Recent evidence suggests that hyperuricemia is an important condition in children and adolescents, particularly in association with noncommunicable diseases. This review aims to summarize our current ...understanding of this condition in pediatric patients. An analysis of serum uric acid reference values in a healthy population indicates that they increase gradually with age until adolescence, with differences between the sexes arising at about 12 years of age. This information should be taken into consideration when defining hyperuricemia in studies. Gout is extremely rare in children and adolescents, and most patients with gout have an underlying disease. The major causes of hyperuricemia are chronic conditions, including Down syndrome, metabolic or genetic disease, and congenital heart disease, and acute conditions, including gastroenteritis, bronchial asthma (hypoxia), malignant disorders, and drug side effects. The mechanisms underlying the associations between these diseases and hyperuricemia are discussed, together with recent genetic information. Obesity is a major cause of hyperuricemia in otherwise healthy children and adolescents. Obesity is often accompanied by metabolic syndrome; hyperuricemia in obese children and adolescents is associated with the components of metabolic syndrome and noncommunicable diseases, including hypertension, insulin resistance, dyslipidemia, and chronic kidney disease. Finally, strategies for the treatment of hyperuricemia, including lifestyle intervention and drug administration, are presented.
Lung fibrosis is increasingly detected with aging and has been associated with poor outcomes in acute lung injury or infection. However, the molecular programs driving this pro-fibrotic evolution are ...unclear. Here we profile distal lung samples from healthy human donors across the lifespan. Gene expression profiling by bulk RNAseq reveals both increasing cellular senescence and pro-fibrotic pathway activation with age. Quantitation of telomere length shows progressive shortening with age, which is associated with DNA damage foci and cellular senescence. Cell type deconvolution analysis of the RNAseq data indicates a progressive loss of lung epithelial cells and an increasing proportion of fibroblasts with age. Consistent with this pro-fibrotic profile, second harmonic imaging of aged lungs demonstrates increased density of interstitial collagen as well as decreased alveolar expansion and surfactant secretion. In this work, we reveal the transcriptional and structural features of fibrosis and associated functional impairment in normal lung aging.
Abstract Background Reference values for lung function tests should be periodically updated because of birth cohort effects and improved technology. This study updates the spirometric reference ...values, including vital capacity (VC), for Japanese adults and compares the new reference values with previous Japanese reference values. Methods Spirometric data from healthy non-smokers (20,341 individuals aged 17–95 years, 67% females) were collected from 12 centers across Japan, and reference equations were derived using the LMS method. This method incorporates modeling skewness (lambda: L ), mean (mu: M ), and coefficient of variation (sigma: S ), which are functions of sex, age, and height. In addition, the age-specific lower limits of normal (LLN) were calculated. Results Spirometric reference values for the 17–95-year age range and the age-dependent LLN for Japanese adults were derived. The new reference values for FEV1 in males are smaller, while those for VC and FVC in middle age and elderly males and those for FEV1 , VC, and FVC in females are larger than the previous values. The LLN of the FEV1 /FVC for females is larger than previous values. The FVC is significantly smaller than the VC in the elderly. Conclusions The new reference values faithfully reflect spirometric indices and provide an age-specific LLN for the 17–95-year age range, enabling improved diagnostic accuracy. Compared with previous prediction equations, they more accurately reflect the transition in pulmonary function during young adulthood. In elderly subjects, the FVC reference values are not interchangeable with the VC values.
The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical ...containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.
Non-recirculating tissue-resident memory T cells (TRMs) are the predominant T cell subset in diverse tissue sites, where they mediate protective immune responses in situ. Here, we reveal a role for ...TRM in maintaining immune homeostasis in the human pancreas through interactions with resident macrophages and the PD-1/PD-L1 inhibitory pathway. Using tissues obtained from organ donors, we identify that pancreas T cells comprise CD8+PD-1hi TRMs, which are phenotypically, functionally, and transcriptionally distinct compared to TRMs in neighboring jejunum and lymph node sites. Pancreas TRMs cluster with resident macrophages throughout the exocrine areas; TRM effector functions are enhanced by macrophage-derived co-stimulation and attenuated by the PD-1/PD-L1 pathways. Conversely, in samples from chronic pancreatitis, TRMs exhibit reduced PD-1 expression and reduced interactions with macrophages. These findings suggest important roles for PD-1 and TRM-macrophage interactions in controlling tissue homeostasis and immune dysfunctions underlying inflammatory disease, with important implications for PD-1-based immunotherapies.
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•The human pancreas contains CD8+ TRMs exhibiting tissue-specific molecular signatures•Pancreas TRMs express high levels of PD-1 yet maintain strong effector function•During homeostasis, pancreas TRMs are regulated by PD-L1+ tissue macrophages•In chronic pancreatitis, TRM PD-1 levels and PD-L1+ macrophage density are reduced
Non-recirculating tissue-resident memory T cells (TRMs) mediate immune responses in non-lymphoid tissues. Using a human organ donor tissue resource, Weisberg et al. reveal that PD-1hi pancreas TRMs are regulated by PD-L1+ macrophages during homeostasis. Comparison with chronic pancreatitis patient samples shows how pancreas TRM regulation is altered during inflammation.
Immune checkpoint inhibitor has greatly altered the standard of care for patients with advanced non–small-cell lung cancer (NSCLC). This prospective study reported the benefits of nivolumab in a ...routine clinical practice. Furthermore, neutrophil-to-lymphocyte ratio was identified as a candidate of predictive markers in nivolumab-treated NSCLC patients.
The immune checkpoint inhibitor nivolumab is entering routine oncologic practice. We investigated the safety and efficacy of nivolumab in the real world and alternative predictive factors for survival in patients with advanced non–small-cell lung cancer (NSCLC).
We performed a prospective observational study to evaluate the activity of nivolumab treatment for chemotherapy-refractory NSCLC. Patients were treated with nivolumab once every 2 weeks, and the efficacy was assessed every 8 ± 2 weeks.
Fifty-two patients were enrolled after nivolumab approval in Japan. These patients received a median of 4 (range, 1-43) cycles of nivolumab. Overall objective response was observed in 12 patients (23.1%). Median progression-free survival was 2.1 (95% confidence interval, 1.0-3.2) months, and 1-year overall survival rate was 59.9%. A total of 23 immune-related adverse events occurred in 20 patients, as follows: 7 cases of pneumonitis, 6 of oral mucositis, 5 of hypothyroidism, 2 of colitis, 2 of liver dysfunction, and 1 of arthritis. All patients recovered after appropriate management. A pretreatment neutrophil-to-lymphocyte ratio (NLR) of ≥ 5 was significantly associated with poor prognosis compared to NLR < 5 (hazard ratio, 4.52; 95% confidence interval, 1.84-11.14; P = .013), independently.
Nivolumab showed promising activity with a manageable safety profile in clinical practice, consistent with effects of previous clinical trials. This drug could affect a specific population of patients with advanced NSCLC, and pretreatment NLR was a candidate for surrogate markers for survival benefit of patients with NSCLC treated with nivolumab.
Adaptive immune responses to SARS-CoV-2 infection have been extensively characterized in blood; however, most functions of protective immunity must be accomplished in tissues. Here, we report from ...examination of SARS-CoV-2 seropositive organ donors (ages 10 to 74) that CD4
T, CD8
T, and B cell memory generated in response to infection is present in the bone marrow, spleen, lung, and multiple lymph nodes (LNs) for up to 6 months after infection. Lungs and lung-associated LNs were the most prevalent sites for SARS-CoV-2–specific memory T and B cells with significant correlations between circulating and tissue-resident memory T and B cells in all sites. We further identified SARS-CoV-2–specific germinal centers in the lung-associated LNs up to 6 months after infection. SARS-CoV-2–specific follicular helper T cells were also abundant in lung-associated LNs and lungs. Together, the results indicate local tissue coordination of cellular and humoral immune memory against SARS-CoV-2 for site-specific protection against future infectious challenges.
Oligometastasis is a state in which cancer patients have a limited number of metastatic tumors; patients with oligometastases survive longer than those with polymetastases. Extensive disease ...(ED)-small cell lung cancer (SCLC) is considered a systemic disease and a poor survival. This study investigated whether the concept of oligometastases is prognostic factor also applicable to patients with ED-SCLC.
We performed a retrospective study of 141 consecutive patients with ED-SCLC between 2008 and 2016. The patients were divided into four subgroups: group 1; patients with solitary metastatic site in one organ (n = 31), group 2; patients with 2-5 metastatic sites in one organ (n = 18), group 3; patients with over 6 metastases in one organ (n = 15), and group 4; patients with 2 or more metastatic organs (n = 77).
It was identified that 49 patients with ED-SCLC had oligometastases (groups 1 + 2) and 92 had polymetastases (groups 3 + 4). The prognoses of patients with ED-SCLC and oligometastases, defined as ≤5 metastases in a single organ, were significantly superior to those of patients with polymetastases 16.0 (95% CI, 11.0-21.0) months vs. 6.9 (95% CI, 6.0-7.8) months; p<0.001. 43 of 49 patients with ED-SCLC and oligometastases were relapsed after initial chemotherapy, and 38 (88%) experienced local recurrence.
Patients with ED-SCLC and oligometastases may have improved survival than those with polymetastases. As oligometastatic ED-SCLC tends to recur locally, local therapy combined with systemic chemotherapy may be a treatment option.
Children with severe motor and intellectual disabilities (SMID) are at a high risk of malnutrition and often require tube feeding to maintain their nutritional status. However, determining their ...energy requirements is difficult since inadequate dietary intake, severe neurological impairment, respiratory assistance, and cognitive impairment are all factors that affect malnutrition in SMID.
This study investigated the factors affecting malnutrition and identified problems affecting the nutritional status of children with SMID.
Forty-two children with SMID with oral motor dysfunction who were receiving home medical care at one of four hospitals were enrolled. Their nutritional status was assessed using a 3-day dietary record, anthropometric measurements, and laboratory tests. The clinical findings associated with malnutrition were compared, and a body mass index (BMI) z-score less than −2SD was defined as malnutrition. The relationship between BMI z-score and other potential predictors was also investigated.
Thirty-three (79%) children received tube feeding, and 20 (48%) experienced malnutrition. The median age of the malnourished children was older than that of non-malnourished children. Respiratory assistance was significantly correlated with higher BMI z-score, independent of other potential confounders such as nutrition method, muscle tonus, and energy intake. Cholesterol levels were significantly higher in children receiving a standard infant formula beyond 3 years of age than in those who switched to enteral formula before 3 years of age.
Malnutrition in children with SMID was mainly associated with age or respiratory condition. Energy requirements should be regularly re-evaluated with considering these factors.
Summary
Background
Exon 19 deletion and L858R point mutation in exon 21 of the epidermal growth factor receptor (
EGFR
) are the most commonly encountered mutations in patients with non-small cell ...lung cancer (NSCLC) and predict better clinical outcomes following treatment with EGFR-tyrosine kinase inhibitors (TKIs). The inflammatory indicator neutrophil-to-lymphocyte ratio (NLR) in peripheral blood serves as a predictive factor for NSCLC patients treated with chemotherapy. Here, we aimed to evaluate the correlation between NLR and clinical efficacy of EGFR-TKIs in NSCLC patients harboring
EGFR
mutations.
Methods
We retrospectively collected information of 205 patients with advanced NSCLC harboring exon 19 deletion or L858R point mutation and receiving gefitinib or erlotinib. The clinical outcomes in the NSCLC patients were evaluated based on NLR level before EGFR-TKI therapy.
Results
The optimal cut-off value for NLR was 3.55. The response rates in the low-NLR and high-NLR groups were 69.2% and 51.5%, respectively. The median progression-free survival (PFS) in the low-NLR and high-NLR groups were 15.7 months and 6.7 months, respectively. The median overall survival (OS) in the low-NLR and high-NLR groups were 37.6 months and 19.2 months, respectively. The multivariate analysis identified performance status (PS), NLR, stage, and smoking status as independent predictors of PFS. Moreover, the PS and NLR were identified as independent predictors of OS.
Conclusions
NLR was a significant predictor of clinical efficacy and OS in NSCLC patients harboring
EGFR
mutations treated with gefitinib or erlotinib.
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