Atypical Rickettsia japonica Infection Involving Critical Illness Diagnosed by Metagenomic Next-Generation Sequencing: A Case Report.

Background: Rickettsia japonica infection is a rare disease, it is rare to report critical and severe case caused by this disease in Zhejiang Province, China. Patient Concerns: We report a patient who initially sought medical attention due to fever and developed coma and convulsions during treatment. The patient did not develop typical eschar and rash. Eventually, the patient needed to be treated in the intensive care unit due to acute respiratory failure. Diagnoses: The patient was diagnosed with Rickettsia japonica bloodstream infection by metagenomic next-generation sequencing (mNGS). Outcomes: Due to the critical illness, the patient was transferred to the intensive care unit, received doxycycline and other treatments, and rapidly recovered and discharged. Conclusion: The patient developed a critical illness after being infected with Rickettsia, when the medical history is unclear and clinical symptoms and signs are atypical, it is necessary to use mNGS examination for diagnosis.

Fibroblast growth factor 23 during septic shock and myocardial injury in ICU patients.

Objective: Fibroblast growth factor 23 (FGF23) has been recognized as an important biomarker of cardiovascular disease and is closely related to inflammation over the past decade. This study aimed to assess the relationship between FGF23 and myocardial injury in patients with sepsis. Methods: We sequentially measured serum FGF23, Klotho, biomarkers of inflammation (CRP, IL-6 and WBC), myocardial injury (cTnI and N-terminal B-type natriuretic peptide) and sepsis (procalcitonin) at peak of intercurrent septic shock and after complete resolution or before death in a series of 29 patients with septic shock. 29 healthy adults without infections were used as controls. Results: There was a difference in serum FGF23 level between patients with septic shock and healthy adults (p < 0.0001), and the peak level of FGF23 in septic shock in the survivor group was higher than that after complete remission (p < 0.0001). No statistical difference was found in the level of FGF23 before and after treatment in the death group (p = 0.0947). At the peak of septic shock, FGF23 was significantly correlated with inflammatory markers, CRP (r = 0.8063, p < 0.0001), PCT (r = 0.6091, p = 0.0005) and WBC (r = 0.8312, p < 0.0001), while the correlation with IL-6 was not statistically significant (r = 0.0098, p = 0.9598). At the same time, it was found that FGF23 was significantly correlated with myocardial injury markers, cTNI (r = 0.8475, p < 0.0001) and NTproBNP (r = 0.8505, p < 0.0001). Nevertheless, FGF23 and klotho are not correlated (r = 0.2609, p = 0.1717). Conclusion: In conclusion, in patients with septic shock and myocardial injury, the exacerbation of inflammation in the septic process was accompanied by a abnormal increase of circulating FGF23 level. FGF23 also subsided after the improvement of inflammation, and the opposite was true for patients who did not survive. The up-regulation of FGF23 may be involved in the response of patients to septic shocks, and it is also speculated that FGF23 is involved in the myocardial injury of septic shock.

Disseminated varicella-zoster virus infection in an aplastic anemia- paroxysmal nocturnal hemoglobinuria syndrome patient: A case report.

Background: Varicella-zoster virus (VZV) is a common and widespread human-restricted pathogen. It is famous for its dermatological manifestations, such as varicella and herpes zoster. Patients with aplastic anemia-paroxysmal nocturnal hemoglobinuria (AA-PNH) syndrome complicated with fatal disseminated varicella zoster virus infection are very rare and in danger. Patient concerns: A 26-year-old man with a history of AA-PNH syndrome was receiving cyclosporine and corticosteroid treatment in the hematology department. During his hospitalization in our hospital, he developed fever, abdominal pain, and lower back pain, and his face, penis, trunk, and limbs developed itchy rash. Subsequently, the patient had to undergo cardiopulmonary resuscitation because of sudden cardiac arrest, and be transferred to ICU for treatment. It was presumed that the cause is unknown severe sepsis. The patient's condition quickly progressed to multiple organ failure, accompanied by liver, respiratory, and circulatory failure, and signs of disseminated intravascular coagulation. Unfortunately, the patient died after 8 h of active treatment. Finally, we collected all the evidence and concluded that the patient died of AA-PNH syndrome combined with poxzoster virus. Conclusion: AA-PNH syndrome patients treated with steroids and immunosuppressants are prone to various infections, considering that herpes virus infection with chickenpox and rash as the initial manifestations is characterized by rapid progress and often accompanied by serious complications. It is more difficult to distinguish it from AA-PNH syndrome with skin bleeding points. If it is not identified in time, it may delay the treatment opportunity, make the condition worse, and cause serious adverse prognosis. Therefore, clinicians need to pay attention to it.

OSU-T315 and doxorubicin synergistically induce apoptosis via mitochondrial pathway in bladder cancer cells.

Bladder cancer (BC) is a common urological malignancy that still lacks an effective treatment. Doxorubicin (Dox) has been widely used in the treatment of various cancers, including BC. However, chemoresistance often hampers the clinical application of Dox, therefore, it is necessary to develop effective strategies to improve its efficacy. By using high-throughput screening, we identified OSU-T315, an integrin-linked kinase (ILK) inhibitor, that can augment the cytotoxicity of Dox against BC cells. We found that OSU-T315 and Dox synergistically induce apoptosis of BC cells via mitochondrial pathway in a caspase-dependent. Mechanically, it was found that OSU-T315 and Dox synergistically induced activation of Bax which is critical for the induction of apoptosis. Moreover, it was also found that the downregulation of BCL-2 and MCL-1 is essential for the activation of BAX induced by OSU-T315 and Dox. OSU-T315 was found to downregulate MCL-1 via the GSK-3ß/FBXW7 axis in BC cells. Our findings suggest that combined treatment with OSU-T315 and Dox may be a promising strategy to treat BC.

Triptolide induces atrophy of myotubes by triggering IRS-1 degradation and activating the FoxO3 pathway.

Triptolide is an active ingredient isolated from an ancient Chinese herb (Tripterygium wilfordii Hook. f) for inflammatory and immune disorders. It has been shown to inhibit the proliferation of skeletal muscle; however, mechanisms of this effect remain unclear. We used mouse C2C12 myotubes as an in vitro model to investigate the effects of triptolide on skeletal muscle. Triptolide markedly inhibited the expression of myosin heavy chain and upregulated the expression of muscle atrophy-related proteins, leading to atrophy of the myotubes. Triptolide dose-dependently decreased the phosphorylation of Forkhead box O3 (FoxO3) and activated FoxO3 transcription activity, which regulates the expression of muscle atrophy-related proteins. Furthermore, triptolide inhibited the phosphorylation of Akt on the site of S473 and T308, and decreased the phosphorylation of insulin receptor substrate-1 (IRS-1) on the site of S302. In addition, triptolide reduced the protein level, but not mRNA level of IRS-1, whereas other upstream regulators of the Akt signaling pathway were not affected. Finally, a time-course experiment showed that the triptolide-induced degradation of IRS-1 in myotubes occurred 12 h prior to both inhibition of Akt activity and the activation of FoxO3. These data indicate that triptolide triggers IRS-1 degradation to promote FoxO3 activation, which subsequently led to atrophy of myotubes, providing us a potential target to prevent triptolide-induced skeletal muscle atrophy.

Risk factors for acquisition and mortality of multidrug-resistant Acinetobacter baumannii bacteremia: A retrospective study from a Chinese hospital.

Bloodstream infection caused by Acinetobacter baumannii has become a major clinical concern, especially multidrug-resistant A baumannii (MDRAB). The aim of this study was to identify the risk factors of nosocomial acquired MDRAB bacteremia and to determine the risk factors related to the mortality of patients with MDRAB bacteremia. Patients with nosocomial acquired A baumannii bacteremia were enrolled between January, 2013 and December, 2017 at the First Affiliated Hospital, School of Medicine, Zhejiang University. Medical records were reviewed, and the clinical and microbial characteristics were collected. Among the 338 patients suffering from A baumannii bacteremia, 274 patients were infected with MDRAB bacteremia. Bacteremia-related mortality was 46.4% for the overall sample; 56.2% for MDRAB bacteremia patients, 4.7% for non-MDRAB bacteremia patients. The identified risk factors for developing MDRAB bacteremia were previous exposure to carbapenems [odds ratio (OR) 5.78, P = .005] and penicillins+ß-lactamase inhibitors (OR 4.29, P = .009). Primary bacteremia tended to develop non-MDR bacteremia (OR 0.10, P = .002). The risk factors for MDRAB bacteremia-related mortality were old age (OR 1.02, P = .036), a high Pitt bacteremia score (OR 1.32, P < .001), bacteremia occurring after severe pneumonia (OR 8.66, P < .001), while catheter-related infection (OR 0.47, P = .049) and operations for treating infection (OR 0.51, P = .043) may have a better outcome. Patients with MDRAB had a higher mortality rate. Patients with previous carbapenems and penicillins+ß-lactamase inhibitor exposure are at an increased risk of MDRAB bacteremia, whereas patients with primary bacteremia tended to develop non-MDR bacteremia. The risk factors for MDRAB bacteremia-related mortality were old age, a high Pitt bacteremia score, and bacteremia occurring after severe pneumonia, whereas catheter-related infection and operations for the treatment of infection may have a better outcome.

EZH2 Inhibition Ameliorates Transverse Aortic Constriction-Induced Pulmonary Arterial Hypertension in Mice.

Background: EPZ005687 is a selective inhibiter of methyltransferase EZH2. In this article, we investigated the protective role and mechanism of EPZ005687 in transverse aortic constriction-induced pulmonary arterial hypertension in mice. Methods: We assigned 15 (6-8 weeks old) male balb/c mice to 3 groups randomly: Sham control + DMSO group, TAC + DMSO group, and TAC + EPZ005687 group (10 mg kg-1, once a week for 4 weeks). On day 28 following TAC operation, the right ventricular systolic blood pressure (RVSBP) was measured, and lung tissues were collected for laboratory examinations (DHE, Western blot, real-time PCR, and ChIP). Results: Murine PAH model was successfully created by TAC operation as evidenced by increased RVSBP and hypertrophic right ventricle. Compared with the sham control, TAC-induced PAH markedly upregulated the expression of EZH2 and ROS deposition in lungs in PAH mice. The inhibiter of methyltransferase EZH2, EPZ005687 significantly inhibits the development of TAC-induced PAH in an EZH2-SOD1-ROS dependent manner. Conclusion: Our data identified that EZH2 serves a fundamental role in TAC-induced PAH, and administration of EPZ005687 might represent a novel therapeutic target for the treatment of TAC-induced PAH.

Oleuropein prevents the development of experimental autoimmune myocarditis in rats.

Oleuropein (OLE) is a natural secoiridoid that is derived from Olea europaea. OLE possesses cardioprotective effects in experimental models of hypertension, myocardial infarction, atherosclerosis and hyperlipidaemia. In the present study, the effects of OLE on experimental autoimmune myocarditis (EAM) were evaluated. EAM in rats were induced by subcutaneous injections of porcine cardiac myosin. Cardiac function parameters, myocardial pathology, myocardial inflammatory cell infiltration and nuclear factor kappa-B (NF-κB) expression were measured. Our data showed that the postmyocarditis rats exhibited increased left ventricular end systolic diameters, left ventricular end diastolic diameters, left ventricular end-diastolic pressures (LVEDP), and decreased ejection fractions. However, OLE significantly suppressed these changes in EAM rats. Histological analysis revealed that myosin induced miliary foci of discolouration on endocardial surfaces and extensive myocardial injuries with inflammatory cell infiltration were significantly improved by OLE therapy. A definitive positive correlation between the histological scores and LVEDP was observed. Moreover, OLE inhibited CD4+, CD8+ cells and macrophage infiltration in myocardium and decreased the serum production of tumour necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß) and IL-6 in EAM rats. Expectedly, the myocardial levels of NF-κB p65, p-IκBa, IKKa were significantly attenuated by OLE, indicating the inhibitory effects of OLE on the NF-κB pathway. Furthermore, OLE decreased the myocardial expressions of phosphorylated-p38 MAPK, phosphorylated-ERK, and did not change the levels of p38 MAPK and ERK in EAM rats. Collectively, our results suggest that OLE effectively prevents the development of myocarditis, at least in part, by inhibiting the MAPKs and NF-κB mediated inflammatory responses.

[A study of the prognostic factors associated with mortality in critically ill patients with tuberculous].

OBJECTIVE: The purpose of this study was to investigate the prognostic factors associated with mortality in critically ill tuberculosis patients, and therefore to provide information for the early diagnosis and treatment of the disease. METHODS: The clinical data of 62 patients with tuberculosis, who were admitted to the intensive care unit (ICU) of Integrated Chinese and Western Medicine Hospital of Zhejiang Province between June 2008 and Feb 2010, were analyzed retrospectively, with the admission date as a start point and the transferring out of ICU date or death date in the ICU as an end point. Forty-eight patients were males and 14 were females, and the patient's age ranging from 20 to years (63 ± 4) years. In addition, these patients were divided into the survival (33 cases) and the death groups (29 cases). A total of 19 factors including age, sex, respiratory failure types, mechanical ventilation, infection, anti-tuberculous drug resistance, chemotherapy, clinical complications, critical illness score, liver damage, were analyzed for a single risk factor by the univariate model, and calculated for the independent death risk factors using the Cox logistic regression multivariate model. The cumulative survival rate based on the Kaplan-Meier survival model was calculated. RESULTS: The mortality was associated with 4 independent factors: fungal infection (HR = 3.44, 95%CI = 1.23 - 9.62), type II respiratory failure (HR = 4.03, 95%CI = 1.56 - 10.38), liver damage (HR = 3.96, 95%CI = 1.30 - 12.10) and elevated APACHEII score (> 25) (HR = 4.91, 95%CI = 1.99 - 12.11). These factors significantly (χ(2) = 5.53 - 11.88, all P < 0.05) increased the in-hospital mortality and decreased the hospital cumulative survival rate (χ(2) = 4.43 - 22.68, all P < 0.05). CONCLUSION: The high mortality of tuberculosis patients admitted to ICU was associated with fungal infection, type II respiratory failure, liver damage, and elevated APACHE II score (> 25).