No. UMIN000012727 and No. UMIN000043849; URL: www.umin.ac.jp.
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Actividades Cotidianas , Tuberculosis Pulmonar , Humanos , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Factores de Riesgo , Linfocitos , HipoxiaRESUMEN
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been widely used. They inhibit proximal tubular glucose reabsorption, resulting in glycosuria. Herein, we report the case of a 65-year-old woman who presented with hypernatremia during the perioperative period of a subarachnoid hemorrhage. The patient continued to take dapagliflozin postoperatively and subsequently developed severe hypernatremia. Based on the urinalysis findings, we diagnosed osmotic diuresis due to glycosuria as contributing to hypernatremia. Hypernatremia improved with the discontinuation of dapagliflozin and the administration of a hypotonic infusion. In the perioperative period, physicians should discontinue SGLT2 inhibitors owing to concerns about the development of hypernatremia.
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Compuestos de Bencidrilo , Glucósidos , Glucosuria , Hipernatremia , Femenino , Humanos , Anciano , Hipernatremia/inducido químicamente , Hipernatremia/diagnóstico , Glucosuria/complicaciones , Diuresis , Glucosa/uso terapéuticoRESUMEN
Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by impaired motile cilia function, particularly in the upper and lower airways. To date, more than 50 causative genes related to the movement, development, and maintenance of cilia have been identified. PCD mostly follows an autosomal recessive inheritance pattern, in which PCD symptoms manifest only in the presence of pathogenic variants in both alleles. Several genes causing PCD have been recently identified that neither lead to situs inversus nor cause definitive abnormalities in ciliary ultrastructure. Importantly, the distribution of disease-causing genes and pathogenic variants varies depending on ethnicity. In Japan, homozygosity for a â¼27.7-kb deletion of DRC1 is estimated to be the most common cause of PCD, presumably as a founder mutation. The clinical picture of PCD is similar to that of sinobronchial syndrome, thus making its differentiation from diffuse panbronchiolitis and other related disorders difficult. Given the diagnostic challenges, many cases remain undiagnosed or misdiagnosed, particularly in adults. While no fundamental cure is currently available, lifelong medical subsidies are provided in Japan, and proper respiratory management, along with continued prevention and treatment of infections, is believed to mitigate the decline in respiratory function. Timely action will be necessary when specific treatments for PCD become available in the future. This narrative review focuses on variations in the disease status of PCD in a non-Western country.
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Trastornos de la Motilidad Ciliar , Adulto , Humanos , Japón/epidemiología , Trastornos de la Motilidad Ciliar/genética , MutaciónRESUMEN
Primary ciliary dyskinesia (PCD) is a genetic disease characterized by motile cilia dysfunction, mostly inherited in an autosomal recessive or X-linked manner. We herein report a 29-year-old woman with PCD caused by a heterozygous frameshift mutation due to a single nucleotide deletion in exon 3 of FOXJ1. Heterozygous de novo mutations in FOXJ1 have been reported as an autosomal-dominant cause of PCD. The patient had situs inversus, congenital heart disease, infertility, and hydrocephalus. However, the nasal nitric oxide level was normal. Long-term macrolide therapy was remarkably effective. This is the first case report of PCD caused by a FOXJ1 variant in Japan.
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Transbronchial lung biopsy (TBLB) culture is not common in clinical practice, and TBLB culture for patients with mycobacterial disease provide limited value because the diagnostic accuracy of TBLB culture is very low. Recently, bronchoscopic devices have been further developed, such as endobronchial ultrasonography with a guide-sheath (EBUS-GS). Therefore, this study investigated the utility of TBLB culture obtained by using EBUS-GS compared to washing cultures. A total of 31 patients who underwent TBLB culture by using EBUS-GS (GS-TBLB) were collected retrospectively at Fukujuji Hospital from January 2018 to December 2022. The diagnostic accuracies of GS-TBLB culture and bronchial and device washing cultures (namely, washing culture) were compared. The patients comprised 13 individuals with nontuberculous mycobacteriosis, 7 with pulmonary aspergillosis, 6 with lung abscess, and 5 with pulmonary tuberculosis. The diagnostic accuracy of GS-TBLB culture was lower to that of TBLB culture than those of washing culture (n = 11 [35.5%] vs. n = 20 [64.5%], p = 0.016), and there was only one patient with positive GS-TBLB culture results and negative washing culture results. Comparing between patients with mycobacteria and non-mycobacteria, GS-TBLB culture positivity were no significant difference between patients with mycobacteria and non-mycobacteria (n = 6 [33.3%] vs. n = 5 [38.5%], p = 1.000), however, patients with mycobacteria diagnosed by washing culture more than those with non-mycobacteria (n = 15 [83.3%] vs. n = 5 [38.5%], p = 0.021). Our results demonstrate that the utility of TBLB culture for the diagnosis of pulmonary infections might provide limited value even if EBUS-GS is performed and lung tissue is successfully obtained.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Broncoscopía/métodos , Biopsia/métodos , Pulmón/diagnóstico por imagen , Pulmón/patología , Endosonografía/métodosRESUMEN
BACKGROUND: Volumetric modulated arc therapy (VMAT) for locally advanced rectal cancer (LARC) has emerged as a promising technique, but the planning process can be time-consuming and dependent on planner expertise. We aimed to develop a fully automated VMAT planning program for LARC and evaluate its feasibility and efficiency. METHODS: A total of 26 LARC patients who received VMAT treatment and the computed tomography (CT) scans were included in this study. Clinical target volumes and organs at risk were contoured by radiation oncologists. The automatic planning program, developed within the Raystation treatment planning system, used scripting capabilities and a Python environment to automate the entire planning process. The automated VMAT plan (auto-VMAT) was created by our automated planning program with the 26 CT scans used in the manual VMAT plan (manual-VMAT) and their regions of interests. Dosimetric parameters and time efficiency were compared between the auto-VMAT and the manual-VMAT created by experienced planners. All results were analyzed using the Wilcoxon signed-rank sum test. RESULTS: The auto-VMAT achieved comparable coverage of the target volume while demonstrating improved dose conformity and uniformity compared with the manual-VMAT. V30 and V40 in the small bowel were significantly lower in the auto-VMAT compared with those in the manual-VMAT (p < 0.001 and < 0.001, respectively); the mean dose of the bladder was also significantly reduced in the auto-VMAT (p < 0.001). Furthermore, auto-VMAT plans were consistently generated with less variability in quality. In terms of efficiency, the auto-VMAT markedly reduced the time required for planning and expedited plan approval, with 93% of cases approved within one day. CONCLUSION: We developed a fully automatic feasible VMAT plan creation program for LARC. The auto-VMAT maintained target coverage while providing organs at risk dose reduction. The developed program dramatically reduced the time to approval.
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Neoplasias Primarias Secundarias , Radioterapia de Intensidad Modulada , Neoplasias del Recto , Humanos , Estudios de Factibilidad , Órganos en RiesgoRESUMEN
BACKGROUND: Bacterial coinfections are observed in 19-66% of patients with Mycobacterium avium complex pulmonary disease (MAC-PD) during the entire duration of the disease. The impact of bacterial coinfection at diagnosis on the clinical course of MAC-PD has not been reported. METHODS: Among 558 patients diagnosed with MAC-PD between January 2016 and December 2020, 218 patients who underwent sputum culture tests twice or more within one year before and after diagnosis were included. We compared the patient characteristics and disease courses between the patients who had the same bacterial species detected twice or more (bacterial culture positive group: BCP group) and those who never had bacteria cultured (bacterial culture negative group: BCN group). RESULTS: We included 70 patients in the BCP group and 74 in the BCN group. The radiological findings showed that BCP at diagnosis correlated with a high modified Reiff score. During the median follow-up period of 42 months, the patients in the BCP group were more likely to accomplish spontaneous sputum conversion of MAC. The treatment initiation rate for MAC-PD in the BCP group was lower than that in the BCN group (41.4% vs. 67.6%, P = 0.003). In contrast, the time to the first bronchiectasis exacerbation in the BCP group was shorter than that in the BCN group, and the frequency of bronchiectasis exacerbations was higher in the BCP group. CONCLUSIONS: Patients with BCP at diagnosis are less likely to initiate treatment for MAC-PD and more likely to develop bronchiectasis exacerbation.
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Bronquiectasia , Enfermedades Pulmonares , Infección por Mycobacterium avium-intracellulare , Humanos , Complejo Mycobacterium avium , Infección por Mycobacterium avium-intracellulare/complicaciones , Infección por Mycobacterium avium-intracellulare/diagnóstico , Infección por Mycobacterium avium-intracellulare/tratamiento farmacológico , Enfermedades Pulmonares/diagnóstico , Bronquiectasia/diagnóstico , PronósticoRESUMEN
Ornithine transcarbamylase (OTC) plays a significant role in the urea cycle, a metabolic pathway functioning in the liver to detoxify ammonia. OTC deficiency (OTCD) is the most prevalent urea cycle disorder. Here, we show that intravenously delivered human OTC (hOTC) mRNA by lipid nanoparticles (LNP) was an effective treatment for OTCD by restoring the urea cycle. We observed a homotrimer conformation of hOTC proteins produced by the mRNA-LNP in cells by cryo-electron microscopy. The immunohistochemistry revealed the mitochondria localization of produced hOTC proteins in hepatocytes in mice. In livers of mice intravenously injected with hOTC-mRNA/LNP at 1.0 mg/kg, the delivered hOTC mRNA levels steeply decreased with a half-life (t1/2) of 7.1 h, whereas the produced hOTC protein levels retained for 5 days and then declined with a t1/2 of 2.2 days. In OTCD model mice (high-protein diet-fed Otcspf-ash hemizygous males), a single dose of hOTC-mRNA/LNP at 3.0 mg/kg ameliorated hyperammonemia and weight loss with prolonged survival rate (22 days) compared with that of untreated mice (11 days). Weekly repeated doses at 0.3 and 1.0 mg/kg were well tolerated in wild-type mice and showed a dose-dependent amelioration of survival rate in OTCD mice, thus, showing the therapeutic potential of LNP-formulated hOTC mRNA for OTCD.
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Distinguishing between nontuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis (TB) is difficult. We aimed to evaluate the usefulness of gastric aspirate examination for NTM-PD diagnosis and for differentiating NTM-PD from other diseases, including pulmonary TB. We retrospectively collected data for 491 patients with negative sputum smears or a lack of sputum production at Fukujuji Hospital. We compared 31 patients with NTM-PD to 218 patients with other diseases (excluding 203 with pulmonary TB). Additionally, we compared 81 patients with NTM cultured from at least one sputum or bronchoscopy sample to the other 410 patients. Gastric aspirate examination for NTM-PD diagnosis showed 74.2% sensitivity and 99.0% specificity for culture positivity. There was no significant difference between the nodular bronchiectatic disease and cavitary disease types for culture positivity (p = 0.515). The significance of NTM isolation from gastric aspirate showed 64.2% sensitivity and 99.8% specificity for culture positivity. Gastric aspirate examination revealed NTM in one TB patient, allowing TB to be ruled out in 98.1% of patients with NTM cultured from gastric aspirates. Gastric aspirate examination is helpful for early-stage NTM diagnosis and ruling out pulmonary TB. This could lead to more accurate and timely treatment.
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Bronquiectasia , Infecciones por Mycobacterium no Tuberculosas , Tuberculosis Pulmonar , Humanos , Estudios Retrospectivos , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , PulmónRESUMEN
BACKGROUND/AIM: This study pursued two goals: Firstly, to search for anatomical structures strongly correlating with dose deterioration, and secondly to investigate the effectiveness of image registration focusing on critical anatomy by comparing it with a conventional method. The aim was to achieve robust image registration to correct for anatomical changes during treatment. PATIENTS AND METHODS: Twenty patients with head and neck cancer were enrolled, and 68 simulation computed tomography (CT) and rescan CT image sets were retrospectively analyzed. Forty volumetric-modulated arc therapy and intensity-modulated proton therapy plans were generated and recalculated according to the rescan CT to evaluate the dose effects of anatomical changes. Correlation coefficients were calculated for the relationships between the six-axis motion of the anatomy and the dose indices for the clinical target volume (CTV) and organs at risk. In the image registration, we compared a conventional method and target-based registration that limited the registration range to the CTV and vertebrae. RESULTS: The CTV coverage and spinal cord dose were correlated with the position error associated with the pitch and vertical position of the vertebrae, and the parotid gland and oral cavity dose were strongly correlated with the position error associated with the roll of the clivus and mandible. The target registration improved CTV coverage and suppressed the increase in dose to organs at risk compared with conventional methods. CONCLUSION: Monitoring vertebral alignment, the assessment and correction of positioning errors associated with the clivus and mandible position errors are important to ensure the quality of daily treatment. Target-based registration may allow for more robust image registration.
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Neoplasias de Cabeza y Cuello , Terapia de Protones , Radioterapia de Intensidad Modulada , Humanos , Dosificación Radioterapéutica , Estudios Retrospectivos , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/radioterapia , Tomografía Computarizada por Rayos X/métodos , Terapia de Protones/métodos , Radioterapia de Intensidad Modulada/métodos , Órganos en RiesgoRESUMEN
Background: This study assessed longitudinal national data on mortality due to nontuberculous mycobacteriosis (NTMosis) and bronchiectasis and the association between the two diseases. Methods: We analysed the national death statistics of Japan from 1970 to 2015. The International Classification of Disease (ICD) codes were used to extract the relevant data. Crude mortality, age-adjusted mortality and standardised mortality rates were calculated using vital statistics and the population in 2000. We also identified domestic publications related to NTMosis and bronchiectasis with an internet-based search system. Results: The total number of bronchiectasis-related deaths remained at the same level, which was approximately 1000, for 45â years, although the number of deaths has consistently decreased in males but increased in females since the mid-1990s. A substantial increasing trend in females was also observed for NTMosis in the same period. The age-adjusted mortality data showed an increase in mortality in women due to NTMosis and confirmed the trend in bronchiectasis in women. The patterns in the number of domestic reports showed a recent slight increase in bronchiectasis and a marked increase in NTMosis. Conclusions: The trends in bronchiectasis-related mortality differed by sex. The epidemiological trends in the two diseases were associated, especially in elderly females since the mid-1990s. It is suggested that pulmonary NTMosis without pre-existing bronchiectasis might be a leading cause of postinfectious bronchiectasis in Japan.
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We herein report a case of peritoneal dialysis-associated peritonitis caused by Lysinibacillus sphaericus in a 40s-year-old patient. Treatment was initiated with intermittent intraperitoneal cefazolin and ceftazidime. Later, both peritoneal dialysate and blood cultures detected L. sphaericus, so the antibiotic was changed to ampicillin (ABPC). The patient was treated with a combination of intraperitoneal intermittent and intravenous ABPC for 7 days, followed by 14 days of amoxicillin. The patient experienced no adverse events and no recurrence for 30 days. The patient had four dogs, and the infection was deemed likely to have been caused by environmental contamination and inadequate catheter replacement.
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Antibacterianos , Diálisis Peritoneal Ambulatoria Continua , Diálisis Peritoneal , Peritonitis , Adulto , Humanos , Ampicilina , Antibacterianos/uso terapéutico , Diálisis Peritoneal/efectos adversos , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Peritonitis/tratamiento farmacológico , Peritonitis/etiologíaRESUMEN
Nucleic acid therapeutics have been utilized for gene regulation, and their recent advancement has led to approval of novel drugs for liver-related disorders. However, systemic extrahepatic delivery remains challenging. Here, we report newly designed mannose-conjugated oligonucleotides for delivering oligonucleotides to macrophages by leveraging the mannose receptor, C-type 1 (MRC1, CD206), which is abundantly expressed in macrophages. We investigated the relationship between cellular uptake and multivalency (mono to tetra) of mannose ligands or linker length and selected a trivalent-mannose ligand. Trivalent-mannose (Man3)-conjugated siRNA induced concentration-dependent gene silencing in both human CD206-overexpressing cells and human macrophages in vitro. After subcutaneous injection into mice, we observed a high distribution of Man3-conjugated oligonucleotides in the liver and pancreata as well as cellular uptake into Kupffer cells and pancreatic macrophages. A single subcutaneous injection of Man3-conjugated siRNA (10 mg/kg) targeting ß2-microglobulin (B2M) silenced B2m mRNA expression by â¼50% and decreased its protein levels in mouse pancreatic macrophages compared to those in saline-treated mice. Of note, multiple subcutaneous injections decreased B2m gene expression and B2M protein levels by â¼80% and â¼85%, respectively. These results show that mannose-conjugation with oligonucleotides is expected to help deliver oligonucleotides to macrophages and regulate gene expression in vivo, particularly in the pancreas.