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BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%-5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. METHODS: A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50â copies/mL) rate at 24 and 48â weeks, time to viral suppression and time to viral rebound (≥100â copies/mL) were compared among the first-line ART regimens. RESULTS: E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888â days. Forty-five started protease inhibitorsâ+â2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat)â+â2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir)â+â2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. CONCLUSIONS: The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.
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Infecciones por VIH , Inhibidores de Integrasa VIH , Integrasa de VIH , VIH-1 , Humanos , VIH-1/genética , Estudios Retrospectivos , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/uso terapéutico , Inhibidores de Integrasa VIH/farmacología , Raltegravir Potásico/uso terapéutico , Integrasa de VIH/genética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Farmacorresistencia Viral/genéticaRESUMEN
INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.
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Infecciones por Citomegalovirus , Enfermedades Reumáticas , Antígenos Virales , Citomegalovirus , Infecciones por Citomegalovirus/complicaciones , Humanos , Estudios Retrospectivos , Enfermedades Reumáticas/complicaciones , Enfermedades Reumáticas/tratamiento farmacológicoRESUMEN
OBJECTIVE: Cancer-associated fibroblasts (CAFs), a major component of cancer stroma, can confer aggressive properties to cancer cells by secreting multiple factors. Their phenotypes are stably maintained, but the mechanisms are not fully understood. We aimed to show the critical role of epigenetic changes in CAFs in maintaining their tumour-promoting capacity and to show the validity of the epigenomic approach in identifying therapeutic targets from CAFs to starve cancer cells. DESIGN: Twelve pairs of primary gastric CAFs and their corresponding non-CAFs (NCAFs) were established from surgical specimens. Genome-wide DNA methylation and H3K27me3 analyses were conducted by BeadArray 450K and ChIP-on-Chip, respectively. Functions of potential a therapeutic target were analysed by inhibiting it, and prognostic impact was assessed in a database. RESULTS: CAFs had diverse and distinct DNA methylation and H3K27me3 patterns compared with NCAFs. Loss of H3K27me3, but not DNA methylation, in CAFs was enriched for genes involved in stem cell niche, cell growth, tissue development and stromal-epithelial interactions, such as WNT5A, GREM1, NOG and IGF2. Among these, we revealed that WNT5A, which had been considered to be derived from cancer cells, was highly expressed in cancer stromal fibroblasts, and was associated with poor prognosis. Inhibition of secreted WNT5A from CAFs suppressed cancer cell growth and migration. CONCLUSIONS: H3K27me3 plays a crucial role in defining tumour-promoting capacities of CAFs, and multiple stem cell niche factors were secreted from CAFs due to loss of H3K27me3. The validity of the epigenetic approach to uncover therapeutic targets for cancer-starving therapy was demonstrated.
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Fibroblastos Asociados al Cáncer/metabolismo , Histona Demetilasas con Dominio de Jumonji/genética , Neoplasias Gástricas/genética , Medios de Cultivo Condicionados , Metilación de ADN , ADN de Neoplasias/genética , Epigenómica/métodos , Ontología de Genes , Estudio de Asociación del Genoma Completo/métodos , Humanos , Histona Demetilasas con Dominio de Jumonji/deficiencia , Mutación , Nicho de Células Madre , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Gastric cancer is heavily influenced by aberrant DNA methylation that alters multiple cancer-related pathways, and may respond to DNA demethylating agents, such as 5-aza-2'-deoxycytidine (5-aza-dC). Here, we aimed to analyze whether 5-aza-dC can sensitize gastric cancer cells to clinically used cytotoxic drugs. METHODS: Ten gastric cancer cell lines were treated with 5-aza-dC for 72 h and their growth was analyzed by conducting WST assay. In vivo effect of the drugs was analyzed using xenografts of OCUM-2 M/SN38 cells. Genome-wide expression and DNA methylation analyses were conducted using microarrays, and biological functions were identified through ingenuity pathway analysis. RESULTS: The cell lines most resistant to SN38 (an active metabolite of irinotecan), CDDP, PTX, and 5-FU, were identified. 5-Aza-dC pre-treatment of the resistant cell lines decreased the IC50 values for SN38 (TMK1, 226.4 nM to 32.91 nM; 44As3, 128.2 nM to 19.32 nM; OCUM2 M/SN38, 74.43 nM to 16.47 nM) and CDDP (TMK1, 5.05 µM to 2.26 µM; OCUM2 M, 10.79 µM to 2.77 µM), but not PTX and 5-FU. The reactivation of apoptosis-related genes, such as RUNX3, PYCARD, TNF, FAS, and FASLG, was induced by pre-treatment with 5-aza-dC, and the DNA demethylation of promoter CpG islands of RUNX3 and PYCARD was confirmed. In a xenograft model with OCUM2 M/SN38, treatment with 5-aza-dC before irinotecan showed markedly enhanced tumor suppression. CONCLUSION: Epigenetic priming with 5-aza-dC can improve the sensitivity of gastric cancer cells to SN38 and CDDP.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Animales , Línea Celular Tumoral , Cisplatino/administración & dosificación , Metilación de ADN/efectos de los fármacos , Decitabina/administración & dosificación , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Irinotecán/administración & dosificación , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Recently published the priming.
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BACKGROUND: Good's syndrome (GS) is characterized by immunodeficiency, and can lead to severe infection, which is the most significant complication. Although Mycobacterium rarely causes infection in patients with GS, disseminated nontuberculous mycobacterial (NTM) infection frequently occurs in GS patients that are also positive for the human immunodeficiency virus (HIV) or anti-interferon (IFN)-γ autoantibodies. Here, we report a rare case of GS with NTM without HIV or IFN-γ autoantibodies. CASE PRESENTATION: A 57-year-old Japanese male with GS and myasthenia gravis (treated with prednisolone and tacrolimus) was diagnosed with disseminated NTM infection caused by Mycobacterium abscessus subsp. massiliense. He presented with fever and back pain. Blood, lumbar tissue, urine, stool, and sputum cultures tested positive for M. abscessus. Bacteremia, spondylitis, intestinal lumber abscess, and lung infection were confirmed by bacteriological examination and diagnostic imaging; urinary and intestinal tract infections were suspected by bacteriological examination but not confirmed by imaging. Despite multidrug combination therapy, including azithromycin, imipenem/cilastatin, levofloxacin, minocycline, linezolid, and sitafloxacin, the patient ultimately died of the infection. The patient tested negative for HIV and anti-IFN-γ autoantibodies. CONCLUSIONS: Since myasthenia gravis symptoms interfere with therapy, patients with GS and their physicians should carefully consider the antibacterial treatment options against disseminated NTM.
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Enfermedades Pulmonares/microbiología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Mycobacterium abscessus , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Antibacterianos/uso terapéutico , Autoanticuerpos/sangre , Quimioterapia Combinada , Resultado Fatal , Fluoroquinolonas/uso terapéutico , Seronegatividad para VIH , Humanos , Interferón gamma/inmunología , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Miastenia Gravis/complicaciones , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Infecciones por Mycobacterium no Tuberculosas/diagnóstico , Infecciones por Mycobacterium no Tuberculosas/inmunología , SíndromeRESUMEN
BACKGROUND: Although primary (PGC) and remnant gastric cancers (RGC) both originate from the same gastrointestinal organ, they have very distinct clinicopathological behaviors. We hypothesized that there would be distinct differences in DNA methylation patterns that would occur during carcinogenesis of RGC and PGC, and that the differences in methylation patterns may help identify the primary factor contributing to chronic inflammation in patients with RGC. METHODS: We investigated the genome-wide DNA methylation patterns of PGC and RGC tissues from 48 patients using the Infinium HumanMethylation450 Beadchip assay. The results were validated by quantitative methylation-specific PCR (qMSP) in separate, independent cohorts. RESULTS: We found that in our training cohort of 48 patients, the most variable genes from the gastric cancer tissues identified by the Infinium HumanMethylation450 Beadchip clustered the resultant heatmap into high and low methylation groups. On multivariate analysis, PGCs contributed significantly to the high methylation group (p = 0.004, OR 12.33), which suggested that the promoter methylation status in PGC is higher than that in RGC. Supporting this conclusion was the finding that in a separate qMSP analysis in a test cohort, the EPB41L3 gene, chosen because of its high ß value on microarray analysis in the gastric cancer tissues, had significantly higher DNA promoter methylation in cancer tissues in the validation PGC tissues than in RGC. CONCLUSIONS: This study demonstrated that promoter methylation status in PGC is higher than in RGC. This result may reflect the effects of the absence of Helicobacter pylori on the reduced DNA methylation in the remnant stomach.
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Metilación de ADN , Muñón Gástrico/patología , Helicobacter pylori/aislamiento & purificación , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Femenino , Estudio de Asociación del Genoma Completo , Infecciones por Helicobacter/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas , Neoplasias Gástricas/genéticaRESUMEN
BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) can deteriorate rapidly to become fatal. Reported poor prognostic factors include radiographic findings, undernutrition, anemia and high inflammation test values. However, the association of these prognostic factors with the pathophysiology of the disease remains unknown. We aimed to clarify the pathophysiology of MAC-LD and develop a new biomarker that reflects the immune response to the disease. METHODS: We performed the cytokine panel analyses of serum from patients with MAC-LD and compared each cytokine level with clinically negative prognostic factors (radiographic disease type, body mass index, albumin, C-reactive protein and hemoglobin) and high-resolution CT scores. RESULTS: We analyzed 27 patients with MAC-LD, 6 with the fibrocavitary form and 21 with the nodular bronchiectatic form on high-resolution CT. Serum CXC motif ligand 10 (CXCL10) concentration was significantly elevated in patients with the fibrocavitary form (p = 0.008). CXCL10 levels correlated with body mass index (r = - 0.60, p = 0.0008), serum albumin concentration (r = - 0.45, p = 0.016) and high-resolution CT scores (r = 0.61, p = 0.0006). Among 14 patients initially untreated, antibiotic therapy was initiated for five during the study period. CXCL10 concentration was significantly higher in these patients (p = 0.046), and receiver operating characteristic analysis for CXCL10 concentration on treatment initiation produced an area under the curve of 0.844, with a sensitivity of 100%, specificity of 66.7%, and cut-off value of 366.5 pg/mL. CONCLUSION: We revealed cytokine profiles in patients with MAC-LD. Serum CXCL10 levels probably reflect the severity of MAC-LD. Our findings suggest that CXCL10 concentration may be a promising biomarker for managing treatment for patients with MAC disease of the lung.
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Quimiocina CXCL10/sangre , Citocinas/sangre , Enfermedades Pulmonares/inmunología , Complejo Mycobacterium avium , Infección por Mycobacterium avium-intracellulare/inmunología , Anciano , Antibacterianos , Biomarcadores , Índice de Masa Corporal , Bronquiectasia/inmunología , Bronquiectasia/microbiología , Femenino , Humanos , Pulmón , Enfermedades Pulmonares/microbiología , Masculino , Persona de Mediana Edad , Pronóstico , Curva ROC , Sensibilidad y EspecificidadRESUMEN
Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.
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Anticuerpos Neutralizantes/sangre , Autoanticuerpos/sangre , Interferón gamma/inmunología , Infecciones por Mycobacterium no Tuberculosas/inmunología , Micobacterias no Tuberculosas/inmunología , Adulto , Anciano , Antibacterianos/uso terapéutico , Profilaxis Antibiótica , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Síndromes de Inmunodeficiencia , Japón , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Micobacterias no Tuberculosas/efectos de los fármacos , Estudios RetrospectivosRESUMEN
BACKGROUND: The risk stratification of healthy individuals after Helicobacter pylori eradication is an urgent issue. The assessment of aberrant DNA methylation accumulated in gastric tissues with normal appearance, which can reflect overall epigenomic damage, is a promising strategy. We aimed to establish novel epigenetic cancer risk markers for H. pylori-eradicated individuals. METHODS: Gastric mucosa was collected from eight healthy volunteers without H. pylori infection (G1), 75 healthy individuals with gastric atrophy (G2), and 94 gastric cancer patients (G3) after H. pylori eradication. Genome-wide analysis was conducted using Infinium 450 K and differentially methylated probes were screened using large difference and iEVORA-based methods. Bisulfite pyrosequencing was used for validation. RESULTS: Screening, using 8 G1, 12 G2, and 12 G3 samples, isolated 57 candidates unmethylated in G1 and differentially methylated in G3 compared with G2. Validation for nine candidate markers (FLT3, LINC00643, RPRM, JAM2, ELMO1, BHLHE22, RIMS1, GUSBP5, and ZNF3) in 63 G2 and 82 G3 samples showed that all of them had significantly higher methylation levels in G3 than in G2 (P < 0.0001). Their methylation levels were highly correlated, which indicated that they reflect overall epigenomic damage. The candidates had sufficient performance (AUC: 0.70-0. 80) and high odds ratios (5.43-23.41), some of which were superior to a previous marker, miR-124a-3. The methylation levels of our novel markers were not associated with gastric atrophy, gender, or age. CONCLUSIONS: Novel epigenetic markers for gastric cancer risk optimized for H. pylori-eradicated individuals were established.
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Biomarcadores de Tumor/genética , Epigénesis Genética , Infecciones por Helicobacter/complicaciones , Neoplasias Gástricas/genética , Adulto , Factores de Edad , Anciano , Atrofia/microbiología , Metilación de ADN , Femenino , Mucosa Gástrica/patología , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Infecciones por Helicobacter/terapia , Helicobacter pylori/patogenicidad , Humanos , Masculino , Reproducibilidad de los Resultados , Neoplasias Gástricas/microbiologíaRESUMEN
Multiple pathogenic mechanisms by which Helicobacter pylori infection induces gastric cancer have been established in the last two decades. In particular, aberrant DNA methylation is induced in multiple driver genes, which inactivates them. Methylation profiles in gastric cancer are associated with specific subtypes, such as microsatellite instability. Recent comprehensive and integrated analyses showed that many cancer-related pathways are more frequently altered by aberrant DNA methylation than by mutations. Aberrant DNA methylation can even be present in noncancerous gastric mucosae, producing an "epigenetic field for cancerization." Mechanistically, H. pylori-induced chronic inflammation, but not H. pylori itself, plays a direct role in the induction of aberrant DNA methylation. The expression of three inflammation-related genes, Il1b, Nos2, and Tnf, is highly associated with the induction of aberrant DNA methylation. Importantly, the degree of accumulated aberrant DNA methylation is strongly correlated with gastric cancer risk. A recent multicenter prospective cohort study demonstrated the utility of epigenetic cancer risk diagnosis for metachronous gastric cancer. Suppression of aberrant DNA methylation by a demethylating agent was shown to inhibit gastric cancer development in an animal model. Induction of aberrant DNA methylation is the major pathway by which H. pylori infection induces gastric cancer, and this can be utilized for translational opportunities.
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Metilación de ADN , Epigénesis Genética/genética , Mucosa Gástrica/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/patogenicidad , Neoplasias Gástricas/etiología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Humanos , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: In contrast to community-acquired pneumonia (CAP), no specific severity assessment tools have been developed for healthcare-associated pneumonia (HCAP) in clinical practice. OBJECTIVES: In this review, we assessed the clinical significance of severity assessment tools for HCAP. METHODS: We identified related articles from the PubMed database. The eligibility criteria were original research articles evaluating severity scoring tools and reporting the outcomes of mortality in patients with HCAP. RESULTS: Eight articles were included in the meta-analysis. The PORT score and CURB-65 were evaluated in 7 and 8 studies, respectively. Using cutoff values of ≥IV and V for the PORT score, the diagnostic odds ratios (DORs) were 5.28 (2.49-11.17) and 3.76 (2.88-4.92), respectively, and the areas under the curve (AUCs) were 0.68 (0.64-0.72) and 0.71 (0.67-0.75), respectively. Conversely, the AUCs for ≥IV and V were 0.71 (0.67-0.76) and 0.74 (0.70-0.78), respectively, when applied only to nonimmunocompromised patients. In contrast, when using cutoff values of ≥2 and ≥3 for CURB-65, the DORs were 3.35 (2.26-4.97) and 2.65 (2.05-3.43), respectively, and the AUCs were 0.65 (0.61-0.69) and 0.66 (0.62-0.70), respectively. Conversely, the AUCs for ≥2 and ≥3 were 0.65 (0.61-0.69) and 0.68 (0.64-0.72), respectively, when applied only to nonimmunocompromised patients. CONCLUSIONS: The PORT score and CURB-65 do not have substantial power compared with the tools for CAP patients, although the PORT score is more useful than CURB-65 for predicting mortality in HCAP patients. According to our results, however, these tools, especially the PORT score, can be more useful when limited to nonimmunocompromised patients.
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Infección Hospitalaria/mortalidad , Neumonía/mortalidad , Área Bajo la Curva , Infección Hospitalaria/inmunología , Humanos , Huésped Inmunocomprometido/inmunología , Oportunidad Relativa , Neumonía/inmunología , Medición de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Nursing and healthcare-associated pneumonia (NHCAP) is a category of healthcare-associated pneumonia that was modified for the healthcare system of Japan. The NHCAP guidelines stated the difficulty in assessing the severity classifications, for instance, A-DROP. We compared the usefulness of different severity classifications (A-DROP, CURB-65, PSI, and I-ROAD) in predicting the prognosis of nursing and healthcare-associated pneumonia. We conducted a retrospective analysis on 303 adult patients hospitalized for nursing healthcare-associated pneumonia and community-acquired pneumonia, which were diagnosed at the Department of Respiratory Medicine of Niigata General City Hospital between January 2012 and December 2014. We evaluated 159 patients with community-acquired pneumonia and 144 with nursing and healthcare-associated pneumonia. In the nursing and healthcare-associated pneumonia group, 30-days mortality and in-hospital mortality rates were 6.5% and 8.7%, respectively, in severe cases and 16.1% and 25.0%, respectively, in the most severe cases, based on A-DROP. With I-ROAD, these rates were 11.1% and 11.1%, respectively, in group B and 14.9% and 20.7%, respectively, in group C. With PSI, the rates were 2.3% and 6.8%, respectively, in class IV and 14.3% and 19.8%, respectively, in class V. Despite some variability due to the small sample size, both the 30-days and in-hospital mortality rates increased as the severity increased. In this study, both the 30-days mortality and in-hospital mortality rates in the nursing and healthcare-associated pneumonia group tended to increase in severity with the A-DROP. We found that A-DROP was useful in predicting the prognosis of nursing and healthcare-associated pneumonia.
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Infección Hospitalaria/epidemiología , Neumonía Bacteriana/epidemiología , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/mortalidad , Femenino , Hospitalización , Humanos , Japón/epidemiología , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/mortalidad , Pronóstico , Estudios RetrospectivosRESUMEN
Serum (1â3) beta-D-glucan (BG) measurement is a useful test for systemic mycoses, and often used. On the other hand, various factors, including administration of intravenous immunoglobulins (IVIG) may cause false-positives. In the present study, we measured BG concentration of seven IVIG preparations with three lots respectively. BG levels varied with individual IVIG preparations (<3.0 - >300 pg/mL), and contamination from manufacturing processes was suspected. With serum BG concentration of clinical specimens obtained in Niigata University Medical & Dental Hospital, the difference between before and after administration of IVIG were calculated. The false-positive rate of BG due to IVIG administration was 9.8 %, and the positive predective value was reduced to 37.5%. Above all, administration of IVIG can complicate the BG test's interpretation, and caution is required.
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beta-Glucanos/sangre , gammaglobulinas/análisis , Anciano , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , gammaglobulinas/administración & dosificaciónRESUMEN
Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.
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Enfermedad de Castleman/patología , Ganglios Linfáticos/patología , Células Plasmáticas/patología , Trombocitopenia/patología , Adulto , Anciano , Femenino , Herpesvirus Humano 8/fisiología , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Síndrome , Trombocitopenia/etiología , Adulto JovenRESUMEN
Subjects exposed to non-tuberculous mycobacterium (NTM) species do not always develop an active disease, which likely reflects underlying host susceptibility factors. Recent reports have shown that anti interferon gamma (IFN-γ) neutralizing autoantibodies (IFN-γ Ab) are associated with the development of disseminated NTM in patients without known evidence of immunodeficiency. The purpose of this study is to establish the screening method if subjects have IFN-γ Ab. Whole blood was obtained from patients with disseminated NTM, those with pulmonary NTM, and healthy controls. The neutralizing capacity to IFN-γ activity was assessed as an inhibition of Signal Transducer and Activation of Transcription 1 (STAT-1) phosphorylation in leukocyte after stimulation with exogenous IFN-γ by flow cytometer. The strength of phosphorylation was described as STAT1 phosphorylation index. Antigen capture assay was performed to measure the relative titer of Immunoglobulin-G fraction of IFN-γ Ab. STAT1 phosphorylation by IFN-γ was significantly inhibited in the leukocytes from patients with disseminated NTM compared to that in healthy subjects, while this inhibition was not observed in patients with pulmonary NTM. All subjects with inhibited STAT1 phosphorylation had high titer of Immunoglobulin-G that reacted with IFN-γ in the antigen capture assay. The measurement of STAT1 phosphorylation index in whole blood leukocytes and antigen capture assay are simple and useful method for detection of anti-IFN-γ neutralizing autoantibodies, and is valuable in the pathophysiological diagnosis of disseminated NTM patients without obvious immunodeficiency.
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Anticuerpos Neutralizantes/inmunología , Autoanticuerpos/inmunología , Interferón gamma/inmunología , Infecciones por Mycobacterium/inmunología , Tuberculosis/inmunología , Anticuerpos Neutralizantes/sangre , Autoanticuerpos/sangre , Bioensayo/métodos , Humanos , Inmunoglobulina G/inmunología , Leucocitos/inmunología , Infecciones por Mycobacterium/sangre , Fosforilación/inmunología , Factor de Transcripción STAT1/inmunologíaRESUMEN
BACKGROUND: Carbapenem is recommended as one of the first-line regimens for ventilator-associated pneumonia (VAP), but no recent systematic review has fully investigated its efficacy. This systematic review aims to evaluate the efficacy of carbapenem compared with non-carbapenem for VAP treatment. METHODS: We performed a systematic review and meta-analysis of studies comparing the efficacy and the safety between carbapenem and non-carbapenem with activity to Pseudomonas aeruginosa in the treatment for VAP. The main outcome was mortality, and the additional outcomes were the clinical cure of pneumonia, length of intensive care unit stay, recurrence, adverse effects, and the development of resistant bacteria. This study was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of the initial 1,730 publications, 9 randomized control trials were enrolled. In the meta-analysis, no difference was observed between the carbapenem and non-carbapenem regimens in improving mortality (odds ratio, 0.83; 95 % confidence interval (CI) 0.67-1.02). While the carbapenem regimen was superior to the non-carbapenem regimen in studies reporting the resolution of pneumonia (odds ratio, 1.09; 95 % CI 1.01-1.17), the effectiveness of carbapenem treatment was not evident in studies assessing the other outcomes. CONCLUSIONS: Carbapenem might have no superiority in survival when treating VAP. Moreover, non-carbapenem antibiotics with activities to P. aeruginosa have a potential option to avoid inducing carbapenem-resistant pathogens.
Asunto(s)
Antibacterianos , Carbapenémicos , Neumonía Asociada al Ventilador , Pseudomonas aeruginosa , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/microbiología , Humanos , Carbapenémicos/uso terapéutico , Antibacterianos/administración & dosificación , Pseudomonas aeruginosa/efectos de los fármacos , Resultado del Tratamiento , Infecciones por Pseudomonas/tratamiento farmacológico , Tiempo de Internación , Unidades de Cuidados Intensivos , Farmacorresistencia Bacteriana , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The primary objective of this study was to identify the predominant organisms associated with ventilator-associated pneumonia (VAP) in Japan. Studies on VAP conducted in Japan were systematically reviewed, and seven studies with a total of 374 cases were included. The detection rate of each bacterium and multidrug-resistant (MDR) pathogen was analyzed using the inverse variance method. Pseudomonas aeruginosa was identified as the predominant pathogen in 29.2â¯% of cases, followed by methicillin-resistant Staphylococcus aureus (MRSA) (12.0â¯%), and Klebsiella spp. (9.5â¯%). An integrated analysis revealed a detection rate of 57.8â¯% (95â¯% confidence interval: 48.7%-66.8â¯%) for MDR pathogens. This review highlights P. aeruginosa and MRSA as the predominant VAP-associated organisms in Japan, with a significant prevalence of MDR pathogens. This analysis provides valuable insights based on the regional distribution of bacteria detected in VAP, which is critical for selecting appropriate empirical therapy.
Asunto(s)
Farmacorresistencia Bacteriana Múltiple , Staphylococcus aureus Resistente a Meticilina , Neumonía Asociada al Ventilador , Pseudomonas aeruginosa , Neumonía Asociada al Ventilador/microbiología , Neumonía Asociada al Ventilador/epidemiología , Humanos , Japón/epidemiología , Pseudomonas aeruginosa/aislamiento & purificación , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Klebsiella/aislamiento & purificación , Prevalencia , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/epidemiologíaRESUMEN
Tuberculosis remains a large health threat, despite the availability of the tuberculosis vaccine, BCG. As BCG efficacy gradually decreases from adolescence, BCG-Prime and antigen-booster may be an efficient strategy to confer vaccine efficacy. Mycobacterial DNA-binding protein 1 (MDP1, namely Rv2986c, hupB or HU) is a major Mycobacterium tuberculosis protein that induces vaccine-efficacy by co-administration with CpG DNA. To produce MDP1 for booster-vaccine use, we have created recombinant MDP1 produced in both Escherichia coli (eMDP1) and Mycolicibacterium smegmatis (mMDP1), an avirulent rapid-growing mycobacteria. We tested their immunogenicity by checking interferon (IFN)-gamma production by stimulated peripheral blood cells derived from BCG-vaccinated individuals. Similar to native M. tuberculosis MDP1, we observed that most lysin resides in the C-terminal half of mMDP1 are highly methylated. In contrast, eMDP1 had less post-translational modifications and IFN-gamma stimulation. mMDP1 stimulated the highest amount of IFN-gamma production among the examined native M. tuberculosis proteins including immunodominant MPT32 and Antigen 85 complex. MDP1-mediated IFN-gamma production was more strongly enhanced when combined with a new type of CpG DNA G9.1 than any other tested CpG DNAs. Taken together, these results suggest that the combination of mMDP1 and G9.1 possess high potential use for human booster vaccine against tuberculosis.
Asunto(s)
Vacuna BCG , Proteínas Bacterianas , Proteínas de Unión al ADN , Interferón gamma , Mycobacterium tuberculosis , Procesamiento Proteico-Postraduccional , Humanos , Interferón gamma/metabolismo , Proteínas Bacterianas/inmunología , Vacuna BCG/inmunología , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Mycobacterium tuberculosis/inmunología , Proteínas Recombinantes/inmunología , Oligodesoxirribonucleótidos/farmacología , Tuberculosis/prevención & control , Tuberculosis/inmunología , Islas de CpG , Mycobacterium smegmatis/inmunología , Mycobacterium smegmatis/metabolismo , Escherichia coli/metabolismo , Escherichia coli/genética , FemeninoRESUMEN
With the rising number of older adults residing at home, there is a growing need for risk assessment and patient management in home nursing. This study aims to develop point-of-care test (POCT) reagents that can aid in risk assessment and home care, especially in settings with limited resources. Our focus was on creating a C-reactive protein (CRP) POCT, which can accurately diagnose clinically significant judgment values in home nursing. Additionally, we assessed the utility of the HemoCue WBC DIFF system in providing differential counts of white blood cells (WBC). These performances were compared with a laboratory test using blood samples from patients with pneumonia. The CRP POCT showed a comparable result to that of a laboratory method, with an average kappa index of 0.883. The leukocyte count showed good agreement with the reference method. While the correlation coefficients for both neutrophil and lymphocyte counts were deemed acceptable, it was observed that the measured values tended to be smaller in cases where the cell count was higher. This proportional error indicates a weak correlation with the neutrophil-to-lymphocyte ratio. CRP POCT and WBC counts provided reliable and accurate judgments. These tools may benefit risk management for older adults at home, patients with dementia who cannot communicate, and those living in depopulated areas.