Disease spectrum and prognostic factors in patients treated for tuberculous meningitis in Shaanxi province, China.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China. Methods: A multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as "confirmed," "probable," or "possible" TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome-assessed using the modified Barthel disability index-were recorded and compared. Findings: A total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 "not TBM." Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298-11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372-10.761), age > 60 years (OR = 3.566; 95%CI: 1.022-12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027-5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score < 12; these patients exhibited less classic meningitis symptoms and signs and had better outcomes compared with those with a TBM score ≥ 12. In this group, signs of disseminated/miliary TB (OR = 12.427; 95%CI: 1.138-135.758) and a higher TBM score (≥15, OR = 8.437; 95%CI: 1.328-53.585) were most strongly associated with death. Conclusion: TBM patients who are older (>60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

Characteristics of Helicobacter pylori Heteroresistance in Gastric Biopsies and Its Clinical Relevance.

BACKGROUND: Antimicrobial susceptibility testing (AST) plays a vital role in anti-Helicobacter pylori treatment, but the traditional AST method has difficulty detecting heteroresistance, which may cause an increased prevalence of resistant strains and eradication failure. AIMS: To investigate the characteristics of heteroresistance in H. pylori in gastric biopsies and investigate its clinical relevance. METHOD: A total of 704 gastric biopsies were selected for 23S rRNA and gyrA gene sequencing, 470 H. pylori isolates from these biopsies were selected for AST, and the clinical characteristics of the patients were reviewed. RESULT: For the 699 biopsies that were positive for 23S rRNA gene, 98 (14.0%) showed a heteroresistance genotype, and a wild type (WT) combined with A2143G (86.7%) genotype was found in most samples. For the 694 biopsies that were positive for gyrA gene, 99 (14.3%) showed a heteroresistance genotype, and a WT combined with 87K (26.3%) or WT combined with 91N (23.2%) genotype was predominant. According to the E-test results, the resistance rates of heteroresistance genotype samples for clarithromycin and levofloxacin were 36.2% and 68.1%, respectively. When dividing the heteroresistance samples into different groups according to the sequencing profile peaks of the mutation position, the resistance rates were higher along with mutation peaks at the mutation position. In addition, patients infected with mutated or heteroresistant strains showed lower peptic ulcer detection rates than those infected with the WT strain (p < 0.05). CONCLUSION: Heteroresistance genotypes for clarithromycin and levofloxacin were not rare in H. pylori. Most cases with a heteroresistance genotype showed a susceptible phenotype for clarithromycin and a resistance phenotype for levofloxacin. Patients infected with heteroresistance genotype strains showed a lower peptic ulcer detection rate than those infected with the WT strain.

Reduction of Human DNA Contamination in Clinical Cerebrospinal Fluid Specimens Improves the Sensitivity of Metagenomic Next-Generation Sequencing.

Metagenomics next-generation sequencing (mNGS) is increasingly available for the detection of obscure infectious diseases of the central nervous system. However, human DNA contamination from elevated white cells, one of the characteristic cerebrospinal fluid (CSF) features in meningitis patients, greatly reduces the sensitivity of mNGS in the pathogen detection. Currently, effective approaches to selectively reduce host DNA contamination from clinical CSF samples are still lacking. In this study, a total of 20 meningitis patients were enrolled, including 10 definitively diagnosed tuberculous meningitis (TBM) and 10 definite cryptococcal meningitis (CM) cases. To evaluate the effect of reduced human DNA in the sensitivity of mNGS detection, three specimen-processing protocols were performed: (i) To remove human DNA, saponin, a nonionic surfactant, was used to selectively lyse white cells in CSF followed by DNase treatment prior to the extraction of DNA; (ii) to reduce host DNA, CSF was centrifuged to remove human cells, and the supernatant was collected for DNA extraction; and (iii) DNA extraction from the unprocessed specimens was set as the control. We found that saponin processing significantly elevated the NGS unique reads for Cryptococcus (P < 0.01) compared with the control but had no effects for Mycobacterium tuberculosis (P > 0.05). However, detection of centrifuged supernatants improved the NGS unique reads for both TBM and CM compared with controls (P < 0.01). Our results demonstrate that the use of mNGS of centrifuged supernatants from clinical CSF samples in patients with TBM and CM is a simple and effective method to improve the sensitivity of pathogen detection.

Fine particulate matter (PM2.5): The culprit for chronic lung diseases in China.

Air pollution is a world public health problem. Particulate matter (PM), a mix of solid and liquid particles in the air, becomes an increasing concern in the social and economic development of China. For decades, epidemiological studies have confirmed the association between fine particle pollutants and respiratory diseases. It has been reported in different populations that increased Fine particulate matter (PM2.5) concentrations cause elevated susceptibility to respiratory diseases, including acute respiratory distress, asthma, chronic obstructive pulmonary disease, and lung cancer. This review will discuss the pathophysiology of PM2.5 in respiratory diseases, which are helpful for the prevention of air pollution and treatment of respiratory tract inflammatory diseases.

Inhibitive Effects of FGF2/FGFR1 Pathway on Astrocyte-Mediated Inflammation in vivo and in vitro After Infrasound Exposure.

Infrasound, a kind of ambient noise, can cause severe disorders to various human organs, specially to central nervous system (CNS). Our previous studies have shown that infrasound-induced CNS injury was closely related with astrocytes activation and astrocytes-mediated neuroinflammation, but the underlying molecular mechanisms are still largely unclear. FGF2/FGFR1 (Fibroblast growth factor 2/Fibroblast growth factor receptor 1) pathway was reported to play an important role in anti-inflammation in CNS disorders. To further study the possible roles of FGF2/FGFR1 pathway in infrasound-induced CNS injury, here we exposed Sprague-Dawley rats or cultured astrocytes to 16 Hz, 150 dB infrasound, and explored the effects of FGF2 on infrasound-induced astrocytes activation and neuroinflammation. Western blotting, immunofluorescence and liquid chip method were used in this experiment. Our results showed that after 3- or 7-day exposure (2 h/day) of rats as well as 2 h exposure of cultured astrocytes to 16 Hz, 150 dB infrasound, astrocyte-expressed FGFR1 was downregulated in vivo and in vitro. FGF2 pretreatment not only inhibited infrasound-induced astrocyte activation in rat hippocampal CA1 region, but also reduced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1ß, IL-18, IL-6, and IFN-γ in vitro and in vivo. However, FGF2 significantly upregulated the expression of FGFR1. Furthermore, we showed that FGF2 could attenuate IκBα phosphorylation, NF-κB p65 translocation, pro-inflammatory cytokines levels, and neuronal loss in the CA1 region induced by infrasound. On the contrary, PD173074, a special antagonist of FGFR1, could reverse the effects above in vitro and in vivo. Taken together, our findings showed that FGF2/FGFR1 pathway may exert inhibitive effects on astrocyte-mediated neuroinflammation in vitro and in vivo after infrasound exposure.

Air pollutants and early origins of respiratory diseases.

Air pollution is a global health threat and causes millions of human deaths annually. The late onset of respiratory diseases in children and adults due to prenatal or perinatal exposure to air pollutants is emerging as a critical concern in human health. Pregnancy and fetal development stages are highly susceptible to environmental exposure and tend to develop a long-term impact in later life. In this review, we briefly glance at the direct impact of outdoor and indoor air pollutants on lung diseases and pregnancy disorders. We further focus on lung complications in later life with early exposure to air pollutants. Epidemiological evidence is provided to show the association of prenatal or perinatal exposure to air pollutants with various adverse birth outcomes, such as preterm birth, lower birth weight, and lung developmental defects, which further associate with respiratory diseases and reduced lung function in children and adults. Mechanistic evidence is also discussed to support that air pollutants impact various cellular and molecular targets at early life, which link to the pathogenesis and altered immune responses related to abnormal respiratory functions and lung diseases in later life.

Effects of particulate matter on allergic respiratory diseases.

The health impact of airborne particulate matter (PM) has long been a concern to clinicians, biologists, and the general public. With many epidemiological studies confirming the association of PM with allergic respiratory diseases, an increasing number of follow-up empirical studies are being conducted to investigate the mechanisms underlying the toxic effects of PM on asthma and allergic rhinitis. In this review, we have briefly introduced the characteristics of PM and discussed its effects on public health. Subsequently, we have focused on recent studies to elucidate the association between PM and the allergic symptoms of human respiratory diseases. Specifically, we have discussed the mechanism of action of PM in allergic respiratory diseases according to different subtypes: coarse PM (PM2.5-10), fine PM (PM2.5), and ultrafine PM.

Targeting Neutrophils in Severe Asthma via Siglec-9.

Severe asthma comprises only 5% of patients with asthma, but the burden it brings to the social health system accounts for more than half of all asthmatics. Clinical evidence shows that severe asthma is often linked to the recruitment and activation of neutrophils in the airways. However, the underlying molecular and immunological mechanisms of neutrophilia in severe asthma are not clear and currently available drugs exert only limited effects on neutrophilic inflammation. Great efforts are underway to address the mystery of neutrophilic inflammation in chronic respiratory disorders. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are members of the immunoglobulin gene family. Of note, Siglec-9 is uniquely expressed by human neutrophils and monocytes, as well as a minor population of natural killer cells. Engaging this structure with antibodies or glycan ligands results in programmed cell death in human neutrophils. Intriguingly, the administration of Siglec-E antibody abolished the recruitment of neutrophils in mouse models of neutrophilic pulmonary inflammation in vivo. Given that neutrophils are probably a major culprit in the generation and perpetuation of inflammation, targeting Siglec-9 could be beneficial for the treatment of severe asthma, chronic obstructive pulmonary disease, and related pulmonary disorders characteristic of neutrophilia.

In vivo near-infrared fluorescence imaging of amyloid-ß plaques with a dicyanoisophorone-based probe.

A dicyanoisophorone-based probe with two-photon absorption and NIR emission was developed for the in vivo fluorescence imaging of amyloid-ß plaques, which exhibited high selectivity toward Aß aggregates over other intracellular proteins. The detection limit was calculated to be as low as 109 nM. In vivo imaging studies indicated that the probe could penetrate the blood-brain barrier and label Aß plaques in the living transgenic mice, and its specific binding to cerebral Aß plaques was further confirmed by one- and two-photon ex vivo fluorescence imaging. All these results featured its promising application prospects for amyloid-ß sensing in basic research and biomedical research.