[The 506th case: fever of unknown origin, negative PET-CT and hemoperitoneum].

A 48-year-old male was admitted to Peking Union Medical College Hospital presented with intermittent fever for two years. The maximum body temperature was 39 ℃, and could spontaneously relieve. The efficacy of antibacterial treatment was poor. He had no other symptoms and positive signs. He had a significant weight loss, and the serum lactate dehydrogenase increased significantly. It was highly alert to be lymphoma, but bone marrow smear and pathology, and PET-CT had not shown obvious abnormalities. Considering high inflammatory indicators, increased ferritin and large spleen, the patient had high inflammatory status, and was treated with methylprednisolone. Then the patient's body temperature was normal, but the platelet decreased to 33×109/L. During hospitalization, he had suddenly hemoperitoneum and hemorrhagic shock. He was found spontaneous spleen rupture without obvious triggers, and underwent emergency splenectomy. The pathological diagnosis of spleen was diffuse large B-cell lymphoma.

Human body numerical simulation: An accurate model for a thigh subjected to a cold treatment.

This article presents the development of a digital twin model of a thigh portion subjected to various thermal treatments. Two scenarios are investigated: cold water immersion (CWI) and whole body cryotherapy (WBC), for which the comparison of numerical results with experimental measurements validates the consistency of the developed model. The use of real geometry on a first subject demonstrates the high heterogeneity of the temperature field and the need for accurate geometry. A second subject with thicker adipose tissue highlights the impact of the subject's actual morphology on the validity of the treatment and the necessity to work with real geometry in order to optimize cold modalities and develop personalized treatments.

[A multi-center analysis of thyroid-stimulating hormone level in apparently healthy elderly population in China].

OBJECTIVE: To investigate serum thyroid stimulating hormone (TSH) level and its changes with age in apparently healthy Chinese elderly population and analyze the differences between TSH levels detected using Roche and Snibe electrochemiluminescence immunoassay analyzers. METHODS: General clinical data and frozen fasting serum samples were collected from 5451 apparently healthy Chinese elderly individuals (> 60 years) from 10 centers in different geographic regions in China. Thyroid function indexes including TSH level were detected using Roche and Snibe electrochemiluminescence immunoassay analyzer, and the median (2.5% and 97.5% quantiles) TSH level was calculated. The variations of TSH level among the participants with geographic regions, gender, and age (with an interval of 5 years) were analyzed to determine the influence of these factors on TSH level. RESULTS: The reference ranges of serum TSH level established using Roche and Snibe electrochemiluminescence immunoassay analyzers were 0.42-9.47 mU/L and 0.36-7.98 mU/L, respectively, showing significant differences between the two methods (P < 0.001). The TSH levels measured at two centers in Western China were significantly higher than those at the other centers (P < 0.05). In elderly male population, serum TSH level tended to increase with age, which was not observed in elderly female population. At the age of 60-75 years, women generally had higher serum TSH level than men, but this difference was not observed in the population beyond 75 years. CONCLUSION: In elderly population, serum TSH level can vary with geographic region, gender, and age, but there was no need for establishing specific reference ranges for these factors. The differences between different detection methods should be evaluated when interpreting the detection results of TSH level.

Threshold of 25(OH)D and consequently adjusted parathyroid hormone reference intervals: data mining for relationship between vitamin D and parathyroid hormone.

PURPOSE: By recruiting reference population, we aimed to (1): estimate the 25(OH)D threshold that maximally inhibits the PTH, which can be defined as the cutoff value for vitamin D sufficiency; (2) establish the PTH reference interval (RI) in population with sufficient vitamin D. METHODS: Study data were retrieved from LIS (Laboratory Information Management System) under literature suggested criteria, and outliers were excluded using Tukey fence method. Locally weighted regression (LOESS) and segmented regression (SR) were conducted to estimate the threshold of 25(OH)D. Multivariate linear regression was performed to evaluate the associations between PTH concentration and variables including 25(OH)D, gender, age, estimated glomerular filtration rate (EGFR), body mass index (BMI), albumin-adjusted serum calcium (aCa), serum phosphate(P), serum magnesium(Mg), and blood collection season. Z test was adopted to evaluate whether the reference interval should be stratified by determinants such as age and gender. RESULTS: A total of 64,979 apparently healthy subjects were recruited in this study, with median (Q1, Q3) 25(OH)D of 45.33 (36.15, 57.50) nmol/L and median (Q1, Q3) PTH of 42.19 (34.24, 52.20) ng/L. The segmented regression determined the 25(OH)D threshold of 55 nmol/L above which PTH would somewhat plateau and of 22 nmol/L below which PTH would rise steeply. Multivariate linear regression suggested that gender, EGFR, and BMI were independently associated with PTH concentrations. The PTH RI was calculated as 22.17-72.72 ng/L for subjects with 25(OH)D ≥ 55 nmol/L with no necessity of stratification according to gender, age, menopausal status nor season. CONCLUSION: This study reported 25(OH)D thresholds of vitamin D sufficiency at 55 nmol/L and vitamin D deficiency at 22 nmol/L, and consequently established PTH RIs in subjects with sufficient vitamin D for northern China population for the first time.

[Palliative care in China: a way out of the dilemma].

It is still common for terminally ill patients to suffer from pain, and the development of palliative care faces many obstacles. The value of death to human society is ignored, and the intrinsic relationship between the meaning of life and the value of death has not been fully explored. This article discusses the current status of palliative care in China, how clinicians reflect and respond, the change of the whole society's concept of palliative care, and suggestions for action, and tries to provide a medical humanistic perspective for walking out of the dilemma of palliative care.

Comparison of Telomere Length between Buccal Cells and Blood Cells.

Telomere length (TL) in blood cells is commonly used as a proxy for TL in other tissue types. The source of DNA of adequate quality and quantity is important for TL analysis. Compared to blood cells, buccal cells easy for genomic DNA preparation would facilitate the rapid and reliable TL analysis. However, the feasibility of buccal cells for TL analysis remains yet unestablished. We characterized TL of buccal cells and blood cells collected from 52 individuals using buccal cell swabs and fingertip sticks. Relative TL (RTL) determined by quantitative PCR showed that there is a strong correlation between buccal RTL and blood RTL (r=0.877, p<0.001), suggesting that buccal cells are adequate sources of DNA for TL analysis. The validity of sampling using buccal cell swabs provides simple operation and good reproducibility for TL analysis, that overcomes the discomfort and risk of infection caused by blood sampling.

Preclinical Immune Response and Safety Evaluation of the Protein Subunit Vaccine Nanocovax for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern. The development of vaccines with high immunogenicity and safety is crucial for controlling the global COVID-19 pandemic and preventing further illness and fatalities. Here, we report the development of a SARS-CoV-2 vaccine candidate, Nanocovax, based on recombinant protein production of the extracellular (soluble) portion of the spike (S) protein of SARS-CoV-2. The results showed that Nanocovax induced high levels of S protein-specific IgG and neutralizing antibodies in three animal models: BALB/c mouse, Syrian hamster, and a non-human primate (Macaca leonina). In addition, a viral challenge study using the hamster model showed that Nanocovax protected the upper respiratory tract from SARS-CoV-2 infection. Nanocovax did not induce any adverse effects in mice (Mus musculus var. albino) and rats (Rattus norvegicus). These preclinical results indicate that Nanocovax is safe and effective.

LncRNA NORAD promotes thyroid carcinoma progression by targeting miR-451.

OBJECTIVE: Long non-coding RNA (lncRNA) NORAD plays an essential role in the development and progress of papillary thyroid carcinoma (PTC). MicroRNA-451 (MiR-451) has been identified as playing an inhibitory role in some types of cancer. However, the molecular mechanism of lncRNA NORAD regulating metastasis of PTC cells by miR-451 has not been fully elucidated. MATERIALS AND METHODS: Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) or Western blot analysis of the expression of NORAD, miR-451, and interleukin-6 receptor (IL-6R) in PTC cell lines were carried out. The detection of Luciferase reporter gene showed the relationship between lncRNA NORAD, miR-451 and IL-6R. Cell Counting Kit-8 (CCK-8) assay and transwell assay were performed to detect the influence of lncRNA NORAD, miR-451 on the proliferation, migration, and invasion of PTC cells. RESULTS: The results of RT-qPCR and Western blotting suggested that the expression of lncRNA NORAD and IL-6R were higher than that of the control group, while the expression of miR-451 was lower. Transwell assay indicated that the knockdown of lncRNA NORAD or overexpression of miR-451 significantly inhibited cell proliferation, migration and invasion in PTC cell lines. In addition, lncRNA NORAD negatively controls the expression of miR-451, resulting in the upregulation of IL-6R. IL-6R overexpression can reverse the inhibitory effect of lncRNA NORAD knockdown or miR-451 on PTC cell proliferation and metastasis. CONCLUSIONS: Our results indicated that the cell migration and invasion were inhibited by knockdown of lncRNA NORAD or overexpression of miR-451, suggesting that the axis of lncRNA NORAD -miR-451- IL-6R was involved in the development of PTC.

[Surveillance and genetic characteristics of imported cases of measles virus of D8 genotype in Hebei province].

Objective: To understand the epidemiological and genotypic characteristics of imported cases of measles virus of D8 genotype in Hebei province. Methods: Epidemiological investigation of measles cases in surveillance was carried out. The throat swabs of the measles cases in acute phase were collected for real time RT-PCR identification, measles virus culture and genotype identification. Results: A total of 36 imported measles cases of genotype D8 were detected. The cases were mainly distributed in 8 counties of Handan city. Number of confirmed measles cases in Cheng'an county was the highest, accounting for 58.33% (21/36) of all the reported cases. All patients had fever and rash, and 55.55% (20/36) of the cases were under 2 years old and 86.11% (31/36) of the cases had no immunization history. The children with pneumonia accounted for 44.12% (15/34) of the total children with D8 genotype measles virus infection. The nucleotide and amino acid homologies between the imported measles virus genotype D8 and the WHO reference strain of D8 genotype (D8-Manchester.UNK/30.94) were 98.4%-98.6% and 97.3%, respectively. Compared with the strains of H1 genotype in China, the nucleotide and amino acid homologies were 92.8%-93.1% and 93.3%, respectively. Conclusions: The imported cases of measles virus of D8 genotype might have caused local transmission in Hebei province. Molecular epidemiological surveillance for measles virus needs to be further strengthened. It is necessary to detect and control the epidemic early and improve the coverage rate and timely rate of measles vaccination. It is also important to prevent cross infection in hospitals.

Upholding ethical values and human rights at the frontier of TB research.

Until recently, human rights have played a minor role in the fight against tuberculosis (TB), even less so in TB research. This is changing, however. The WHO's End TB Strategy and Ethics Guidance stress respect for human rights and ethical principles in every area of TB care, including research. The desired reductions in TB incidence and mortality are impossible without new tools and strategies to fight the disease. Yet, little suggests that the current state of TB research-including funding levels, evidence being produced, and community involvement-will alleviate concerns related to the availability, accessibility, and acceptability of TB diagnostics, drugs, and prevention in the near future. In this article, we consider these ethics concerns in relation to the right to enjoy the benefits of scientific progress and the right to health. We also reflect on community involvement in research and offer recommendations in the spirit of the rights to health and science, such as involving affected communities in all aspects of research planning, execution, and dissemination. Finally, we argue that states have a responsibility under international law for the continued realization of the right to health. This realization rests, in part, on the realization of the right to science.

MiR-526b suppresses cell proliferation, cell invasion and epithelial-mesenchymal transition in breast cancer by targeting Twist1.

OBJECTIVE: The aberrant expression of microRNAs (miRNAs) acts as crucial regulators in the tumorigenesis of breast cancer (BC). The aim of the study is to investigate the functional effects of miR-526b expression in breast cancer progression. PATIENTS AND METHODS: The expression level of miR-526b in breast cancer tissues and cell lines was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cell proliferation, migration, and invasion capacity was detected by CCK-8 cell proliferation, colony formation, and transwell invasion assays after up-regulating or down-regulating miR-526b expression in breast cancer cells. Bioinformatics analysis and Dual-Luciferase reporter gene assays were used to demonstrate that Twist1 was a target of miR-526b. Western blot analysis was also performed. RESULTS: We showed that miR-526b expression was significantly downregulated in breast cancer tissues compared to adjacent normal tissues. Lower miR-526b expression was associated with lymph node metastasis in breast cancer patients. Function assays showed that upregulation of miR-526b expression suppressed cell proliferation, cell colony formation, and cell invasion ability in breast cancer. Furthermore, the upregulation of miR-526b suppressed EMT makers Vimentin expression but increased the E-cadherin expression. Mechanically, we showed that miR-526b inhibited cell EMT process by targeting Twist1 expression. CONCLUSIONS: Thus, our evidence indicated that miR-526b may serve as a potential target of breast cancer treatment.

Plasmonics of Diffused Silver Nanoparticles in Silver/Nitride Optical Thin Films.

Metal-dielectric multilayers are versatile optical devices that can be designed to combine the visible transmittance of dielectrics with the electronic properties of metals for plasmonic and meta-material applications. However, their performances are limited by an interfacial optical absorption often attributed entirely to the metal surface roughness. Here, we show that during deposition of AlN/Ag/AlN and SiNx/Ag/SiNx multilayers, significant diffusion of Ag into the top dielectric layer form Ag nanoparticles which excite localized surface plasmon resonances that are primarily responsible for the interfacial optical absorption. Based on experimental depth profiles, we model the multilayer's silver concentration profile as two complementary error functions: one for the diffused Ag nanoparticles and one for the interface roughness. We apply the Maxwell-Garnett and Bruggeman effective medium theories to determine that diffusion characteristics dominate the experimental absorption spectra. The newfound metal nanoparticle diffusion phenomenon effectively creates a hybrid structure characteristic of both metal-dielectric multilayer and metal-dielectric composite.

Bacillus coagulans and its applications in medicine.

Bacillus coagulans is a probiotic bacterium that produces spores. Due to its excellent stability, it has been widely used in medicine, food and chemical industry. Recent studies have shown that B. coagulans has therapeutic effects on intestinal diseases, such as acute diarrhoea, irritable bowel syndrome, antibiotic-related diarrhoea, constipation and colitis via modulation of the microbiota composition, host immunity and metabolism. Additionally, toxicological experiments and a large number of clinical observations have showed that B. coagulans is safe and has no effect of mutagenicity, teratogenicity or genotoxicity. This review summarises the latest advances associated with B. coagulans, from its biological features, probable action mechanisms, toxicity, and medical applications.

Bacillus coagulans and its applications in medicine.

Bacillus coagulans is a probiotic bacterium that produces spores. Due to its excellent stability, it has been widely used in medicine, food and chemical industry. Recent studies have shown that B. coagulans has therapeutic effects on intestinal diseases, such as acute diarrhoea, irritable bowel syndrome, antibiotic-related diarrhoea, constipation and colitis via modulation of the microbiota composition, host immunity and metabolism. Additionally, toxicological experiments and a large number of clinical observations have showed that B. coagulans is safe and has no effect of mutagenicity, teratogenicity or genotoxicity. This review summarises the latest advances associated with B. coagulans, from its biological features, probable action mechanisms, toxicity, and medical applications.

Quantitative determination of endogenous cardiolipin in rat cerebral tissues by high-performance liquid chromatography using standard addition method.

Cardiolipin is an important cellular component, and its normal level is a key prerequisite for maintaining the structure and function of mitochondria. To accurately quantify endogenous cardiolipin content in mitochondria, a standard addition method (SAM) was developed to establish a high-performance liquid chromatographic (HPLC) technique that is both reliable and accurate. Increasing amounts of cardiolipin standards were added to a constant amount of isolated mitochondria prior to the extraction procedure, and the two were extracted together. By limiting the interference effects that occur to within an acceptable range in an analytical system examined, this procedure ensures an ideal match of the sample composition in the standards, even if the composition is extremely complex or completely unknown. Then, the desired results can be obtained by extrapolation. As such, the authentic content of the endogenous cardiolipin can be obtained with greater accuracy than with classical detection methods, e.g. external standard calibration (ESC) and internal standard calibration (ISC). This method provides an excellent means of quantifying endogenous substances in living cells. The authors expect this method to be useful for researchers working on mitochondria-related mechanisms, cell survival-related mechanisms and similar topics.

Smad nuclear interacting protein 1 (SNIP1) inhibits intestinal inflammation through regulation of epithelial barrier function.

Smad nuclear interacting protein 1 (SNIP1) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms involved are still largely unknown. Our results demonstrated that SNIP1 was markedly decreased in intestinal epithelial cells (IEC) from IBD patients compared with healthy controls. Impaired expression of SNIP1 caused a significant decrease of transepithelial electrical resistance but an increase of fluorescein isothiocyanate-dextran flux in Caco-2 monolayers, whereas overexpression of SNIP1 reversed such effects. Overexpression of SNIP1 also inhibited the activity of NF-κB p65 and proinflammatory cytokine production (e.g., TNF-α, IL-1ß, and IL-8) by IEC. Importantly, supplementation of exogenous SNIP1 significantly ameliorated intestinal mucosal inflammation in experimental colitis, characterized by less-severe intestinal epithelial barrier damage and decreased proinflammatory cytokine production. Our data thus demonstrated a novel mechanism whereby SNIP1 regulates intestinal inflammation through modulating intestinal epithelial barrier function. Targeting SNIP1 may provide a therapeutic approach for the treatment of IBD.

Microbiota metabolite short-chain fatty acid acetate promotes intestinal IgA response to microbiota which is mediated by GPR43.

Intestinal IgA, which is regulated by gut microbiota, has a crucial role in maintenance of intestinal homeostasis and in protecting the intestines from inflammation. However, the means by which microbiota promotes intestinal IgA responses remain unclear. Emerging evidence suggests that the host can sense gut bacterial metabolites in addition to pathogen-associated molecular patterns and that recognition of these small molecules influences host immune response in the intestines and beyond. We reported here that microbiota metabolite short-chain fatty acid acetate promoted intestinal IgA responses, which was mediated by "metabolite-sensing" GPR43. GPR43-/- mice demonstrated lower levels of intestinal IgA and IgA+ gut bacteria compared with those in wild type (WT) mice. Feeding WT but not GPR43-/- mice acetate but not butyrate promoted intestinal IgA response independent of T cells. Acetate promoted B-cell IgA class switching and IgA production in vitro in the presence of WT but not GPR43-/- dendritic cells (DCs). Mechanistically, acetate-induced DC expression of Aldh1a2, which converts Vitamin A into its metabolite retinoic acid (RA). Moreover, blockade of RA signaling inhibited the acetate induction of B-cell IgA production. Our studies thus identified a new pathway by which microbiota promotes intestinal IgA response through its metabolites.