Hemorrhagic fever with renal syndrome with secondary hemophagocytic lymphohistiocytosis in West China: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an excessive systemic inflammatory response, which can be classified as primary HLH (pHLH) and secondary HLH (sHLH). Viruses are the primary pathogens causing sHLH. Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by hantaviruses. Its main characteristics include fever, circulatory collapse with hypotension, hemorrhage, and acute kidney injury. The case of HFRS presented with sHLH is very rare in clinic. We reported the HFRS inducing by Hantaan virus (HTNV) presented with sHLH as the first case in Shaanxi province of west China. CASE PRESENTATION: A case of HFRS in 69-year-old Chinese woman, which had persistent fever, cytopenia, coagulopathy, ferritin significantly increased, hepatosplenomegaly and superficial lymphadenopathy. The hemophagocytosis was found in bone marrow, which was consistent with the characteristics of the HLH. The patient recovered completely after timely comprehensive treatments. CONCLUSIONS: HTNV should be considered as one of the underlying viruses resulting in hemophagocytosis, and if occurs, the early diagnosis and rapid therapeutic intervention are very important to the prognosis of sHLH.

Metabolic kinetics of 5-hydroxytryptamine and the research targets of functional gastrointestinal disorders.

5-Hydroxytryptamine (5-HT) is an important neurotransmitter in both the central and enteric nervous systems. It has diverse functions in regulating gastrointestinal motility and visceral sensitivity, emotion, appetite, pain and sensory perception, cognition, sexual activity and sleep. These functions are mainly associated with the metabolic kinetics of 5-HT in different tissues. Tryptophan hydroxylase is the rate-limiting enzyme and modulates serotonin synthesis. Vesicular monoamine transporter 1 plays a role in 5-HT storage and release. Degradation of 5-HT is mediated by monoamine oxidase-A. All these factors influence the action of 5-HT in vivo. Functional gastrointestinal disorders (FGIDs) are characterized by a series of symptoms including abdominal pain, diarrhea, constipation, anxiety and depression, in the absence of identifiable structural or biochemical abnormalities. They are frequently accompanied by changed gut motility or visceral sensitivity. An increasing body of research has found FGIDs to be closely associated with 5-HT, and drugs such as citalopram, paroxetine, venlafaxine, alosetron, tegaserod, prucalopride and mosapride have all been developed or discovered from the perspective of the metabolic kinetics of 5-HT. This review discusses the relationship between the metabolic kinetics of 5-HT and research targets in the field of FGIDs and suggests areas of future study that may be useful for understanding these disorders and identification of potential therapeutic targets.

DADS suppresses human esophageal xenograft tumors through RAF/MEK/ERK and mitochondria-dependent pathways.

Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro-apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma.

Hyperamylasemia Caused by the Hantaan Virus: A Retrospective Study of 101 Patients with Hemorrhagic Fever with Renal Syndrome in West China.

Background: Hyperamylasemia (HA) is an inconspicuous manifestation of hemorrhagic fever with renal syndrome (HFRS) in Baoji city, West China. Hantaan virus (HTNV) is the only pathogen-caused HFRS in this region, but the knowledge about HA in the local HFRS patients has been limited. The aim of this study was to investigate the characteristics of HA and its predictive risk factors for doctors to engage in timely monitoring and dealing with the possible serious changes prewarned by HA in the early stages of the disease to improve the final outcome. Methods: All HFRS patients with and without HA (HA and nHA groups, respectively) were treated in Baoji People's Hospital. The clinical characteristics between the two groups were compared by Student's t-test or Chi-square test. The risk factors for prognosis were measured by the logistic regression analysis. The predictive effects of prognosis in clinical and laboratory parameters were analyzed by the receiver operating characteristic curves. Results: 46.53% of the patients demonstrated HA, among which 71.7% were severe and critical types of HFRS, greater than that in the nHA group (19.57%, P < 0.001). The hospitalization day and the general incidence of acute pancreatitis (AP) were longer or greater in the HA group than in the nHA group (P < 0.01). Age and the time from the onset of the first symptom to the patient being admitted to hospital (T OA) were the predictive risk factors for HA. The best cut-off values were the age of 54 years and T OA of 5.5 days. Conclusion: HTNV-induced HA is a common clinical presentation of HFRS patients in West China. It can increase the severity, the hospitalization days of patients, and the incidence of AP in HFRS. Age and T OA constituted independent risk factors for HA caused by HTNV.

miR-34 increases in vitro PANC-1 cell sensitivity to gemcitabine via targeting Slug/PUMA.

miR-34 was deregulated in tumor tissues compared with corresponding noncancerous tissue samples. Furthermore, miR-34 may contribute to cancer-stromal interaction associated with cancer progression. However, whether miR-34 could decrease chemoresistance of cancer cells to chemotherapeutic agent remains unclear. In our study, we examined whether overexpression of miR-34 could sensitize gemcitabine -mediated apoptosis in human pancreatic cancer PANC-1 cells. We found that miR-34 markedly induced gemcitabine -mediated apoptosis in PANC-1 cells. miR-34 induced down-regulation of Slug expression and upregulation of p53 up-regulated modulator of apoptosis (PUMA) expression. The over-expression of Slug or downregulation of PUMA by Slug cDNA or PUMA siRNA transfection markedly blocked miR-34-induced gemcitabine sensitization. Furthermore, miR-34 induced PUMA expression by downregulation of Slug. Taken together, our study demonstrates that miR-34 enhances sensitization against gemcitabine-mediated apoptosis through the down-regulation of Slug expression, and up-regulation of Slug-dependent PUMA expression.

Diallyl disulfide inhibits the metastasis of type â ¡ esophageal­gastric junction adenocarcinoma cells via NF-κB and PI3K/AKT signaling pathways in vitro.

Esophageal-gastric junction adenocarcinoma (AEG) is an aggressive tumor with high incidence and dismal prognosis worldwide. Despite significant advances in therapeutic strategies, the 5-year survival rate still remains low. Diallyl disulfide (DADS), which is one of the major volatile components isolated from garlic, has been shown to have multi-targeted antitumor activities in a variety of cancer cells. However, the exact anti-metastatic effects and underlying molecular mechanisms of DADS in AEG have not been elucidated. The present study demonstrated that DADS inhibited cell viability of OE19 cells with low cytotoxicity to healthy hepatocytes, L02 cells, in vitro. Non-toxic doses of DADS were ≤10 µg/ml for a 24-h treatment. Our data showed that these non-toxic doses of DADS were found to block the metastasis of OE19 cells by suppressing MMPs, increasing u-PA and TIMPs, as well as altering the balance of MMPs/TIMPs, which at least in part resulted from the suppression of NF-κB and PI3K/AKT signaling pathways. The present study provides a previously neglected insight into the investigation of DADS in suppressing tumor metastasis and its underlying molecular mechanisms in vitro. Hence, DADS could be a promising anticancer agent for anti-metastatic treatment of AEG in the future.

Rapid determination of dopamine and its metabolites during in vivo cerebral microdialysis by routine high performance liquid chromatography with electrochemical detection.

OBJECTIVE: To determine dopamine and its metabolites during in vivo cerebral microdialysis by routine high performance liquid chromatography with electrochemical detection. METHODS: Microdialysis probes were placed into the right striatum of Wistar rat brains and perfused with Ringer's solution at a rate of 1.5 microL/min. A reverse phase HPLC with electrochemistry was used to assay DA, DOPAC, and HVA after cerebral microdialysates were collected every 20 minutes from awake and freely moving rats. In order to identify the reliability of this method, its selectivity, linear range, precision and accuracy were tested and the contents of DA, DOPAC, and HVA in rat microdialysates were determined. RESULTS: The standard curve was in good linear at the concentration ranging from 74 nmol/L to 1.5 micromol/L for DOPAC (r2=0.9996), from 66 nmol/L to 1.3 micromol/L for DA (r2=1.0000) and from 69 nmol/L to 1.4 micromol/L for HVA (r2=0.9992). The recovery of DOPAC (0.30, 0.77, 1.49 micromol/L), DA (0.26, 0.69, 1.32 micromol/L), and HVA (0.27, 0.71, 1.37 micromol/L) was 82.00+/-1.70%, 104.00+/-4.00%, 98.70+/-3.10%; 92.30+/-1.50%, 105.30+/-2.30%, 108.00+/-2.00%; 80.00+/-7.80%, 107.69+/-8.00%, and 108.66+/-3.10%, respectively at each concentration. Their intra-day RSD was 3.3%, 3.4%, and 2.5%, and inter-day RSD was 4.2%, 2.3%, and 5.6%, respectively. The mean extracellular concentrations of DOPAC, DA, and HVA in rat brain microdialysates were 10.7, 2.4, and 9.2 micromol/L (n=6), respectively. CONCLUSION: The findings of our study suggested that the simple, accurate and stable method can be applied to basic researches of diseases related to monoamines neurotransmitters by cerebral microdialysis in rats.

[Effects of tetramethylpyrazine on brain oxidative damage induced by intracerebral perfusion of L-DOPA in rats with Parkinson's disease].

OBJECTIVE: To observe the effects of tetramethylpyrazine (TMP) on brain oxidative damage induced by intracerebral perfusion of levodopa (L-DOPA) in rats with Parkinson's disease (PD). METHODS: PD model rats were induced by intracerebral injection of 6-hydroxyl dopamine (6-OHDA) and perfused in brain with L-DOPA using microdialysis technique. Changes in levels of 2,3-dihydroxy benzyl acid (2.3-DHBA) and 2,5-dihydroxy benzyl acid (2,5-DHBA) in striatum of rats, formed by extracellular hydroxyl radical from salicylic acid capturing, were dynamically observed at various time points by HPLC-ED. RESULTS: After treatment with L-DOPA, 2,3-DHBA and 2,5-DHBA in the model group showed significantly higher levels at 6 and 7 time points as compared with those in the sham-operated group at the corresponding time points (P <0.05 or P< 0.01), while these abnormal elevations were significantly inhibited in the TMP treated groups, either in large or small dose (P<0.05 or P<0.01). CONCLUSION: TMP could reduce the L-DOPA induced brain oxidative damage in PD rats.

microRNA-203 suppresses invasion of gastric cancer cells by targeting ERK1/2/Slug/ E-cadherin signaling.

BACKGROUND AND AIMS: Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer (GC). Expression of microRNA-203 (miR-203) has been reported to decrease in GC. In addition, overexpression of miR-203 inhibits grow of GC cells in vitro and in vivo. However, whether miR-203 affects cell migration and invasion of GC remains unclear. This study aimed to reveal the role of miR-203 on migration and invasion of GC, and its potential mechanisms. METHODS: Synthetic pre-miR-203 (miR-203), anti-miR-203 and scrambled negative control RNAs was transfected into the gastric cancer SGC7901 cells to generate miR-203 or anti-miR-203-transfected stable clones. The roles of miR-203 on cell invasion and motility were then analyzed by Transwell migration assay and Wound healing assay in vitro. Using siRNA to targeting ERK1/2, Slug, and E-cadherin or Slug cDNA transfection (to increase Slug expression) to examine the miR-203 signaling pathway. We also examined the efficacies of miR-203 or anti-miR-203 on peritoneal metastasis of SGC7901 cells in the nude mouse model. RESULTS: Overexpression of miR-203 inhibits SGC7901 cell invasion and motility, followed by decreased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as increased E-cadherin expression. Re-expression of Slug in miR-203/SGC7901cells decreased E-cadherin expression and restored the invasive phenotypes. Targeting E-cadherin in miR-203/SGC7901cells also restored the invasive phenotypes. Inhibition of miR-203 promotes SGC7901 cell invasion and motility, followed by increased phospho-ERK1/2 (pERK1/2) and Slug expression, as well as decreased E-cadherin expression. Targeting ERK1/2 or Slug in anti-miR-203/SGC7901cells increased E-cadherin expression and reversed the invasive phenotypes. In addition, targeting ERK1/2 decreased Slug and increased the E-cadherin expression. Significantly, we found that miR-203 could exert marked inhibition of the peritoneal metastasis of SGC7901 in nude mice in vivo. Targeting miR-203 could exert marked promotion of the peritoneal metastasis of SGC7901 in nude mice in vivo. CONCLUSIONS: miR-203/ERK1/2/Slug/E-cadherin signaling pathway plays an essential role on SGC7901 cell invasion and motility. miR-203 can be novel modalities to prevent peritoneal metastasis of invasive cancers such as gastric cancer.

Potential rat model of anxiety-like gastric hypersensitivity induced by sequential stress.

AIM: To establish a rat model of anxiety-like gastric hypersensitivity (GHS) of functional dyspepsia (FD) induced by novel sequential stress. METHODS: Animal pups were divided into two groups from postnatal day 2: controls and the sequential-stress-treated. The sequential-stress-treated group received maternal separation and acute gastric irritation early in life and restraint stress in adulthood; controls were reared undisturbed with their mothers. Rats in both groups were followed to adulthood (8 wk) at which point the anxiety-like behaviors and visceromotor responses to gastric distention (20-100 mmHg) and gastric emptying were tested. Meanwhile, alterations in several anxiety-related brain-stomach modulators including 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), brain-derived neurotrophic factor (BDNF) and nesfatin-1 in the rat hippocampus, plasma and gastric fundus and the 5-HT1A receptor (5-HT1AR) in the hippocampal CA1 subfield and the mucosa of the gastric fundus were examined. RESULTS: Sequential-stress-treated rats simultaneously demonstrated anxiety-like behaviors and GHS in dose-dependent manner compared with the control group. Although rats in both groups consumed similar amount of solid food, the rate of gastric emptying was lower in the sequential-stress-treated rats than in the control group. Sequential stress significantly decreased the levels of 5-HT (51.91 ± 1.88 vs 104.21 ± 2.88, P < 0.01), GABA (2.38 ± 0.16 vs 5.01 ± 0.13, P < 0.01) and BDNF (304.40 ± 10.16 vs 698.17 ± 27.91, P < 0.01) in the hippocampus but increased the content of nesfatin-1 (1961.38 ± 56.89 vs 1007.50 ± 33.05, P < 0.01) in the same site; significantly decreased the levels of 5-HT (47.82 ± 2.29 vs 89.45 ± 2.61, P < 0.01) and BDNF (257.05 ± 12.89 vs 536.71 ± 20.73, P < 0.01) in the plasma but increased the content of nesfatin-1 in it (1391.75 ± 42.77 vs 737.88 ± 33.15, P < 0.01); significantly decreased the levels of 5-HT (41.15 ± 1.81 vs 89.17 ± 2.31, P < 0.01) and BDNF (226.49 ± 12.10 vs 551.36 ± 16.47, P < 0.01) in the gastric fundus but increased the content of nesfatin-1 in the same site (1534.75 ± 38.52 vs 819.63 ± 38.04, P < 0.01). The expressions of 5-HT1AR in the hippocampal CA1 subfield and the mucosa of the gastric fundus were down-regulated measured by IHC (Optical Density value: Hippocampus 15253.50 ± 760.35 vs 21149.75 ± 834.13; gastric fundus 15865.25 ± 521.24 vs 23865.75 ± 1868.60; P < 0.05, respectively) and WB (0.38 ± 0.01 vs 0.57 ± 0.03, P < 0.01) (n = 8 in each group). CONCLUSION: Sequential stress could induce a potential rat model of anxiety-like GHS of FD, which could be used to research the mechanisms of this intractable disease.

Reflux characteristics of 113 GERD patients with abnormal 24-h multichannel intraluminal impedance-pH tests.

OBJECTIVE: To analyze reflux parameters by means of combined multichannel intraluminal impedance and pH (MII-pH) monitoring in patients with gastroesophageal reflux disease (GERD) symptoms off medication, and to find the reflux characteristics of Chinese GERD patients and the influences of gender, age, body posture, and body mass index (BMI) on gastroesophageal reflux (GER). METHODS: Between Dec. 2008 and May 2014, 125 patients with typical GERD symptoms were subjected to 24-h MII-pH monitoring. Twelve patients with normal MII-pH profiles were not considered for analysis. The reflux parameters of 113 GERD patients with abnormal MII-pH results were analyzed. RESULTS: (1) DeMeester scores were above the normal range in 46.90% (53/113) of GERD patients. Weakly acidic refluxes were prevalent in GERD patients, and the frequency of abnormal weakly acidic reflux was 75.22% (85/113). The frequencies of abnormal symptom index (SI) and symptom association probability (SAP) were 19.47% (22/113) and 14.16% (16/113), respectively. (2) The frequencies of DeMeester scores, the %time at pH<4, and the numbers of reflux episodes and of long reflux episodes >5 min were significantly higher in male patients than in female patients. (3) The %time at pH<4 was much higher during upright periods than during supine periods. During supine periods, 31.86% (36/113) of GERD patients had delayed bolus clearance time, compared with 19.47% (22/113) during upright periods. (4) The number of abnormal DeMeester scores, %time at pH<4, and the number of acid refluxes during upright periods were significantly higher in obese GERD patients than in GERD patients with a normal BMI. Overweight GERD patients also had many more acid refluxes during upright periods than GERD patients with a normal BMI. CONCLUSIONS: Weakly acidic refluxes were prevalent in Chinese GERD patients. The factors male, gender, upright position, obesity (BMI≥25), but not age, may increase the frequency and severity of GER.