Development and validation of a novel prediction model for Carbapenem-resistant organism infection in a large-scale hospitalized patients.

Carbapenem-resistant organism (CRO) are defined as gram-negative bacteria. The lack of safe and effective antibiotics has led to an increase in incidence rate. The purpose of this study is to establish and determine a risk nomogram to predict CRO infection in hospitalized patients. Hospitalized patients' information were collected from the electronic medical record system of hospital between January 2019 and December 2022. Based on the inclusion and exclusion criteria, we identified 131390 inpatients who met the criteria for this study. For the training cohort, the area under the curves (AUC) for predicting the CRO infection was 0.935. For the validation cohort, the AUC for predicting the CRO infection was 0.937. We have developed the first novel nomogram to predict CRO infection in hospitalized patients, which is reliable and high-performance. The nomogram performs well among hospitalized patients and has good predictive ability.

P2X7-Mediated Antigen-Independent Activation of CD8+ T Cells Promotes Salt-Sensitive Hypertension.

BACKGROUND: CD8+ T cells (CD8Ts) have been implicated in hypertension. However, the specific mechanisms are not fully understood. In this study, we explore the contribution of the P2X7 (purinergic receptor P2X7) receptor to CD8T activation and subsequent promotion of sodium retention in the kidney. METHODS: We used mouse models of hypertension. Wild type were used as genetic controls, OT1 and Rag2/OT1 mice were utilized to determine antigen dependency, and P2X7-knockout mice were studied to define the role of P2X7 in activating CD8Ts and promoting hypertension. Blood pressure was monitored continuously and kidneys were obtained at different experimental end points. Freshly isolated CD8Ts from mice for activation assays and ATP stimulation. CD8T activation-induced promotion of sodium retention was explored in cocultures of CD8Ts and mouse DCTs. RESULTS: We found that OT1 and Rag2/OT1 mice, which are nonresponsive to common antigens, still developed hypertension and CD8T-activation in response to deoxycorticosterone acetate/salt treatment, similar to wild-type mice. Further studies identified the P2X7 receptor on CD8Ts as a possible mediator of this antigen-independent activation of CD8Ts in hypertension. Knockout of the P2X7 receptor prevented calcium influx and cytokine production in CD8Ts. This finding was associated with reduced CD8T-DCT stimulation, reversal of excessive salt retention in DCTs, and attenuated development of salt-sensitive hypertension. CONCLUSIONS: Our findings suggest a novel mechanism by which CD8Ts are activated in hypertension to exacerbate salt retention and infer that the P2X7 receptor on CD8Ts may represent a new therapeutic target to attenuate T-cell-mediated immunopathology in hypertension.

The link between immunity and hypertension in the kidney and heart.

Hypertension is the primary cause of cardiovascular disease, which is a leading killer worldwide. Despite the prevalence of this non-communicable disease, still between 90% and 95% of cases are of unknown or multivariate cause ("essential hypertension"). Current therapeutic options focus primarily on lowering blood pressure through decreasing peripheral resistance or reducing fluid volume, but fewer than half of hypertensive patients can reach blood pressure control. Hence, identifying unknown mechanisms causing essential hypertension and designing new treatment accordingly are critically needed for improving public health. In recent years, the immune system has been increasingly implicated in contributing to a plethora of cardiovascular diseases. Many studies have demonstrated the critical role of the immune system in the pathogenesis of hypertension, particularly through pro-inflammatory mechanisms within the kidney and heart, which, eventually, drive a myriad of renal and cardiovascular diseases. However, the precise mechanisms and potential therapeutic targets remain largely unknown. Therefore, identifying which immune players are contributing to local inflammation and characterizing pro-inflammatory molecules and mechanisms involved will provide promising new therapeutic targets that could lower blood pressure and prevent progression from hypertension into renal or cardiac dysfunction.

The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote Hypertension.

BACKGROUND: Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated. METHODS: We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+ T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis. RESULTS: We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models. CONCLUSIONS: Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.

Transcriptome analysis reveals the efficacy of ginsenoside-Rg1 in the treatment of nonalcoholic fatty liver disease.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease and lacks for safe and effective drug to therapy completely. Ginsenoside-Rg1 is one of the main components of ginseng and has been proved to counteract a variety of diseases. However, there is currently a lack of sufficient evidence to support the efficacy of ginsenoside-Rg1 in the treatment of NAFLD. Our aim was to investigate whether Ginsenoside-Rg1 is a potential drug for NAFLD. MAIN METHODS: NAFLD model in rats was established by giving a high-fat diet (HFD), ginsenoside-Rg1 was intragastrically administered 100 mg/kg/d for 8 weeks in NAFLD rat. Serum biochemical indices were measured. Liver tissues were stained with hematoxylin and eosin (HE) and oil red O. Total RNA was extracted from liver and was used for high throughput sequencing to identify the changes of transcriptome. The relevant hub genes were verified by quantitative real-time PCR and western blot. KEY FINDINGS: Serum biochemical analysis indicated that ginsenoside-Rg1 improved liver function. Additionally, the staining of HE and oil red O indicated ginsenoside-Rg1 could remit pathology process of NAFLD. The transcriptome changes also support this result and reveals Atf3 and Acox2 were key genes. SIGNIFICANCE: Taken together, these results suggest that the efficiency of ginsenoside-Rg1 against NAFLD and confirmed that ginsenoside-Rg1 is a potential effective drug in treatment of NAFLD.

[Effect of acupuncture at Renying (ST 9) on blood pressure in patients with ischemic stroke complicated with essential hypertension].

OBJECTIVE: To observe the effect of acupuncture at Renying (ST 9) on morning blood pressure, daytime peak blood pressure and 24-hour blood pressure load in patients with ischemic stroke complicated with essential hypertension. METHODS: A total of 80 patients (3 cases dropped off) were randomized into an observation group (39 cases) and a control group (38 cases). Xingnao Kaiqiao acupuncture and nifedipine were given in the control group. On the basis of treatment in the control group, acupuncture at Renying (ST 9) was applied in the observation group, once a day, 6 times a week for 4 weeks. The changes of morning blood pressure, daytime peak blood pressure and blood pressure load were observed before and after treatment in the two groups. RESULTS: Compared before treatment, morning blood pressure, daytime peak blood pressure and blood pressure load after treatment were reduced in the two groups (all P<0.05). The change of morning systolic pressure in the observation group was not significant as compared with that in the control group (P>0.05); the changes of morning diastolic pressure, daytime peak blood pressure and blood pressure load in the observation group were larger than those in the control group (all P<0.05). CONCLUSION: On the basis of Xingnao Kaiqiao acupuncture and nifedipine, acupuncture at Renying (ST 9) can effectively reduce morning blood pressure, daytime peak blood pressure and blood pressure load in patients with ischemic stroke complicated with essential hypertension.

[Effect of " Huoxue Sanfeng acupuncture" auxiliary therapy on morning blood pressure and blood pressure load in elderly patients with stroke complicated with hypertension].

OBJECTIVE: To observe the effects of "Huoxue Sanfeng acupuncture" auxiliary therapy on neurological function, blood pressure load and morning blood pressure in elderly patients with stroke complicated with hypertension, on the basis of "Xingnao Kaiqiao acupuncture" combined with nifedipine. METHODS: Seventy patients with stroke complicated with hypertension were randomly divided into an observation group and a control group, 35 cases in each group. "Xingnao Kaiqiao acupuncture" and conventional nifedipine controlled release tablets were given in the control group. Regarding regaining consciousness with acupuncture, the main acupoint is Shuigou (GV 26), combined with Neiguan (PC 6) and Sanyinjiao (SP 6), retaining needle for 20 min, additionally, the quick needling technique was applied to Shangjiquan (Extra), Chize (LU 5) and Weizhong (BL 40) of the affected side, nifedipine controlled release tablets were orally administered 30 mg once a day for a total of 6 weeks. The "Huoxue Sanfeng acupuncture" was added on the basis treatment in the observation group, the acupuncture was applied at Renying (ST 9) as the main acupoint, combined with Quchi (LI 11), Hegu (LI 4), Zusanli (ST 36) and Taichong (LR 3). The strict manipulation quantitative acupuncture was used and the needle was retained for 20 min. Both acupuncture methods were performed once a day, 5 times a week, and continued treatment at intervals of 2 days, 10 times for one course, and a total of 3 courses were needed. The morning blood pressure and 24 h blood pressure load were measured before and after treatment. The National Institute of Health stroke scale (NIHSS) score and the Barthel index (BI) classification were observed before and after treatment. RESULTS: The systolic and diastolic blood pressures were significantly lower than those before treatment in the two groups (all P<0.01), and the systolic and diastolic blood pressures in the observation group were lower than those in the control group (both P<0.01). There was no significant difference between the difference of systolic blood pressure before and after treatment in the two groups (P>0.05), and the difference of the diastolic blood pressure before and after treatment in the observation group was higher than that in the control group (P<0.01). The systolic and diastolic pressures load in the two groups were lower than those before treatment (all P<0.01), and the systolic and diastolic pressures load in the observation group were lower than those in the control group (both P<0.05), the difference of systolic and diastolic pressure load before and after treatment in the observation group were higher than those in the control group (both P<0.05). After treatment, the NIHSS scores in the two groups were lower than those before treatment (both P<0.01). The NIHSS scores in the observation group were lower than those in the control group (P<0.05). The difference of NIHSS scores before and after treatment in the observation group was higher than that in the control group (P<0.01). After treatment, the BI grading was better than that before treatment in the two groups (both P<0.05), and the BI grading in the observation group was superior to that in the control group (P<0.05). CONCLUSION: On the basis of "Xingnao Kaiqiao acupuncture" combined with nifedipine controlled release tablets in the treatment of elderly patients with stroke complicated with hypertension, "Huoxue Sanfeng acupuncture" can further improve the function of nerve and limbs, effectively reduce the morning blood pressure level of elderly patients, especially diastolic blood pressure, and significantly improve systolic blood pressure and diastolic blood pressure load.

Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress.

Oxidative/nitrative stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Notch1 participates in the regulation of cardiogenesis and cardiac response to hypertrophic stress, but the function of Notch1 signaling in MI/R has not been explored. This study aims to determine the role of Notch1 in MI/R, and investigate whether Notch1 confers cardioprotection. Notch1 specific small interfering RNA (siRNA, 20 µg) or Jagged1 (a Notch ligand, 12 µg) was delivered through intramyocardial injection. 48 h after injection, mice were subjected to 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress), 24 h (for infarct size and cardiac function), or 2 weeks (for cardiac fibrosis and function) of reperfusion. Cardiac-specific Notch1 knockdown resulted in significantly aggravated I/R injury, as evidenced by enlarged infarct size, depressed cardiac function, increased myocardial apoptosis and cardiac fibrosis. Downregulation of Notch1 increased expression of inducible NO synthase (iNOS) and gp(91phox), enhanced the production of NO metabolites and superoxide, as well as their cytotoxic reaction product peroxynitrite. Moreover, Notch1 blockade also reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, and increased expression of PTEN, a key phosphatase involved in the regulation of Akt phosphorylation. In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury. These data indicate that Notch1 signaling protects against MI/R injury partly though PTEN/Akt mediated anti-oxidative and anti-nitrative effects.

Impaired mitochondrial biogenesis due to dysfunctional adiponectin-AMPK-PGC-1α signaling contributing to increased vulnerability in diabetic heart.

Impaired mitochondrial biogenesis causes skeletal muscle damage in diabetes. However, whether and how mitochondrial biogenesis is impaired in the diabetic heart remains largely unknown. Whether adiponectin (APN), a potent cardioprotective molecule, regulates cardiac mitochondrial function has also not been previously investigated. In this study, electron microscopy revealed significant mitochondrial disorders in ob/ob cardiomyocytes, including mitochondrial swelling and cristae disorientation and breakage. Moreover, mitochondrial biogenesis of ob/ob cardiomyocytes is significantly impaired, as evidenced by reduced Ppargc-1a/Nrf-1/Tfam mRNA levels, mitochondrial DNA content, ATP content, citrate synthase activity, complexes I/III/V activity, AMPK phosphorylation, and increased PGC-1α acetylation. Since APN is an upstream activator of AMPK and APN plasma levels are significantly reduced in ob/ob mice, we further tested the hypothesis that reduced APN in ob/ob mice is causatively related to mitochondrial biogenesis impairment. One week of APN treatment of ob/ob mice activated AMPK, reduced PGC-1α acetylation, increased mitochondrial biogenesis, and attenuated mitochondrial disorders. In contrast, knocking out APN inhibited AMPK-PGC-1α signaling and impaired both mitochondrial biogenesis and function. The ob/ob mice exhibited lower survival rates and exacerbated myocardial injury after MI, when compared to controls. APN supplementation improved mitochondrial biogenesis and attenuated MI injury, an effect that was almost completely abrogated by the AMPK inhibitor compound C. In high glucose/high fat treated neonatal rat ventricular myocytes, siRNA-mediated knockdown of PGC-1α blocked gAd-enhanced mitochondrial biogenesis and function and attenuated protection against hypoxia/reoxygenation injury. In conclusion, hypoadiponectinemia impaired AMPK-PGC-1α signaling, resulting in dysfunctional mitochondrial biogenesis that constitutes a novel mechanism for rendering diabetic hearts more vulnerable to enhanced MI injury.