Toxic Epidermal Necrolysis Induced by Sintilimab: A Case Report.

Sintilimab is an anti-programmed cell death receptor-1 antibody. The phase III clinical trial ORIENT-12 confirmed the safety of sintilimab combined with pemetrexed/platinum in the treatment of advanced squamous non-small cell lung cancer. Skin reactions are the most commonly reported adverse events of immune checkpoint inhibitors and are rarely severe. We describe a case of toxic epidermal necrolysis related to sintilimab in an elderly oncologic patient. 3 weeks after immunotherapy, the patient developed an extensive rash and diffuse itching, rapidly evolving into macules, blisters, bullae and erosions. Causal evaluation was performed based on the algorithm of drug causality for epidermal necrolysis and national Food and Drug Administration qualitative analysis. The patient responded to high-dose glucocorticosteroid and supportive therapy, alongside with local wound care. If immune checkpoint inhibitors need to be extrapolated clinically, strictly following evidence-based research, promptly detecting and treating adverse reactions is crucial.

Vancomycin dosing in an obese patient with acute renal failure: A case report and review of literature.

BACKGROUND: Vancomycin is the most commonly used drug for methicillin-resistant Staphylococcus aureus. The empirical clinical doses of vancomycin based on non-obese patients may not be optimal for obese ones. CASE SUMMARY: This study reports a case of vancomycin dosing adjustment in an obese patient (body mass index 78.4 kg/m2) with necrotizing fasciitis of the scrotum and left lower extremity accompanied with acute renal failure. Dosing adjustment was performed based on literature review and factors that influence pharmacokinetic parameters are analyzed. The results of the blood drug concentration monitoring confirmed the successful application of our dosing adjustment strategy in this obese patient. Total body weight is an important consideration for vancomycin administration in obese patients, which affects the volume of distribution and clearance of vancomycin. The alterations of pharmacokinetic parameters dictate that vancomycin should be dose-adjusted when applied to obese patients. At the same time, the pathophysiological status of patients, such as renal function, which also affects the dose adjustment of the patient, should be considered. CONCLUSION: Monitoring vancomycin blood levels in obese patients is critical to help adjust the dosing regimen to ensure that vancomycin concentrations are within the effective therapeutic range and to reduce the incidence of renal injury.

Chinese Medicinal Herb-Derived Carbon Dots for Common Diseases: Efficacies and Potential Mechanisms.

The management of hemorrhagic diseases and other commonly refractory diseases (including gout, inflammatory diseases, cancer, pain of various forms and causes) are very challenging in clinical practice. Charcoal medicine is a frequently used complementary and alternative drug therapy for hemorrhagic diseases. However, studies (other than those assessing effects on hemostasis) on charcoal-processed medicines are limited. Carbon dots (CDs) are quasi-spherical nanoparticles that are biocompatible and have high stability, low toxicity, unique optical properties. Currently, there are various studies carried out to evaluate their efficacy and safety. The exploration of using traditional Chinese medicine (TCM) -based CDs for the treatment of common diseases has received great attention. This review summarizes the literatures on medicinal herbs-derived CDs for the treatment of the difficult-to-treat diseases, and explored the possible mechanisms involved in the process of treatment.

Vesicle-Cloaked Virus Clusters Are Optimal Units for Inter-organismal Viral Transmission.

In enteric viral infections, such as those with rotavirus and norovirus, individual viral particles shed in stool are considered the optimal units of fecal-oral transmission. We reveal that rotaviruses and noroviruses are also shed in stool as viral clusters enclosed within vesicles that deliver a high inoculum to the receiving host. Cultured cells non-lytically release rotaviruses and noroviruses inside extracellular vesicles. In addition, stools of infected hosts contain norovirus and rotavirus within vesicles of exosomal or plasma membrane origin. These vesicles remain intact during fecal-oral transmission and thereby transport multiple viral particles collectively to the next host, enhancing both the MOI and disease severity. Vesicle-cloaked viruses are non-negligible populations in stool and have a disproportionately larger contribution to infectivity than free viruses. Our findings indicate that vesicle-cloaked viruses are highly virulent units of fecal-oral transmission and highlight a need for antivirals targeting vesicles and virus clustering.

Short-day signals are crucial for the induction of anthocyanin biosynthesis in Begonia semperflorens under low temperature condition.

The leaves of Begonia semperflorens accumulate anthocyanins and turn red in autumn in sub-temperate areas. This induction of anthocyanin biosynthesis in autumn has been attributed to the effects of low temperature, but the effects of different light regimes on this process are still being debated. In the present work, short days were found to be necessary for anthocyanin biosynthesis at low temperature. Under the same low-temperature conditions, Begonia seedlings grown under the short-day condition accumulated more carbohydrates and abscisic acid (ABA), which both induce anthocyanin biosynthesis. However, fewer carbohydrates and more gibberellin (GA) accumulated under the long-day conditions to maintain growth, which blocked anthocyanin biosynthesis and resulted in a lack of increases in the activities of dihydroflavonol 4-reductase (DFR) and flavonoid-3-O-glucosyl transferase (UFGT). Consequently, carbon flux, which was altered due to the blockade of anthocyanin synthesis, was channelled into the production of quercetin and phenolic acids but not lignin.

Orderly Replication and Segregation of the Four Replicons of Burkholderia cenocepacia J2315.

Bacterial genomes typically consist of a single chromosome and, optionally, one or more plasmids. But whole-genome sequencing reveals about ten per-cent of them to be multipartite, with additional replicons which by size and indispensability are considered secondary chromosomes. This raises the questions of how their replication and partition is managed without compromising genome stability and of how such genomes arose. Vibrio cholerae, with a 1 Mb replicon in addition to its 3 Mb chromosome, is the only species for which maintenance of a multipartite genome has been investigated. In this study we have explored the more complex genome of Burkholderia cenocepacia (strain J2315). It comprises an extra replicon (c2) of 3.21 Mb, comparable in size to the3.87Mb main chromosome (c1), another extra replicon(c3) of 0.87 Mb and a plasmid of 0.09 Mb. The replication origin of c1 is typically chromosomal and those of c2 and c3 are plasmid-like; all are replicated bidirectionally. Fluorescence microscopy of tagged origins indicates that all initiate replication at mid-cell and segregate towards the cell quarter positions sequentially, c1-c2-p1/c3. c2 segregation is as well-phased with the cell cycle as c1, implying that this plasmid-like origin has become subject to regulation not typical of plasmids; in contrast, c3 segregates more randomly through the cycle. Disruption of individual Par systems by deletion of parAB or by addition of parS sites showed each Par system to govern the positioning of its own replicon only. Inactivation of c1, c2 and c3 Par systems not only reduced growth rate, generated anucleate cells and compromised viability but influenced processes beyond replicon partition, notably regulation of replication, chromosome condensation and cell size determination. In particular, the absence of the c1 ParA protein altered replication of all three chromosomes, suggesting that the partition system of the main chromosome is a major participant in the choreography of the cell cycle.

Enteroviruses harness the cellular endocytic machinery to remodel the host cell cholesterol landscape for effective viral replication.

Cholesterol is a critical component of cellular membranes, regulating assembly and function of membrane-based protein/lipid complexes. Many RNA viruses, including enteroviruses, remodel host membranes to generate organelles with unique lipid blueprints on which they assemble replication complexes and synthesize viral RNA. Here we find that clathrin-mediated endocytosis (CME) is harnessed by enteroviruses to traffic cholesterol from the plasma membrane (PM) and extracellular medium to replication organelles, where cholesterol then regulates viral polyprotein processing and facilitates genome synthesis. When CME is disrupted, cellular cholesterol pools are instead stored in lipid droplets, cholesterol cannot be trafficked to replication organelles, and replication is inhibited. In contrast, replication is stimulated in cholesterol-elevated cells like those lacking caveolins or those from Niemann-Pick disease patients. Our findings indicate cholesterol as a critical determinant for enteroviral replication and outline roles for the endocytic machinery in both the enteroviral life cycle and host cell cholesterol homeostasis.

Changes in small intestinal morphology and digestive enzyme activity with oral administration of copper-loaded chitosan nanoparticles in rats.

The experiment was conducted to evaluate the effect of copper-loaded chitosan nanoparticles on the small intestinal morphology and activities of digestive enzyme and mucosal disaccharase in rats. Forty male Sprague-Dawley rats, with average body weight of 82 g, were randomly allotted to five groups (n = 8). All rats were received a basal diet (control) or the same basal diet added with 80 mg/kg BW CuSO(4), 80 mg/kg BW chitosan (CS-I), 80 mg/kg BW copper-loaded chitosan nanoparticles (CSN-I), 160 mg/kg BW copper-loaded chitosan nanoparticles (CSN-II), respectively. The experiment lasted 21 days. The results showed that the villus heights of the small intestinal mucosa in groups CSN-I and CSN-II were higher than those of the control, group CuSO(4) or CS-I. The crypt depth of duodenum and ileum mucosa in group CSN-I or CSN-II was depressed. Compared with the control, there were no significant effects of CuSO(4) or CS-I on the villus height and crypt depth of small intestinal mucosa. Supplementation with CSN improved the activities of trypsin, amylase and lipase in the small intestinal contents and maltase, sucrase and lactase of duodenum, jejunum, and ileum mucosa while there were no significant effects of CuSO(4) on the digestive enzyme activities of the small content compared with the control. The results indicated that intestinal morphology, activities of digestive enzyme in digesta and mucosal disaccharase were beneficially changed by treatment of copper-loaded chitosan nanoparticles.

[Expression of SDF-1 in lung tissues and intervention of AMD3100 in asthmatic rats].

OBJECTIVE: To study the expression of stromal cell derived factor-1(SDF-1) in the airway and to investigate the role of SDF-1 receptor antagonist AMD3100 intervention in rats with asthma. METHODS: Thirty Sprague-Dawley rats were randomly divided into three groups: normal control and asthma with and without AMD3100 intervention. The rat model of asthma was prepared by aerosolized ovalbum (OVA) challenge. The AMD3100 intervention group was administered with AMD3100 of 50 µg 30 minutes before challenge every other day, for 10 times. The characteristic airway inflammation and alterations of airway structures were observed by hemetoxylin and eosin staining. The levels of interleukin 4 and interleukin 5 in whole lung homogenates were measured using ELISA. RT-PCR was used to evaluate the expression of SDF-1 mRNA in the lung. RESULTS: The airway wall thickness in the untreated asthma group was greater than that in the control and the AMD3100 intervention groups (P<0.05). The levels of interleukin 4 and interleukin 5 in whole lung homogenates in the AMD3100 intervention group were lower than those in the untreated asthma group (P<0.05). The expression of SDF-1 mRNA in the untreated asthma group was higher than that in the control and the AMD3100 intervention groups (P<0.05). CONCLUSIONS: SDF-1 may be associated with airway inflammation and remodeling in rats with asthma. AMD3100 may reduce the airway inflammation and improve airway remodeling by inhibiting the bioactivity of SDF-1.

[Expression of perforin and granzyme B in asthmatic rats and intervention of recombinant human growth hormone].

OBJECTIVE: To study the expression of perforin and granzyme B (GzmB) in the lungs of asthmatic rats and the effect of recombinant human growth hormone (rhGH) on the expression. METHODS: Thirty Sprague-Dawley male rats were randomly divided into a normal control group and asthma groups with and without rhGH treatment. An asthma model was prepared by repeated sensitization with ovalbumin and aluminium hydroxide. The morphological changes of the airway were observed by hematoxylin and eosin staining. Terminal deoxyribonucleotide transferase-mediated Dutp-bintin (TUNLE) was used to detect the apoptosis of epithelial cells in the airway. RT-PCR was used to detect the mRNA transcripts of perforin and GzmB in the lung tissues. RESULTS: A significantly increased apoptosis rate of airway epithelial cells was noted in the untreated asthma group. The apoptosis rate was significantly ruduced in the rhGH-treated asthma group (P<0.05). Compared with the control group, perforin and GzmB expression in the lungs in the untreated asthma group increased significantly. The rhGH-treated asthma group demonstrated significantly decreased perforin (0.48 ± 0.08 vs 0.63 ± 0.08; P<0.05) and GzmB (0.44 ± 0.13 vs 0.71 ± 0.15; P<0.05) expression in the lungs compared with the untreated asthma group. Both PFP (r=0.800, P<0.05) and GzmB (r=0.806, P<0.01) were positively correlated with the apoptosis rate of airway epithelial cells. CONCLUSIONS: Perforin and GzmB may play important roles in the pathogenesis of asthma. rhGH treatment can inhibit apoptosis of airway epithelial cells and airway remodeling, possibly through a reduction in perforin and GzmB expression.

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.

[Community structure and time-space distribution characteristic of airborne fungi in a municipal landfill site].

In order to determine the community structure and time-space distribution characteristics of airborne fungi in waste landfill sites, supervisory points were set in sanitary landfill area, leachate treatment area and living area in a Waste Sanitary Landfill Site in Beijing. Airborne fungi were collected by Andersen six stages sampler, and the study on the community structure and distribution of airborne fungi was carried out systematically. The results show that fifteen genera of culturable fungi are identified (exclusion Non-sporing), Cladosporium, Aspergillus, Penicillium and Non-sporing are the dominant genera. The concentration of airborne fungi in sanitary landfill area and leachate treatment area are about 1750 CFU x m(-3), which is higher than that in living area (p < 0.05). Monthly change curve of the airborne fungi concentration shows double peak type, the peak value appears in May and September-October, which can reach at 5 000 CFU x m(-3). It indicates a trend that the concentration is higher at 09:00-11:00 than that at 15:00-16:00 from April to July, but it performs reserved trend from August to the next January. 75% of the airborne fungi distributes in stage III - V. The counted median diameters (CMD) of airborne fungi in three functional areas are 2.9 microm, 2.9 microm and 2.8 microm respectively, there are no statistical difference (p > 0.05).

Preparation, characterization and antibacterial properties against E. coli K(88) of chitosan nanoparticle loaded copper ions.

The present study was conducted to prepare and characterize chitosan nanoparticle loaded copper ions, and evaluate their antibacterial activity. Chitosan nanoparticles were prepared based on ionotropic gelation, and then the copper ions were loaded. The particle size, zeta potential and morphology were determined. Antibacterial activity was evaluated against E. coli K(88) by determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in vitro. Results showed that the antibacterial activity was significantly enhanced by the loading of copper ions compared to those of chitosan nanoparticles and copper ions. The MIC and MBC of chitosan nanoparticle loaded copper ions were 21 times and 42 times lower than those of copper ions, respectively. To confirm the antibacterial mechanism, morphological changes of E. coli K(88) treated by chitosan nanoparticle loaded copper ions were dynamically observed with an atomic force microscope (AFM). It was found that chitosan nanoparticle loaded copper ions killed E. coli K(88) through damage to the cell membrane.

Preparation, characterization and adsorption properties of chitosan nanoparticles for eosin Y as a model anionic dye.

The present study dealt with the adsorption of eosin Y, as a model anionic dye, from aqueous solution using chitosan nanoparticles prepared by the ionic gelation between chitosan and tripolyphosphate. The nanoparticles were characterized by atomic force microscopy (AFM), size and zeta potential analysis. A batch system was applied to study the adsorption of eosin Y from aqueous solution by chitosan nanoparticles. The results showed that the adsorption of eosin Y on chitosan nanoparticles was affected by contact time, eosin Y concentration, pH and temperature. Experimental data followed Langmuir isotherm model and the adsorption capacity was found to be 3.333 g/g. The adsorption process was endothermic in nature with an enthalpy change (DeltaH) of 16.7 kJ/mol at 20-50 degrees C. The optimum pH value for eosin Y removal was found to be 2-6. The dye was desorbed from the chitosan nanoparticles by increasing the pH of the solution.

[Drug distribution in gastric cancer and adjacent tissues by preoperative intraperitoneal chemotherapy with Co-fluorouracil liposome].

OBJECTIVE: To examine the distribution of fluorouracil in gastric cancer (CA), lymph node (LN), normal gastric mucosa (NG), peritoneum (PE), greater omentum (GO) and lesser omentum (LO) by preoperative intraperitoneal chemotherapy with Co-fluorouracil liposome (Co 5-Fu), and offer an experimental basis for clinic practice. METHODS: Ninety-six gastric cancer patients were divided into four groups: Co 5-Fu i.v. injection group (Co 5-Fu i.v.), Co 5-Fu intraperitoneal perfusion group (Co 5-Fu i.p.), 5-Fu i.v. injection group (5-Fu i.v.) and intraperitoneal perfusion group (5-Fu i.p.) given on day-2, day-1 and 60 minutes before operation. Fluorouracil concentration in all tissues collected during operation were examined by high performance liquid chromatography (HPLC). RESULTS: The fluorouracil concentration in the tissues in Co 5-Fu i.p. group was significantly higher than that in Co 5-Fu i.v. or 5-Fu i.p. group (P < 0.05 or P < 0.01), and that in 5-Fu i.p. group was greatly higher than that at 5-Fu i.v. group (P < 0.01). In Co 5-Fu i.p. group, the concentration of drug in LN, CA, PE, NG, GO and LO decreased gradually with the former 3 tissues significantly higher than the latter 3 tissues (P < 0.01), and adjacent lymph node was the highest. In Co 5-Fu i.v. group, the ranking was LN, CA, NG, PE, GO and LO with the former 3 tissues significantly higher than the latter 3 tissues (P < 0.01) and showing tumor tissues higher than the other tissues (P < 0.01). In 5-Fu i.p. group, the ranking was PE, LN, CA, NG, GO and LO with the former 2 tissues significantly higher than the latter tissues (P < 0.01). CONCLUSION: Co 5-Fu possesses drug targeting, slow release and long effect in gastric cancer tissues and adjacent lymph nodes. Preoperative chemotherapy with Co 5-Fu i.p. is more advantageous than 5-Fu given i.v. or 5-Fu i.p.